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“Handling of solid” “Pharmaceutical Granulation ’’

Guided By:Dr. V.B. PokharkarVice-PrincipalPoona College of PharmacyPune

Presented By:Neeraj RawatM.Pharmacy 1st year

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Contents

•S0lid Handling•Granulation•Dispensing of granules•Purpose of granulation•Methods of granulation•Compression

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Solid handling •Conveying :- the term conveying is

applied to the transportation of solids.

• Objectives :- 1) Decreased product cost and increase

manufacturing capacity.2) Decrease cost of raw material.3) Decrease processing time and conservation 4) Minimum contamination and dust formation

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Conveyors are classified into 5 major group1. Belt conveyors2. Screw conveyors3. Pneumatic conveyors4. Chain conveyors5. Bucket conveyors

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1 Belt conveyors• For transporting light- and medium-weight loads

between operations, departments, levels, and buildings

• When an incline or decline is required• Provides considerable control over the

orientation and placement of the load.• No smooth accumulation, merging, and sorting

on the belt• The belt is roller or slider bed supported; the

slider bed is used for small and irregularly shaped items.

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Belt Conveyor

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2 Screw conveyors•Consists of a tube or U-shaped stationary

trough through which a shaft-mounted helix revolves to push loose material forward in a horizontal or inclined direction

•One of the most widely used conveyors in the processing industry.

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3 Pneumatic Conveyoys•Can be used for both bulk and unit

movement of materials•Air pressure is used to convey materials

through a system of vertical and horizontal tubes

•Major advantages are that material is completely enclosed and it is easy to implement turns and vertical moves.

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4 Chain Conveyors•Uses one or more endless chains on which

loads are carried directly•Parallel chain configuration used to

transport pallets•Vertical chain conveyor used for

continuous high-frequency vertical transfers.

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5 Bucket Conveyors•Used to move bulk materials in a vertical or inclined path•Buckets are attached to a cable, chain, or belt•Buckets are automatically unloaded at the end of the conveyor run.

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Granulation• Granulation is the process in which primary powder

particles are made to adhere to form larger, multi-particle entities called granules.

•  It is the process of collecting particles together by creating bonds between them.

•  Bonds are formed by compression or by using a binding agent.

• Granulation is extensively used in the manufacturing of tablets and pellets

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•Granulation may be defined as a size enlargement process which converts fine or coarse particles into physically stronger and larger agglomerates having good flow property, better compression characteristics and uniformity.

Granulation Technology•The art and science for process and

production of granules is known as Granulation Technology.

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Granules

•Granules are powder particles that have been aggregated to form a larger particle, which is usually 0.2 - 4.0 mm in diameter.

•Granules are also prepared as an intermediate in tablet manufacture. These are smaller in size.

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Dispensing of Granules•Bulk granules for internal use•Divided granules (i.e. single preparations)

for internal use•Insufflations for administration to ear,

nose or throat•Antibiotic syrups to be reconstituted

before use•Powders for reconstitution into injections•Dry powder inhalers.

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Why we prepare granules when we have powders….?

• To prevent segregation of the constituents of the powder mix.

• To improve the flow properties of the mix.

• To improve the compression characteristics of the mix.

• To reduce caking of hygroscopic materials on storage.

• As granules are denser than the parent powder mix, occupy less volume per unit weight. Easy for storage.

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Granulation to Prevent Segregation

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Advantages• It improves flow property and compression

characteristics and increases density of granules.

• Better distribution of color and soluble drug if added in the binding solution.

• It reduces dust hazards.

• Prevents segregation of powders.

• Makes hydrophobic surfaces more hydrophilic.

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Disadvantages• Process is expensive because of labor, space, time

special equipment and energy requirement.

• Loss of material during various stages of processing.

• Moisture sensitive and thermolabile drugs are poor candidates.

• Any incompatibility between the formulation components is aggravated during the processing.

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GRANULATION METHOD1. Dry granulation2. Wet granulation

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When To Choose DRY method?

•Drug dose is too high.

•Do not compress well after wet granulation.

•Heat sensitive drugs.

•Moisture sensitive drugs. e.g. Aspirin , Vitamins

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Dry Granulation •Dry granulation methods, powder

particles are aggregated under high pressure.

•The dry granulation process is use to form granules without using liquid solution because the product to be granulated may be sensitive to moisture and heat.

•Two method are used for dry granulation.

