Why tablets Why tablets The most used form of administration The most used form of administration

in pharmacy (in pharmacy (++70 of all drugs used)70 of all drugs used) Easy and comfortable use for the patientEasy and comfortable use for the patient High dosing precisionHigh dosing precision Large scale industrial productionLarge scale industrial production Constant and reproducible quality Constant and reproducible quality A lot of experience in the industryA lot of experience in the industry Stable because it is dryStable because it is dry Low transport costsLow transport costs

TabletsTablets

DisadvantagesDisadvantages Formulation difficulties if drug resist Formulation difficulties if drug resist

compressioncompression Some drugs have poor wetting or Some drugs have poor wetting or

poor water solubility or poor poor water solubility or poor dissolution might affect the drugrsquos dissolution might affect the drugrsquos bioavailabilitybioavailability

Bitter taste of the drug might require Bitter taste of the drug might require coatingcoating

Tablet propertiesTablet properties A tablet shouldA tablet should

Be elegant and free of defects such as chips Be elegant and free of defects such as chips cracks discoloration and contaminationcracks discoloration and contamination

Have sufficient strength to withstand Have sufficient strength to withstand mechanical shocks encountered during mechanical shocks encountered during manufacture packaging shipping and manufacture packaging shipping and dispensingdispensing

Have chemical and physical stability over Have chemical and physical stability over timetime

Must be able to release the drug in the body Must be able to release the drug in the body in a predictable and reproducible mannerin a predictable and reproducible manner

4 Basic OSD Physical and Biological

Oral Tablets for IngestionOral Tablets for Ingestion

Compressed tablets (CT)Compressed tablets (CT) Multiple compressed tablets (MCT)Multiple compressed tablets (MCT) Chewable tabletsChewable tablets Fast-dissolving tabletsFast-dissolving tablets Repeat-action tabletsRepeat-action tablets Delayed-action and enteric coated tabletsDelayed-action and enteric coated tablets Sugar- and chocolate-coated tabletsSugar- and chocolate-coated tablets

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

TabletsTablets

DisadvantagesDisadvantages Formulation difficulties if drug resist Formulation difficulties if drug resist

compressioncompression Some drugs have poor wetting or Some drugs have poor wetting or

poor water solubility or poor poor water solubility or poor dissolution might affect the drugrsquos dissolution might affect the drugrsquos bioavailabilitybioavailability

Bitter taste of the drug might require Bitter taste of the drug might require coatingcoating

Tablet propertiesTablet properties A tablet shouldA tablet should

Be elegant and free of defects such as chips Be elegant and free of defects such as chips cracks discoloration and contaminationcracks discoloration and contamination

Have sufficient strength to withstand Have sufficient strength to withstand mechanical shocks encountered during mechanical shocks encountered during manufacture packaging shipping and manufacture packaging shipping and dispensingdispensing

Have chemical and physical stability over Have chemical and physical stability over timetime

Must be able to release the drug in the body Must be able to release the drug in the body in a predictable and reproducible mannerin a predictable and reproducible manner

4 Basic OSD Physical and Biological

Oral Tablets for IngestionOral Tablets for Ingestion

Compressed tablets (CT)Compressed tablets (CT) Multiple compressed tablets (MCT)Multiple compressed tablets (MCT) Chewable tabletsChewable tablets Fast-dissolving tabletsFast-dissolving tablets Repeat-action tabletsRepeat-action tablets Delayed-action and enteric coated tabletsDelayed-action and enteric coated tablets Sugar- and chocolate-coated tabletsSugar- and chocolate-coated tablets

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Tablet propertiesTablet properties A tablet shouldA tablet should

Be elegant and free of defects such as chips Be elegant and free of defects such as chips cracks discoloration and contaminationcracks discoloration and contamination

Have sufficient strength to withstand Have sufficient strength to withstand mechanical shocks encountered during mechanical shocks encountered during manufacture packaging shipping and manufacture packaging shipping and dispensingdispensing

Have chemical and physical stability over Have chemical and physical stability over timetime

Must be able to release the drug in the body Must be able to release the drug in the body in a predictable and reproducible mannerin a predictable and reproducible manner

