Solid preparations

62
Solid preparations Chapter 4

description

Solid preparations. Chapter 4. I.Introduction. A.characteristics (1)better stability when compared with liquid preparations (2)similar preparation process (3)absorbed into blood circulation only after released from preparations. B.Flow profiles of preparation process raw materials - PowerPoint PPT Presentation

Transcript of Solid preparations

Page 1: Solid preparations

Solid preparations

Chapter 4

Page 2: Solid preparations

I.Introduction

A.characteristics

(1)better stability when compared with liquid preparations

(2)similar preparation process

(3)absorbed into blood circulation only after released from preparations

Page 3: Solid preparations

B.Flow profiles of preparation process

raw materials

crushing

sieving

mixing powder

granulation granule capsule

pressure tablet

Page 4: Solid preparations

C.process of absorption in vivo of solid preparations

oral administration

disintegration (coarse particles) (tablet and capsule)

dissolution(fine particles)

absorption into blood(biological membrane)

Page 5: Solid preparations

order of absorption speed :

solution>suspension>powder>granule>capsule>tablet>pill

Page 6: Solid preparations

D.Noyes-Whitney equation dC/dt=KS(Cs-C), K=D/(Vδ) at the sink condition, C 0 then: dC/dt=KSCs

dC/dt—dissolution rateK—constant of dissolution rateS—interface area of dissolutionCs– solubility(saturated concentration) of drugC—drug concentration in release solvent at time of tD—diffusion coefficientV—volume of release solventδ—thickness of diffusion layer

Page 7: Solid preparations

↑ S, ↑ K and (or) ↑ Cs in order to ↑ dC/dt

↑ S depends on ↓ size ↑ K depends on stirring

↑ Cs is better and more frequently used which depends on modern techniques

Page 8: Solid preparations

II. Powders

A.definition

drug(s) +excipient(s), mixing

B.properties

(1)quick effect and large effect area

(2)easy preparation

(3)poor stability

Page 9: Solid preparations

C.preparation process

raw materials

crushing

sieving

mixing

quality evaluation

dosage and package

Page 10: Solid preparations

(1)crushing aims: ↑ dissolution rate and bioavailability improving mixing process mechanism: energy exchange(mechanical energy

surface energy) evaluating parameter: comminution degree:

n=D1/D2

equipment: mortar, ball mill(P100), fluid-energy mill(P101)…

types: dry and wet crushing occlusion crushing and free crushing open crushing and recirculating crushing low-temperature crushing

Page 11: Solid preparations

(2)sieving

aims: homogenize the size of particles

grades: No.1~9 sieve mesh

the larger the number, the smaller the mean size

equipment: sieves

Page 12: Solid preparations

(3)mixing

aims: homogenize the whole materials in order to keep uniform of drug concentration

evaluation parameters:

σ, σ2: the smaller the better ( 0)

M: the larger the better (0~1)

mechanisms: convective, shear, diffusion

along with segregation

Page 13: Solid preparations

impact factors: particles—size distribution(sieving) ratios of different particles(balanced

progressive mixing) density(beginning with the light

followed by the heavy) adhesive(the massive amount one

followed by the less one) electrostatic(surfactants) liquid(absorbers) eutectic mixture(effectiveness) equipment—rotary (V-shaped) operating conditions—filling amount, time,

speed etc

Page 14: Solid preparations

D. Package

dosage—weight, volume

note: fluidity, wettability (CRH%)

E. Quality evaluation

Chp2005 edition

Page 15: Solid preparations

III. Granules

A. Definition: drug+excipients, mixing, granulation

B. Types: soluble, suspension, effervescent

C. Properties

(1)more stable when compared to powders

(2)convenient to administration

(3)be coated in order to sustained release

(4)segregation(compound ones)

Page 16: Solid preparations

D. Preparation process

drug

crushing

sieving

mixing fillers, disintegrants, adhesives

soft materials extrusion or in fluiding-bed

wet granules dry, sieving

dry granules quality control(Chp2005 edition)

dosage and package

Page 17: Solid preparations

IV. Tablets

A. Definition: drug+adjuvants, mixing, (granulation), pressure

B. Properties

(1)homogeneous dosage

(2)promising stability

(3)low cost (mechanization and automation)

