Introduction to Solid Dosage Processing

Stages of pharmaceutical manufacturing

API

Excipients

PrimaryPackaging

SecondaryPackaging

API FinishedProduct

Starting Materials(Chemicals)

Drug product manufacture

Dosage Form

Wetgranulation

milling

blending

Fluid Bed Dryer

lubrication

tabletingcoating

imprintingProcess combines the drug and excipients into the dosage form

ExcipientsAPI

crystallization

filtration

oven drying

Dry granulation/ milling

Directcompression

Solid dosage processing• Dosage forms

Quality factors

• Excipients• Particle properties• Processing routes• Unit operations

Size reduction (milling) Blending Dry granulation (roll compaction) Wet granulation Drying Tablet compaction Coating

Solid dosage forms

• Oral Tablets

• Lozenges• Chewable tablets• Effervescent tablets• Multi-layer tablets• Modified release

Capsules• Hard gelatin• Soft gelatin

Powders

• Inhaled Aerosol

• Metered dose inhalers• Dry powder inhalers

Singh, Naini (2002), Dosage Forms: Non-Parenteral, Encyclopedia of Pharmaceutical Technology

Quality factors for solid dosage forms

Functional quality factors

-Disintegrates to desired size quickly-The constituent particle size of the dosage form should dissolve and be absorbed in the GI tract at a pre-determined rate

Physical quality factors

-Must not break up on processing, packaging, transportation, dispensing or handling-Surface of tablet or capsule must be free of defects-Must be stable under anticipated environmental conditions-Have the same weight and composition for each tablet or capsule

Sensorial quality factors

-Easy and pleasant to swallow

Fung and Ng (2003), AIChE Journal, 49(5), 1193-1215

Models at different scales

Scale Subject Problems

Enterprise Business process Sourcing, contract manufacturing, capacity planning

Plant Process synthesis, simulation, development

Generation of process alternatives, process optimization

Equipment Equipment selection, performance, sizing, costing

Mixing, classification, granulation, milling

Continuum Flow and handling of powders Granular flow

Particle Particle attributes: composition, size distribution, density, strength, shape

Interparticle forces, breakage

Molecule Enantiomers and polymorphs, material properties

Polymorph prediction, prediction of physical and chemical properties

Ng (2002), Powder Technology, 126, 205-210

Product and process functions

• Product function

Product property: Content uniformity, dissolution, flowability, dust formation

Particle Properties: Particle size, particle shape, surface characteristics

• Process function

Process parameters: Type of unit operation, operational parameters

Product property = F(particle properties, formulation)

Particle properties = F(process parameters, raw material/intermediate properties)

Particle properties

Potential Impact Processing Behavior

Product Quality Factors

Property Flow Blending Wetting Drying Mechanical Dissolution Stability

Particle Size X X X X X X X

Surface Area X X X X X X X

Particle Shape X

Surface Energy X X X

Bulk Density X X X

Pore Size X X X

Internal Friction X X

Wall Friction X X

Hygroscopicity X X X

Hlinak et al, Journal of Pharmaceutical Innovation, 1 (2006)

Product property = F(particle properties, formulation)

Mean particle size and flowability

Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan.

Size distributions for various powders

Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan.

Powder flow and tablet weight variations

Hancock, Bruno (2007). Dosage Form Specific Tests. Short course on Material Properties, Purdue University.

Excipients

• To aid in the processing of the drug delivery system during its manufacture;

• To protect, support, or enhance stability, bioavailability or patient acceptability;

• To assist in product identification;• To enhance any other attribute of the overall safety, effectiveness,

or delivery of the drug during storage or use.

Excipients are substances, other than the active drug substance, or finished dosage form, that have been appropriately evaluated for safety and are included in drug delivery systems:

USP, General Information Chapter <1078>, Good Manufacturing Practices for Bulk Pharmaceutical Excipients

Excipient functions

Component Function Examples

Fillers Increase size and weight of final dosage form

Microcrystalline cellulose, sucrose

Binders Promote particle aggregation Pregelatinized starch, hydroxypropyl methylcellulose

Disintegrants Promote break down of aggregates Sodium starch glycolate

Flow Aids Reduce interaction between particles Talc

Lubricants Reduce interactions between particles and surfaces of processing equipment

Magnesium stearate

Surfactants Promotes wetting Sodium lauryl sulfate, Polysorbate

Modified Release Agents

Influences the release of active Hydroxypropyl methylcellulose, Surelease,

Hlinak (2005)

Most popular excipients• Magnesium stearate (lubricant)• Lactose (compression aid)• Microcrystalline cellulose

(compression aid)• Starch (corn) (compression aid)• Silicon dioxide (glidant)• Stearic acid (lubricant)• Sodium starch glycollate (disintegrant)• Gelatin (binder)• Talc (film coating adjuvant, glidant)• Sucrose (sweetener, coating)• Calcium stearate (lubricant)

• Povidone (binder)• Pre-gelatinized starch (binder)• Hydroxypropylmethylcellulose (film

coating, binder)• OPA products (film coats and dyes)• Crosscarmelose sodium (disintegrant)• Hydroxypropylcellulose (binder, film

coating)• Ethylcellulose (enteric coating)• Dibasic calcium phosphate

(compression aid)• Crospovidone (disintegrant)• Shellac and Glaze (coating agent)

International pharmaceutical excipients council of the americas, http://www.ipecamericas.org/public/faqs.html

Processing routes

Fill die

Coating, Packaging etc..