4 Basic OSD Physical and Biological

Oral Tablets for IngestionOral Tablets for Ingestion

Compressed tablets (CT)Compressed tablets (CT) Multiple compressed tablets (MCT)Multiple compressed tablets (MCT) Chewable tabletsChewable tablets Fast-dissolving tabletsFast-dissolving tablets Repeat-action tabletsRepeat-action tablets Delayed-action and enteric coated tabletsDelayed-action and enteric coated tablets Sugar- and chocolate-coated tabletsSugar- and chocolate-coated tablets

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

4 Basic OSD Physical and Biological

Oral Tablets for IngestionOral Tablets for Ingestion

Compressed tablets (CT)Compressed tablets (CT) Multiple compressed tablets (MCT)Multiple compressed tablets (MCT) Chewable tabletsChewable tablets Fast-dissolving tabletsFast-dissolving tablets Repeat-action tabletsRepeat-action tablets Delayed-action and enteric coated tabletsDelayed-action and enteric coated tablets Sugar- and chocolate-coated tabletsSugar- and chocolate-coated tablets

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Oral Tablets for IngestionOral Tablets for Ingestion

Compressed tablets (CT)Compressed tablets (CT) Multiple compressed tablets (MCT)Multiple compressed tablets (MCT) Chewable tabletsChewable tablets Fast-dissolving tabletsFast-dissolving tablets Repeat-action tabletsRepeat-action tablets Delayed-action and enteric coated tabletsDelayed-action and enteric coated tablets Sugar- and chocolate-coated tabletsSugar- and chocolate-coated tablets

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Other Types of TabletsOther Types of Tablets

Tablets Used in OralTablets Used in Oral

CavityCavity Buccal tabletsBuccal tablets Sublingual tabletsSublingual tablets Troches and lozengesTroches and lozenges Dental conesDental cones

Tablets Tablets AdministeredAdministered

by Other Routesby Other Routes Implantation tabletsImplantation tablets Vaginal tabletsVaginal tablets

Tablets Used toTablets Used toPrepare SolutionsPrepare Solutions Effervescent tabletsEffervescent tablets Dispensing tabletsDispensing tablets Hypodermic tabletsHypodermic tablets Tablet trituratesTablet triturates

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

FORMULA SEDIAAN TABLETFORMULA SEDIAAN TABLET

Zat khasiat zat aktif APIZat khasiat zat aktif API Bahan pengisi Bahan pengisi (filler)(filler) Bahan pengikat Bahan pengikat (binder)(binder) Bahan penghancur Bahan penghancur (desintegrant)(desintegrant) LubrikanLubrikan Korigensia (bila perluKorigensia (bila perlu Adsorben (bila perlu)Adsorben (bila perlu) Bahan pembasah (bila perlu)Bahan pembasah (bila perlu)

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

ZAT AKTIF DALAM SEDIAAN ZAT AKTIF DALAM SEDIAAN TABLETTABLET

Ada 2 kelompok obat yang doberikan Ada 2 kelompok obat yang doberikan secara oral dalam bentuk tablet secara oral dalam bentuk tablet

Obat yang tidak larut diharapkan bekerja Obat yang tidak larut diharapkan bekerja lokal da saluran cerna misal antasida anti lokal da saluran cerna misal antasida anti cacing dan adsorbencacing dan adsorben

Obat yang larut diharapkan mempunyai Obat yang larut diharapkan mempunyai efek sistemik setelah obat terdisolusi dalam efek sistemik setelah obat terdisolusi dalam saluran cerna yang dilanjutkan dengan saluran cerna yang dilanjutkan dengan absorpsiabsorpsi

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Tujuan mendesain kedua kelompok obat tersebutTujuan mendesain kedua kelompok obat tersebut Untuk obat yang tidak larut kerja obat terutama Untuk obat yang tidak larut kerja obat terutama

dipengaruhi oleh fenomena permukaandipengaruhi oleh fenomena permukaan Jadi desain produk yang segera terdispersi Jadi desain produk yang segera terdispersi

merupakan factor kritis dalam menghasilkan partikel merupakan factor kritis dalam menghasilkan partikel yang halus dengan luas permukaan yang besaryang halus dengan luas permukaan yang besar