(4)many types

(5)difficult to swallow

Page 18: Solid preparations

C. Types

(1)tablets for oral administration

compressed

coated (sugar, film, enteric)

effervescent

chewable

dispersible

sustained or controlled release

multilayer

Page 19: Solid preparations

(2)tablets for oral cavity sublingual toroches buccal(3)tablets for hypodermis implant hypodermic (disappeared)(4)tablets for external use solution vaginal

Page 20: Solid preparations

D.adjuvants(excipients)(1)diluents or fillers aims: to produce tablets with a reasonable

size types: starch, sugar, dextrin, lactose,

pregelatinized starch, MCC, inorganic salts etc

Page 21: Solid preparations

(2)moistening agents and adhesives

moistening agents: induce the adhesion of other materials

distilled water, ethanol with different concentration

adhesives: have adhesion themselves

starch paste, MC, HPC, HPMC, CMC-Na, EC, PVP, PEG, gelatin solution etc

Page 22: Solid preparations

(3)disintegrants

aims: disintegrate the tablets into small particles

mechanisms: capillary, swelling, heat of wetting, gas

types: starch, CMS-Na, L-HPC, CCNa, PVPP, NaHCO3+weak acid

addition methods: in the raw materials(inside the particles), before pressure (outside the particles), combination of the two (the best)

Page 23: Solid preparations

(4)lubricants glidants: reduce the friction among particles

such as MgO, starch, talc, aerosil, MgCO3

antiadherents: reduce the adhesion between materials and punches

such as most lubricants, starch, talc lubricants: reduce the friction between the

tablets and punches soluble: PEG, sodium benzoate insoluble: calcium, magnesium and zinc salts of

stearic acid, talc, light mineral oil, paraffin

Page 24: Solid preparations

(5)others

pigments: soluble, insoluble (Lake)

flavors: essences

note: no addition or lower the amount

Page 25: Solid preparations

E. Preparation techniques

wet

granulation

dry

powder compact

direct compression

blank granulation

Page 26: Solid preparations

(1)wet granulation (the most frequently used) drugs+adjuvants crushing sieving blending of dry ingredients mixing wet granules moistening agents or adhesives dry screening lubricants blending compression

Page 27: Solid preparations

(2)dry granulation (heat-sensitive materials) drugs+adjuvants crushing sieving mixing compression large tablets crushing screening lubricants blending pressure

Page 28: Solid preparations

(3)direct compression ( powder or crystal with good pressing ability and fluidity)

It is always necessary to employ promising excipients, such as MCC, lactose, aerosil etc (so-called “compression aids”)

Page 29: Solid preparations

(4)blank granulation (heat- and humidity-sensitive drugs with poor compression ability)

drugs

crushing

sieving

mixing + blank granules

blending lubricants

compression

Page 30: Solid preparations

F. Tableting equipment

(1)granulators

extruding (p121)

rolling (p122)

high-speed stirring (p123)

fluidized bed (p124)

spray-drying (p126)

microwave vacuum drying

Page 31: Solid preparations

(2)tablet presses

single-station (single-punch) (p134)

multistation (rotary) (p136)

the same steps:

filling compression ejection

Feed shoe upper (and lower) punches lower punches

Page 32: Solid preparations

G.Coating of tablets(1)aims: increase stability enhance patient compliance separate different medicines optimize appearance control release site and rate(2)types: sugar coating film coating (including enteric

coating)

Page 33: Solid preparations

(3)coating process sugar coating: core(using tooling with deep concave geometry, note the friability)

sealing coat(moisture barriers, shellac, CAP etc, 3-5)

subcoat(a good bridge between the main coating and the sealed coat, as well as rounding off any sharp corners, warm subcoat syrup+subcoat powder, acacia or gelatin +talc, starch, calcium carbonate, 15-18)

sugar coat(produce a smooth surface, a syrup free from suspended powders, 10-15)

colored coat(convenient to reorganization and beautiful appearance, colorants in syrup, 8-15)

polishing(high luster and evaporated any traces of solvent, canvas side walls +dilute wax solution or powder)

Page 34: Solid preparations

equipment: a revolving pan

properties: beautiful appearance

cover nasty taste and smell

good moisture barriers

complexity and time-consuming(more than 50% weight gains)

Efforts were made to develop film coatings!