Compress Tablet

Direct Compression

DrugDiluentGlidantDisintegrant

Lubricant

Dry Granulation

Disintegrant GlidantLubricant

DrugDiluentLubricant

Mixing

Compression

Comminution

Screening

Mixing

Mixing

Wetting

Granulation

Drying

Screening

Mixing

DrugDiluent

BinderSolvent

Disintegrant GlidantLubricant

Wet Granulation

Other Routes

Fluidized bed granulationExtrusion / rotary granulation

Tablet Compression

Unit operations

• Process function

Process parameters: Type of unit operation, operational parameters

• Type of unit operation Size reduction (Milling) Blending Dry granulation (Roll compaction) Wet granulation Drying Tablet compression Coating

Particle properties = F(process parameters, feed/intermediate properties)

Unit operations

• Size reduction (milling) Advantages and disadvantages Forces in milling Milling equipment (dry milling) Media mills (wet milling) Mill selection Energy requirements

Particle size reduction

• Mixing is more uniform if ingredients are roughly the same size• Milling of wet granules can promote uniform and efficient drying• Increased surface area can improve dissolution rate and

bioavailablity• Improved content uniformity of dosage units

• Excessive heat generation can lead to degradation, change in polymorphic form

• Increase in surface energy can lead to agglomeration• May result in excessive production of fines or overly broad particle

size distribution

Benefits

Disadvantages

Forces in milling

• Shear (cutting forces)• Compression (crushing

forces)• Impact (high velocity

collision)

Griffith theory• T = Tensile stress• Y = Young’s modulus• ε = Surface energy• c = fault length

YT

c

Rumpf (1965), Chem Ing Tech, 37(3), 187-202

Milling equipment – screen mills

• Critical parameters for a conical screen mill Screen Hole Size/Shape Impeller Type Impeller Clearance Speed

• Evaluate impact on aspirin granulation Particle size reduction Milling time and energy requirements Overall milling performance

• Milling Work Index = Size reduction / Milling work• Milling Time Index = Size reduction / Milling time

Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779

Milling equipment – screen mills

• Screen hole size has largest impact on particle size reduction, milling time and energy requirements

• Milling work index significantly lower for smaller screen hole sizes

• Impeller type has largest effect on overall milling performance

• Impeller clearance not significant at small clearances• Milling work index lower at higher mill speeds

Deflection of material away from screens

Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779

Milling work index= Particle size reduction / Milling work

Milling equipment – impact mills

• Significant wear on surfaces

• Hammer mills Medium to coarse size reduction Peripheral speed 20-50 m/sec

• Pin mills Peripheral speed up to 200 m/sec Capable of fine grinding Can be used to mill sticky materials

Milling equipment – jet mill

• Superfine to colloid size reduction• Can be used for heat sensitive products• Different configurations

Pancake (spiral) jet mill• Fines exit from center

Loop/oval jet mill• Fines exit from top

Opposing jet mills• Particles impact each other in opposing jets

Fluidized bed jet mill• Particles are jetted towards center (low wear on equipment)

Fixed/moving target jet mills• Particles impact on surface of target (wear can be significant)

Milling equipment – stirred media mill

• Critical parameters Agitator speed Feed rate Size of beads Bead charge Density of beads Design of blades Mill chamber Residence time

Mill selection

Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648

Energy based analysis – ball mill

• Macroscale energy-size relationships (Chen et al., 2004) Calculate specific energy for a given size reduction Functional form derived from theoretical considerations Rittinger’s model

• Energy required for particle size reduction is proportional to the area of new surface created

Kick’s model• Energy required to break a particle is proportional to the ratio of the particle

volume before reduction to the volume after reduction

Chen et al. (2004), J Pharm Sci, 93(4), 113-132

1 1PR R

P F

m tE C

W x x

lnP FK K

P

m t xE C

W x

Energy based analysis – ball millKick’s LawHigh loadingLow frequencyRolling attrition

Rittinger’s LawLow loadingHigh frequencyImpact fragmentation

1F

PR

xx

k t

exp( )p F Kx x k t

Attrition

Fragmentation

Size Reduction of α–Lactose Monohydrate in a Ball Mill

Chen et al. (2004), J Pharm Sci, 93(4), 113-132

Unit operations

• Blending Blending equipment Impact of size difference Radial vs axial mixing

Blending – diffusion mixing

• Critical parameters Blender load Blender speed Blending time V-Blender

Cross FlowBlender

Bin Blender

Double ConeBlender

Blending – convective mixingRibbon Blenders Orbiting Screw Blenders

Planetary Blenders

Horizontal Double Arm Blenders

Forberg Blenders

Vertical High Intensity Mixers

Horizontal High Intensity MixersDiffusion Mixers with Intensifier/Agitator

Size difference and mixing uniformity

Campbell and Bauer (1966), Chem Eng, 73, 179

Mixing in a bin blender – axial mixing

Sudah et al. (2002), Powder Technology, 126, 191-200

Composition after 30 revolutions (10rpm, 60%fill, w/o baffle)