Parameter kritis adalah efek formulasi granulasi Parameter kritis adalah efek formulasi granulasi dan tableting terhadap sifat-sifat permukaan bahan dan tableting terhadap sifat-sifat permukaan bahan dan kemampuannya untuk melepaskan diri dari dan kemampuannya untuk melepaskan diri dari sediaan (ketika mencapai usus) dengan sifat sediaan (ketika mencapai usus) dengan sifat permukaan yang optimumpermukaan yang optimum

Pada obat-obat yang ditujukan untuk efek sistemik Pada obat-obat yang ditujukan untuk efek sistemik desain sediaan yang cepat terdesintegrasi dan desain sediaan yang cepat terdesintegrasi dan melarut mungkin merupakan hal yang kritis melarut mungkin merupakan hal yang kritis tergantung pada lokasi absorpsi dan sifat kelarutan tergantung pada lokasi absorpsi dan sifat kelarutan pada atau sebelum lokasi absorpsipada atau sebelum lokasi absorpsi

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Active (Drug)Active (Drug)

Compaction and flow propertiesCompaction and flow properties Salt form polymorphsSalt form polymorphs Melting pointMelting point Purity of activePurity of active Particle sizeParticle size

Affects segregation of powders (blend Affects segregation of powders (blend uniformity)uniformity)

Affects dissolutionAffects dissolution

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Excipients Excipients Excipients are components of tablets that Excipients are components of tablets that

that have a role other than the therapeutic that have a role other than the therapeutic effect they includeeffect they include Fillers (diluents)Fillers (diluents) BindersBinders DisintegrantsDisintegrants Lubricants and glidantsLubricants and glidants PreservativesPreservatives Flavoring agentsFlavoring agents Film formersFilm formers Opacifiers and colorsOpacifiers and colors

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

ExcipientsExcipients All excipients must meet the following All excipients must meet the following

criteria in the formulationcriteria in the formulation NontoxicNontoxic Low costLow cost Physiologically inertPhysiologically inert Physically and chemically stable alone and in Physically and chemically stable alone and in

combinationscombinations Free of any unacceptable microbial loadFree of any unacceptable microbial load Color compatibleColor compatible Have no effect on the designated bioavailability of Have no effect on the designated bioavailability of

the drugthe drug Tetracycline bioavailability reduce to frac12 when combined Tetracycline bioavailability reduce to frac12 when combined

with calcium phosphate filler (complexation-solubility with calcium phosphate filler (complexation-solubility reduction)reduction)

Must not be contraindicated by themselves to any Must not be contraindicated by themselves to any segment of the population (sucrose-diabetes)segment of the population (sucrose-diabetes)

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

DILUENT FILLER

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Fillers (diluents)Fillers (diluents) increase the bulk of a tablet or capsule which is increase the bulk of a tablet or capsule which is

useful when the therapeutic component is a useful when the therapeutic component is a small quantity (potent drugs) small quantity (potent drugs)

The use of fillers allows more accurate dosing The use of fillers allows more accurate dosing because the tiny amount of active compound is because the tiny amount of active compound is dispersed into a diluent making it easier to dispersed into a diluent making it easier to administer administer

For round tablets a eight of 120-700 mg is For round tablets a eight of 120-700 mg is acceptable For oval tablets which are easier to acceptable For oval tablets which are easier to swallow about 800-1000mg is acceptableswallow about 800-1000mg is acceptable

Other benefits that diluents might bring to the Other benefits that diluents might bring to the formulationformulation

Improve cohesion- for direct compression useImprove cohesion- for direct compression use Promote flowPromote flow

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Fillers (diluents)Fillers (diluents) ExamplesExamples

LactoseLactose StarchStarch DextroseDextrose Mannitol-chewable tabletsMannitol-chewable tablets SorbitolSorbitol SucroseSucrose Microcrystalline celluloseMicrocrystalline cellulose

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Factors Influencing Choice ofFactors Influencing Choice of FillersFillers

CompressibilityCompressibility FlowabilityFlowability Particle size andParticle size and

distributiondistribution Moisture contentMoisture content Bulk densityBulk density Compatibility withCompatibility with

activeactive

SolubilitySolubility StabilityStability

Individual Individual excipientsexcipients

Finished tabletsFinished tablets Physiological Physiological

inertnessinertness CostavailabilityCostavailability GovernmentalGovernmental

acceptabilityacceptability

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

B I N D E R

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Binders Binders hold everything together in the tablet into a hold everything together in the tablet into a

solid mass Can be added dry or with the solid mass Can be added dry or with the liquid during wet granulation They also liquid during wet granulation They also promote cohesiveness for directly promote cohesiveness for directly compressible formulationscompressible formulations