Page 35: Solid preparations

film coating:

core film coat and dry(weight gains of only 2-6%)

solidify(the film coating, 6-8h)

dry slowly(evaporate any traces of solvent, 12-24h)

equipment: a revolving pan, fluidized beds, spray-drying etc

properties: simpler and easier to automate

distinctive identification markings

promising stability

Page 36: Solid preparations

commonly used film-coating materials: nonenteric—MC, EC, HPMC, CMC-Na,

PVP, PEGs etc enteric—shellac, CAP, PVAP, HPMCP,

methacrylic acid and its eaters(Eudragit L and S)

plasticizers—glycerin, propylene glycol, citrate esters, PEG, triacetin etc

agents adjusting release rate antiadhesives colorants

Page 37: Solid preparations

(4)coating equipment

conventional coating pans

fluidized beds

compression coating presses(core+fine free-flowing materials, especially used by instable drugs’ coating)

Page 38: Solid preparations

H.quality control Chp2005 edition appearance weight variation hardness and crushing strength disintegration testing dissolution rate (if done, the above can be omitted) uniformity of dosage units (if done, the following

can be omitted) concentrationI.package multi- and unit-dose packaging

Page 39: Solid preparations

V.Capsules

A.Definition: solid dosage forms in which the drug substance is enclosed within either a hard or soft shell usually from gelatin

B.properties(1)enhance stability and cover unpleasant taste and

odor(2)quick effect(3)turn liquid drug into solid form(4)adjust drug release rate and site(5)note drug choice (shell effects and irritation) and

difficult swallowing by some patients

Page 40: Solid preparations

C.Hard capsules(1)advantages better bioavailability when compared

with tablets easier to formulate multiple fillings (beads, granules,

minitablets, powders, semisolids) in order to overcome incompatibility and modify or control drug release

Page 41: Solid preparations

(2)disadvantages relative higher cost drug choice (such as highly soluble salts) difficulty in swallowing(3)preparation process empty hard shells filling materials filling and closuring package quality evaluation

Page 42: Solid preparations

Empty hard shell

shell composition: gelatin+plasticizers+colorants+opaquing agents+preservatives+water

shell manufacture: dipping+rotation+drying+stripping+trimming+joining

shell sizes and shapes:

8 types (No.000,00,0,1~5), smaller

self-locking closure

Page 43: Solid preparations

Filling materials

dosage forms:

powders

granules

beads or pellets

tablets or minitablets

liquid or pasty materials

Page 44: Solid preparations

ingredients: must not dissolve, alter or otherwise adversely affect the integrity of the shell

active ingredient fillers—increase the bulk of the formulation

(such as starch, lactose, dicalcium phosphate) glidants—improve the fluidity of powders(such

as talc, MS) lubricants—ease the ejection of plugs, reduce

filming on pistons and adhesion of powder to mental surfaces, reduce friction between sliding surfaces in contact with powder (such as MS, stearic acid)

disintegrants, surfactants, hydrophilization etc

Page 45: Solid preparations

Filling rectification separation of caps from bodies dosing of fill materials replacement of caps and ejection of filled

capsules

semiautomatic or fully automatic capsule-filling machines (p152)

Page 46: Solid preparations

D.soft capsules(1)advantages more suitable to liquid or volatile drugs or

drugs dissolved, solubilized or suspended in a liquid vehicle with rapid release and potential enhanced bioavailability

suitable to drugs subjected to atmospheric oxidation because of effective barrier to oxygen of the shell

a wide variety of sizes and shapes(tube form and bead form)