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MixingCompaction of powder

Milling

Screening

Steps in Dry Granulation

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Dry Granulation methods1. SLUGGING

•The powders is forced into the dies of a large capacity tablet press and is compacted by means flat and faced punches , the compacted mass called Slugs and the process is called to as a Slugging.

• The resulting slugs are milled to yield a tablet granulation.

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2. Roller compaction• This method is used for dry granulation

on large scale on a specially designed machine called roller compactor.

• In this method powders is compressed in a roller compactor forming a sheet or large pieces that are broken down into a tablet granulation.

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Roller Compactors

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Chilsonator Roller Compactors

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Advantage of dry granulation•Increased production capacity.•Greater control of compaction pressure.•No need for excessive lubrication.•Less number of step. •Less time consuming.•Useful for moisture and heat sensitive

material

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Wet granulation•Wet granulation involves the massing of a mix

of dry primary powder particles using a granulating fluid.

•The fluid contain a solvent which must be volatile so that it can be removed by drying.

•Typically liquid include water, ethanol or isopropanol either alone or in combination.

•primary advantages of water are that:• it is non-flammable, which means that

expensive safety precautions not be taken.

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1 • Mixing of the drug(s) and excipients

2• Mixing of binder solution with powder

mix. to form wet mass

3• Coarse screening of wet mass using a suitable sieve .

(6-12 # screens)

4 • Drying of moist granules.

5• Screening of dry granules through a suitable sieve (14-20 #

screen).

Steps in wet granulation

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Granulating liquid

-Volatile -Non-

toxice.g.

Water, Ethanol ,

Isopropanol

Binding agent-

Natural Polymers:  

Starch, Pregelatinized

Starch

synthetic binders: 

PVP, MC, HPMC,Maltrodextrin

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Method of wet granulation•Mixing :-The first stage in the wet

granulation process is often a dry mixing stage in which the active component is mixed with a diluents. The purpose of the mixing stage is to ensure that the powder blend and hence the resulting tablets are homogeneous in content.

•Granulation :- Granulation is a unit operation in which mixed powders are simultaneously mixed with a suitable fluid, e.g. water, isopropanol or ethanol.

•DRYING :- After the process of granulation, the product exists as a wet mass from which the liquid must be removed. Water is usually removed by evaporation for which energy is needed.

•SEIVING :- When the drying process is complete, it is likely that the product will have cohered into relatively large masses, especially if tray drying has been used. The dried material is therefore passed through a sieve (usually 250–700 mm) to break up aggregates and to give a relatively uniformly sized granules.

•MIXING OF ADDITIVES :- A second mixing stage now follows in which several important ingredients of the formulation are added.

 Glidant :-     To increase flow of material during manufacturing processes

  Lubricant :-   To  avoid sticking with wall of dyes.

 Disintegrating agent:-  To disintegrate in GIT tract.

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Wet Granulation EquipmentI. Shear granulators•Planetary mixer e.g. Hobart, Collette,

Beken

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•High shear mixture has been widely used in Pharmaceutical industries for blending and granulation.

•Wet agglomeration in a high-shear mixer involves typically 3 phases: Dry Powder mixing ( 2-5 mins) Liquid binder addition (1-2 mins) Wet massing

Advantages: Highly cohesive material can be granulated.Disadvantages: Mechanical degradation.

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Wet Granulation Equipment•Oscillating Granulator

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Wet Granulation EquipmentII. High Speed mixers/Granulators•Little ford Lodige mixer

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Wet Granulation Equipment•The Gral Mixer-granulator

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Fluidized Bed Granulator

Air inletAir filter

Air outlet

Spray nozzleProduct container

Granulating liquid

Exhaust filter

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•The powder particles are fluidized in a stream of air.

• Granulation fluid is pumped from a reservoir and sprayed from a nozzle on to the bed of powders.

• Heated and filtered air is blown through the bed of unmixed powders to fluidize the particles and mix the powders.

•The fluid causes the primary powder particles to adhere when the droplets and powders collide.

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•Sufficient liquid is sprayed to produce granules of the required size, at which point the spray is turned off but the fluidizing air continued.

• The wet granules are then dried in the heated

fluidizing air stream.

Advantages•It reduces product loss.•It improves worker safety.

Disadvantages•time consuming.•Difficulty of assuring reproducibility

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Spray Dryer

suspension

Fluidization air

screen

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• Granular product is made from a solution or a suspension rather than initially dry primary powder particles.