This is especially important for tablet This is especially important for tablet formulations made from powders that would formulations made from powders that would otherwise be loose and fluffy and hard to otherwise be loose and fluffy and hard to consolidate into tablets and for certain consolidate into tablets and for certain timed-release products where the binder timed-release products where the binder acts as a matrix from which the drug is acts as a matrix from which the drug is gradually released gradually released

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

BindersBinders

Promote adhesion of powder particlesPromote adhesion of powder particles Maintain integrity of final tabletMaintain integrity of final tablet

Binder concentrationBinder concentration Affects hardness and friability of tabletAffects hardness and friability of tablet

ExamplesExamples 1048778 1048778 StarchStarch 1048778 1048778 Polyvinylpyrrolidone (PVP)Polyvinylpyrrolidone (PVP) 1048778 1048778 Cellulosic derivativesCellulosic derivatives

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Binders Binders ExamplesExamples

Acacia and tragacanth (natural gums)Acacia and tragacanth (natural gums) Usually used in wet granulation with 10-25 Usually used in wet granulation with 10-25

concentration in the granulating fluidconcentration in the granulating fluid One problem associated with these binders is One problem associated with these binders is

microbial proliferation if drying is delayedmicrobial proliferation if drying is delayed Gelatin Gelatin Starch Starch Methylcellulose used for wet granulation Methylcellulose used for wet granulation

and for direct compressionand for direct compression

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

DISINTEGRANTS

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Disintegrants Disintegrants Allow the tablet to break apart in the GI Allow the tablet to break apart in the GI

tract usually in the stomach or small tract usually in the stomach or small intestine so that dissolution can occur then intestine so that dissolution can occur then the active component can be absorbed by the active component can be absorbed by the body the body

Disintegrants may function by drawing Disintegrants may function by drawing water into the tablet swelling and causing water into the tablet swelling and causing the tablet to burstthe tablet to burst

Disintegrant concentrationDisintegrant concentration Affects rate of disintegrationAffects rate of disintegration

ExamplesExamples StarchStarch Veegum and bentonite used only in colored Veegum and bentonite used only in colored

tablets because of there off-white appearancetablets because of there off-white appearance

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Disintegration ProcessDisintegration Process

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Disintegrant MechanismsDisintegrant Mechanisms

All disintegrants are hygroscopic and draw All disintegrants are hygroscopic and draw liquidliquid into the matrix (liquid uptake or into the matrix (liquid uptake or wickingwicking action)action) May generate a hydrostatic pressureMay generate a hydrostatic pressure

As they sorb liquid they mayAs they sorb liquid they may Swell extensively (Sodium Starch Glycolate Swell extensively (Sodium Starch Glycolate

NF)NF) Recover shape with little swelling Recover shape with little swelling

(Crospovidone(Crospovidone NF Starch NF)NF Starch NF) Swell radially and straighten out [fibrous Swell radially and straighten out [fibrous

material]material] (Croscarmellose Sodium NF)(Croscarmellose Sodium NF)

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Disintegrant MechanismDisintegrant Mechanism (continued)(continued)

Together these phenomena create aTogether these phenomena create a disintegrating force within the matrixdisintegrating force within the matrix

The rapid buidup of a disintegrating forcepromotes rapid disintegration

bullThe liquid uptake may also contribute by initiating binder andor matrix dissolution to weaken the tablet

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Types and Use Levels of Types and Use Levels of DisintegrantsDisintegrants

Starch 5-15Starch 5-15 Croscarmellose sodiumCroscarmellose sodium

DC 1-3DC 1-3 Wet Granulation 2-4Wet Granulation 2-4

CrospovidoneCrospovidone 2-42-4

Sodium Starch GlycolateSodium Starch Glycolate 4-64-6___________________

Super-Disintegrants

Note For powder filled hard gelatin capsules 4-8 is usuallyused Crospovidone and Starch not recommended for capsules

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Classification of SuperClassification of Super DisintegrantsDisintegrants