Mixing in a bin blender – radial mixing

Sudah et al. (2002), Powder Technology, 126, 191-200

Composition after 30 revolutions (10rpm, 60%fill, w/o baffle)

Unit operations

• Dry granulation (roll compaction) Critical parameters Johanson’s theory Feed system Impact of granulation on flow properties

• Wet granulation Monitoring liquid addition

• Drying Fluidised bed dryer

Roll compaction

• Critical parameters Roll speed and pressure Horizontal and vertical

feed speed, deaeration Roll diameter and

surface

• Advantages Improve powder flow Reduce segregation

potential No moisture addition,

drying

Johanson’s theory

Slip Region

Nip Region

Johanson’s theory

Slip region

Nip region

Yu et al. (2013), Chem Eng Sci, 86, 9-18

Compressibility

Eff. angle of friction Wall angle of friction

Johanson’s theory – nip angle

Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

Johanson’s theory - stress profile

Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

Eff. angle of friction and peak pressure (Johanson’s theory)

Eff. Angle of Friction

Eff. angle of friction and nip angle (Johanson’s theory)

Eff. Angle of Friction

Nip Angle

Effect of lubrication on friction properties

Yu et al. (2013), Chem Eng Sci, 86, 9-18

Effect of lubrication on peak roll pressure

Yu et al. (2013), Chem Eng Sci, 86, 9-18

Effect of lubrication on nip angle

Yu et al. (2013), Chem Eng Sci, 86, 9-18

Falzone et al. (1992), Drug Dev Ind Pharm, 18(4), 469-489

Avicel PH 101

Compressibility Mean particle size

Impact of feed and roll speed on granule properties

HH

RR

Impact of feed and roll speed on granule properties

Mean particle size

Hydrous Lactose

HH

Falzone et al. (1992), Drug Dev Ind Pharm, 18(4), 469-489

VV

R=4 R=8

Effect of entrained air on feeding and discharging

Johanson (1989), Powder Bulk Eng, Februay, 43-46

Characterization of flowability

• Hausner ratio = tapped density / bulk density Excellent 1.05–1.10 Good 1.11–1.15 Fair 1.15–1.20 Passable 1.21–1.25 Poor 1.26–1.31 Very Poor 1.32–1.37 Extremely Poor 1.38–1.45

Roll compaction and flow properties

Soares et al. (2005), Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech

Before Compaction (poor)

After Compaction (excellent)

High shear wet granulation

• Advantages Improve flow Improve uniformity Increase bulk density Enhance resistance to

segregation

• Critical parameters Amount of binder Rate of addition Time of granulation Speed

Mixer Blade

Bowl

Chopper Blade

Discharge

Wet granulation – monitoring liquid addition

Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243

(A) 0.24 ml/g

Impeller Torque for α–Lactose Monohydrate/MCC granulation

(C) 0.47 ml/g agglomeration

(B) 0.36 ml/g nucleation

(D) 0.53 ml/g agglomerate growth

Wet granulation – monitoring liquid addition

Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243

(A) 0.24 ml/g (1 min)

SEM of α–Lactose Monohydrate/MCC granules

(C) 0.47 ml/g (2 min) agglomeration

(B) 0.36 ml/g (1.5 min) nucleation

(D) 0.53 ml/g (2.25 min) agglomerate growth

bar = 500 μm

Fluid bed drying

Air Flow

Inlet FilterCondensorSteamDamper

Damper Outlet Filter

Air Flow

ProductTemperature

InletTemperature

OutletTemperature

From Granulator

To Mill

Drying Zone

Filter Bag

Air Flow

RetainingScreein

Unit operations

• Tablet compaction Relative density and compaction pressure

• Coating Objectives Critical parameters

Rotary tablet press

Relative density changes in manufacture of tablets

Hancock et al. (2004), Pharm Tech, April 2003, 64-80

Equivalence of tablets made with different presses

Hancock et al. (2004), Pharm Tech, April 2003, 64-80

Pan coating

• Benefits Mask taste Chemical barrier Controlled release Appearance

• Critical Parameters Air flow Spray Drum dynamics

• Rotational speed• Fill fraction

Air+Moisture

Dry Air

Rotation

Baffle

Spray Nozzle

Air Flow

Inlet FilterSteamInlet

Temperature

Inlet Air

Outlet AirOutlet Filter

OutletTemperature

References

• Theory and Practice of Industrial Pharmacy, L. Lachman et al. (eds) (1986).

• Handbook of Pharmaceutical Granulation Technology, D. M. Parikh (ed), Marcel Dekker (1997).

• Pharmaceutical Dosage Forms: Tablets, vol 2, Marcel Dekker (1990).

• Encyclopedia of Pharmaceutical Technology, Marcel Dekker (2003).

• Perry’s Chemical Engineers Handbook, 7th Ed., McGraw Hill (1997).