• The resultant granules are free-flowing hollow spheres and the distribution of the binder in such granules results in good compaction properties.

Advantages•1. Rapid and continuous process.•2. Reduces overall cost •3. Offers minimal product handling and

operator exposure to dust.•4. Suitable for heat sensitive product.

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Mechanisms of Granule Formation•Three stages :1. Nucleation-Particle-particle contact adhesion due to liquid bridges form the pendular stateagitation densities the pendular bodies bodiesact as nuclei for granule growth.

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Mechanisms of Granule Formation2. Transition

Nuclei Growthsingle particles two or more nuclei added to the nuclei may combineby pendular bridges

• Here presence of a large number of small granules with a wide size distribution can be seen.

• This is a suitable end-point for granules used in capsule and tablet manufacture to have uniform tablet die or capsule fill.

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Mechanisms of Granule Formation3. Ball growthFurther granule growth large, sphericalgranules mean particle size will increase with time.

•Ball growth seen in planetary mixers essential feature of some spheronizing equipment

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Advantage Disadvantage

Excellent cohesiveness and compressibility due to added binder

High labour and equipment cost.

Excellent flow properties High space and time requirement.

Good distribution and uniform content for low dose drugs.

Large no. of steps.

Prevention of segregation. Migration of soluble dyes.

Improve the dissolution rates for hydrophobic drugs

Aggravation of incompatibilities between formulation components

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Compression

“External mechanical force applied to a powder mass reduction in bulk volume’’

• After preparation of granules they are compressed to get final product.

• The compression is done either by single punch machine or by multi station machine (rotary press)

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• Consolidation “Increase in mechanical strength of material due to particle-particle interaction”

• Compaction “It is the compression & consolidation of two phases (solid & gas) system due to applied force”

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Effect of CompressionWhen external mechanical forces applied to

a powder mass there is reduction in bulk volume as follows:

Particles deformation1) Elastic deformation eg. Acetyl salicylic

acid2) Plastic deformation -at yield point of

elastic.

Brittle fracture eg. Sucrose

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Sequence of events involved in formation of tablets

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Compression Stages•Particle rearrangement• Deformation• Fragmentation• Bonding• Decompression• Ejection

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1) Particle Rearrangement•During initial stage of compression

particles are subjected to low pressure during this particles moves with respect to each other.

•Small particles enter voids bet larger particles as a result volume decreases and density increases.

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2) Deformation• Elastic – When force is applied

deformation occurs and deformation disappears when release of stress.

•Plastic – The deformation which doesn’t completely recover after removal of stress.

• Yield strength – Force required to initiate plastic deformation.

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3) Fragmentation•As compression force increases deformed

particles start undergoing fragmentation due to high load particles breaks into smaller fragments leading to formation of new bonding areas.

• Some particles undergo structural break down called as brittle fracture.

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5) DecompressionAs the upper punch is withdrawn from the die the tablet is confined in die cavity by radial pressure consequently any radial change during decompression must occur in axial direction.

4) Bonding • When particles approach each other close

enough the unsatisfied forces present on their surface lead to formation of strong attractive forces/bonding formation of strong attractive forces.

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6) Ejection•As lower punch rises and push tablet

upward there is continuous residual die wall pressure and energy may be expanded due to die wall friction.

• As the tablet is removed from die pressure is released.

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CASE STUDY

A COMPARATIVE EVALUATION OF DIRECT COMPRESSION AND WET GRANULATION METHODS FOR FORMULATION OF STAVUDINE TABLETS.

By Prof. Sunil Kumar Prof. K. P. R. Chowdary Prof. P. Suresh

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ABSTRACT

•The objective of the present study is to make a comparative evaluation of direct compression and wet granulation methods for formulation of stavudine tablets.

• Stavudine is a widely prescribed antiretroviral drug used for treating HIV infections.

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EXPERIMENTAL

Materials:

•Stavudine•Acacia, PVP K30,•Crospovidone, Lactose, Lubritose AN,

Lubritose SD,•Lubritose MCC, Talc and Magnesium

stearate•PGS-MCC, PGSPVP,•Starch phosphate and starch citrate

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Methods:Preparation of Tablets by Direct Compression Method:

•All the materials required as per the formulae were blended in a closed polyethylene bag.