Page 47: Solid preparations

(2)disadvantages inexpensive dosage form for the need of

necessary filling equipment and expertise increase the possibility of interaction between

drugs and shell(migration of a drug into the shell)

(3)composition of the shell gelatin(1part)+water(1part)+plasticizers(0.4-

0.6part)+dyers+opacifiers+preservatives+flav-ors

Page 48: Solid preparations

(4)filling materials a single liquid, a combination of miscible liquids, a

solution of a drug in a liquid, or a suspension of a drug in a liquid (do not have an adverse effect on the gelatin walls and pH2.5~7.5)

types of vehicles: water-immiscible, volatile, or more likely nonvolatile liquids (vegetable oils, mineral oils etc)

water-miscible, nonvolatile liquids (PEG400, PEG600)

water(greater than 5% of contents) and low molecular weight organic agents cannot be encapsulated

Page 49: Solid preparations

(5)manufacture of soft capsules

dripping process (p153)

compacting process (p154)

Page 50: Solid preparations

E. Enteric capsules

coated the surface of shell by enteric materials

Page 51: Solid preparations

F. Quality evaluation Chp2005 edition appearance water concentration weight variation disintegration or dissolution G. Package unit-dose container: blister and strip packaging multi-dose container: glass(amber) or plastic

bottles

Page 52: Solid preparations

VI. Dripping pills

A. Definition drugs+bases, melting, quick freezing shapes: spherical, oval, olive etc

B. Properties(1)simple operation and equipment(2)liquid solid(3)adjust drug release rate through the property of

base(4)enhance stability

Page 53: Solid preparations

C. Preparation technique(1) drugs(insoluble and moderate soluble)

melting + water-soluble bases(PEGs, poloxamers etc )

dripping freezing

oily freezing solvent

Key step: quick freezing(solid dispersion)

quicker release and higher bioavailability

Page 54: Solid preparations

(2) drugs(soluble)

melting + water-insoluble bases(stearic acid, hydrogenized

vegetable oil )

freezing

freezing solvent(water or alcohol)

sustained release and prolonged effective time

Page 55: Solid preparations

D. Equipment

P157

Page 56: Solid preparations

VII. Pills

A. Definition spherical pellets with diameter below 2.5mm in general, enclosed with hard capsules drug+base(core) with film coatingB. Properties(1)convenient to adjust release rate(2)higher drug content in capsules(3)more uniform absorption, higher

bioavailability and lower irritation(4)easy preparation

Page 57: Solid preparations

C. Types

soluble film-coated pills(gel barrier)

insoluble film-coated pills(erosion, suitable for water-soluble drugs)

insoluble film-coated pills with micropores (caused by water-soluble materials)

Page 58: Solid preparations

D. Preparation process drug+base pills polymer coating

base(blank core)+drug layers base: starch, sugar and dextrin etc polymer coating: PVP, MC, AC, CAP etcMethods: traditional methods, fluidized bed,

spray-drying, spray-freezing, dry-in-liquid, dispersion-in-water and spherical crystallization etc

Page 59: Solid preparations

VIII. Films

A. Definition

drugs+film materials

B. Properties

(1)simple preparation process

(2)great stability

(3)easy to adjust drug release rate through different kinds of membrane materials

(4)low drug-loading rate

Page 60: Solid preparations

C.Membrane materials and excipients(1)natural polymers: gelatin, acacia, starch,

dextrin etc (2)Synthetic polymers: PVA: PVA05-88+PVA17-88(1:3) EVA(3)plasticizers: glycerin(4)surfactants: Tween-80, SLS-Na(5)fillers: CaCO3, SiO2, starch(6)colorants: pigments, TiO2

(7)defilming agents: liquid paraffin

Page 61: Solid preparations

D. Preparation process

(1) Homogenization: PVA

(2) Thermoplast: EVA

(3) Complex: sustained release films

Page 62: Solid preparations

E. Quality evaluation

Chp2005 edition

(1)appearance

(2)weight variation

(3)microorganism test