Modified Cellulose [Croscarmellose Sodium NF]Modified Cellulose [Croscarmellose Sodium NF] (Sodium carboxymethyl cellulose which has been (Sodium carboxymethyl cellulose which has been

crosslinked tocrosslinked to render it insoluble)render it insoluble) AcDiSol (FMC Corp)AcDiSol (FMC Corp)

Crosslinked Polyvinylpyrrolidone [Crospovidone Crosslinked Polyvinylpyrrolidone [Crospovidone NF)NF) (High MW and cross linking render it insoluble)(High MW and cross linking render it insoluble)

Polyplasdone XL (ISP Corp)Polyplasdone XL (ISP Corp)

Modified Starch [Sodium Starch Glycolate NF]Modified Starch [Sodium Starch Glycolate NF] (Sodium carboxymethyl starch crosslinking reduces (Sodium carboxymethyl starch crosslinking reduces

solubility)solubility) Primojel (Generichem Corp)Primojel (Generichem Corp) Explotab (Edward Mendell Co)Explotab (Edward Mendell Co)

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Sodium Starch GlycolateSodium Starch Glycolate

Upon Exposure to 100 RH Air

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

When formulations are granulatedWhen formulations are granulated (wet or dry) disintegrants are best(wet or dry) disintegrants are best addedadded

12 before granulation (intragranular)12 before granulation (intragranular) 12 after granulation (extragranular)12 after granulation (extragranular)

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

LUBRICANTS

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

The Three Lubricant Roles

True Lubricant RoleTrue Lubricant Role Reducing friction between sliding surfacesReducing friction between sliding surfaces

traditionally at the tablet-die wall interface traditionally at the tablet-die wall interface duringduring tablet formation and ejection Also tablet formation and ejection Also applies toapplies to capsule plugscapsule plugs

Antiadhesion Antiadhesion Antiadherent Antiadherent RoleRole Preventing sticking to surfaces eg the faces Preventing sticking to surfaces eg the faces

ofof tablet punches capsule tamping pinstablet punches capsule tamping pins

Glidant RoleGlidant Role Improving flow by modifying the interactionImproving flow by modifying the interaction

between particlesbetween particles

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Lubricants In a general sense

LubricantLubricant TypicalTypicalLevelLevel

TrueTrueLubricaLubricantntActivityActivity

AntiadherenAntiadherenttActivityActivity

GlidantGlidantActivityActivity

MetallicMetallic

StearatesStearates

eg mag eg mag stst

calcium stcalcium st

05 - 105 - 1 ExcellentExcellent GoodGood PoorPoor

Stearic Stearic AcidAcid

1-51-5 Good Good Good Good NilNil

Colloidal Colloidal SilicasSilicas

lt1lt1 NilNil GoodGood ExcellentExcellent

TalcTalc 1-51-5 PoorPoor ExcellentExcellent GoodGood

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Concept of a Lubricant System

Frequently two substances are used Frequently two substances are used in ain a formulation to maximize overall formulation to maximize overall lubricant effect inlubricant effect in all three areasall three areas For example combining magnesium For example combining magnesium

stearate withstearate with a colloidal silicaa colloidal silica

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Some Lubricant Issues

The most effective true lubricants areThe most effective true lubricants are hydrophobic and if too much is used they hydrophobic and if too much is used they cancan interfere with disintegration and interfere with disintegration and dissolutiondissolution Magnesium stearateMagnesium stearate Calcium stearateCalcium stearate

Lubricant generally interfere with bonding Lubricant generally interfere with bonding andand can soften tabletscan soften tablets

Alkaline metal stearates are incompatible Alkaline metal stearates are incompatible withwith some drugs eg aspirin and ascorbic some drugs eg aspirin and ascorbic acidacid

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Some Lubricant Issues (continued)

Laminar lubricants Laminar lubricants (magnesium stearate(magnesium stearate calciumcalcium stearate) are stearate) are mixing sensitivemixing sensitive Under the rigors of Under the rigors of

mixing they mixing they delaminate todelaminate to increase increase their Nwtheir Nw

The effect can be The effect can be equivalent to adding equivalent to adding tootoo much lubricantmuch lubricant

Laminar Structure of Magnesium Stearate

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Some Lubricant Issues (continued)