• The blends were compressed into tablets on a tablet punching machine to a hardness of 6 kg/cm sq. using 9 mm concave punches.

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Preparation of Tablets by Wet Granulation Method:

• Drug (stavudine), acacia, PVP K30 and lactose were thoroughly blended in a dry mortar and granulated with water (q.s.). The water (q.s.) was added and mixed thoroughly to form dough mass.

• The mass was passed through mesh No. 12 to obtain wet granules. The wet granules were dried at 600°C for 2 h.

• The dried granules were passed through mesh No. 16 to break the aggregates. Crospovidone and the lubricants (talc and magnesium stearate) were passed through mesh No 100 on to dry granules and blended in a closed polyethylene bag.

• The tablet granules were compressed into tablets on a tablet punching machine to a hardness of 6 kg/cm 2 using 9 mm round and flat punches.

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Evaluation of Tablets:

•All the tablets prepared were evaluated for content of active ingredient, hardness, friability, and disintegration time and dissolution rate.

• Hardness of the tablets was tested using Monsanto Hardness tester.

•Friability of the tablets was determined in a Roche friabilator.

• Disintegration time was determined in a Labindia tablet disintegration test machine (Model: DT 1000) using water as test fluid.

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Estimation of Drug Content in the Tablets

•From each batch of tablets prepared 20 tablets were accurately weighed and powdered.

• Tablet powder equivalent to 50 mg of drug was taken for assay into a 100 ml conical flask and extracted with 3x20 ml quantities of methanol.

•The methanolic extracts were filtered and collected into a 100 ml volumetric flask and the volume was made up to 100 ml with methanol.

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•The solution was then suitably diluted with 0.01 M hydrochloric acid.

•The absorbance of the solution was measured at 266 nm.

•Drug content of the tablets was calculated using the standard calibration curve.

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Dissolution Rate Study:•Dissolution rate of the tablets prepared was

studied employing USP 8 station Dissolution Rate Test Apparatus with a paddle stirrer at 50 rpm. Hydrochloric acid, 0.01 M (900 ml) was used as dissolution fluid as prescribed for stavudine tablets in I.P 2010.

• One tablet was used in each test. A temperature 37±1°C was maintained throughout.

• Samples of dissolution medium (5 ml) were withdrawn through a filter (0.45μ) at different time intervals and assayed for stavudine at 266 nm.

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RESULTS AND DISCUSSION

•Hardness of the tablets was in the range 5. 0–6.5 Kg / sq. cm.

•Weight loss in the friability test was in the range 0.65 – 1.65 %.

• The drug content of the tablets was within 100 ± 3%

•Lubritose MCC, Starch citrate and Starch phosphate gave very rapid disintegration of the tablets within 1 min.

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•Co-processed excipients, PGS-MCC and PGS-PVP also gave rapid disintegration within 2-3 min.

•Lubritose MCC, starch phosphate and starch citrate gave relatively higher dissolution than the others.

•Tablets prepared using PVP as binder gave higher dissolution than those prepared using acacia as binder.

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CONCLUSIONS•Tablets of good quality fulfilling the

official specifications with regard to drug content, hardness, friability and disintegration time could be prepared by both the methods.

•The tablets prepared by direct compression method disintegrated very rapidly when compared to those prepared by wet granulation method.

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•Tablets prepared by direct compression method gave very rapid dissolution of the contained drug, 100% within 20 min.

• In the case of wet granulation method, the tablets gave relatively low dissolution. When compared to those prepared by direct compression method. The dissolution was complete (100%) in 60 min.

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References 1. Pharmaceutics : The Science of Dosage Form Design, edited by

M. E. Aulton, 2nd edition, Churchill Livingstone Publications.2. Eichie, F. E. and Kudehinbu, A. O., Effect of particle size of

granules on some mechanical properties of paracetamol tablets, African Journal of Biotechnology Vol. 8 (21), pp. 5913-5916, 2 November, 2009 Available online at http://www.academicjournals.org/AJB

3. Garett Jonathan Morin, The Effects of Lubrication on Pharmaceutical Granules, 2012

4. Remington : The Science and Practice of Pharmacy, Vol 1, 20th edition, Lippincott Williams and Wilkins, 2001

5. Lachman L., Liberman H. A., Kanig J. L., The Theory and Practice of Pharmacy, 3rd edition, Indian edition, Varghese Publishing House, 1987

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