Lubricants are always added last after all Lubricants are always added last after all otherother components have been thoroughly components have been thoroughly mixedmixed Mixing time of 2-5 minutesMixing time of 2-5 minutes

Water soluble lubricants are not nearly asWater soluble lubricants are not nearly as effective as the hydrophobic lubricantseffective as the hydrophobic lubricants Used when a tablet must be completely waterUsed when a tablet must be completely water

soluble (eg effervescent tablets)soluble (eg effervescent tablets) Examples DL Leucine sodium benzoateExamples DL Leucine sodium benzoate

polyethylene glycol 8000polyethylene glycol 8000

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Glidants Usually added to enhance the flowability of Usually added to enhance the flowability of

directdirect compression mixturescompression mixtures

There is an optimim concentration at which There is an optimim concentration at which flowflow is bestis best Usually lt1 and often 025 - 05 for theUsually lt1 and often 025 - 05 for the

colloidal silicascolloidal silicas The optimimum concentration is related to theThe optimimum concentration is related to the

amount needed to just coat the bulk powderamount needed to just coat the bulk powder particlesparticles

Higher concentrations may be needed to Higher concentrations may be needed to correctcorrect serious adhesion (sticking) to serious adhesion (sticking) to punch facespunch faces

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Effect of Concentration of Glidant onFlow Rate

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

PreservativesPreservatives Help prevent chemical breakdown of Help prevent chemical breakdown of

the active agent eg anti-oxidantsthe active agent eg anti-oxidants

Flavouring agentsFlavouring agents Make tablets more palatable esp Make tablets more palatable esp

chewable tablets or lozenges eg chewable tablets or lozenges eg fructosefructose

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Film FormersFilm Formers Protects active from degradation Protects active from degradation

strengthens tablet may facilitate strengthens tablet may facilitate administration of tablet eg various administration of tablet eg various polymers and carbohydratespolymers and carbohydrates

Opacifiers and colorsOpacifiers and colors Protects light-sensitive drugs Protects light-sensitive drugs

contributes to tablet appearance eg contributes to tablet appearance eg titanium oxidetitanium oxide

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

ExcipientsExcipients

The choice of excipient combinations is very The choice of excipient combinations is very specific to the product being formulated into specific to the product being formulated into tablets because the physico-chemical tablets because the physico-chemical properties of the drug itself could influence properties of the drug itself could influence the behavior of the other tablet componentsthe behavior of the other tablet components

The choice of excipients will also be The choice of excipients will also be determined by the preferred manufacturing determined by the preferred manufacturing process for that drug and on the experience process for that drug and on the experience and equipment available to the manufacturerand equipment available to the manufacturer

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

ColorsColors

FDampC dyesFDampC dyes Water soluble Water soluble

colorscolors FDampC lakesFDampC lakes

Insoluble aluminum Insoluble aluminum salts of dyessalts of dyes

Iron oxidesIron oxides

Primary reason for Primary reason for using colors using colors MarketingMarketing

Spray-dried and Spray-dried and other flavorsother flavors

Natural sweetenersNatural sweeteners Artificial sweetenersArtificial sweeteners

Reasons for using Reasons for using flavorssweetenersflavorssweeteners Mask bad taste of Mask bad taste of

drugsexcipientsdrugsexcipients Mask bad odorMask bad odor

Flavors and Sweeteners

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

Properties of Good Tablets

Physical StabilityPhysical Stability Remain whole Remain whole

duringduring manufacturetranspmanufacturetransportort dispensingdispensing

Chemical StabilityChemical Stability Amount of drugAmount of drug

present as labeledpresent as labeled beyond expiration beyond expiration datedate

Esthetic AppearanceEsthetic Appearance Free of chipscracksFree of chipscracks

contamination contamination unevenuneven colorationcoloration

BioavailabilityBioavailability

Weight and ContentWeight and Content

UniformityUniformity

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||

ALUR PROSES TAB DG GRANULASI BSHALUR PROSES TAB DG GRANULASI BSH

AquademinKollidon 25 Pelarutan

Lactose Pencamp Krg Granulasi BasahZat AktifAvicel PH 101 Pengeringan

Pengayakan

Talcum PencampuranExplotab

Pencamp AkhirMg Stearat

Pencetakan tabPenyalutan

Pengemasan

mixing || granulasi || pengeringan || mesin cetak || blister ||