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Introduction to Solid Dosage Processing
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Stages of pharmaceutical manufacturing
Finished Product API Primary Packaging Secondary Packaging API Excipients Starting Materials (Chemicals)
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Drug product manufacture
API crystallization filtration oven drying Excipients milling blending Direct compression lubrication Wet granulation Dry granulation / milling tableting coating Fluid Bed Dryer Process combines the drug and excipients into the dosage form imprinting Dosage Form
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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
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Solid dosage forms Oral Inhaled Tablets Capsules Powders Aerosol
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
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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),
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Models at different scales
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,
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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)
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Product Quality Factors
Particle properties Product property = F(particle properties, formulation) Potential Impact Processing Behavior Product Quality Factors Property Flow Blending Wetting Drying Mechanical Dissolution Stability Particle Size X Surface Area Particle Shape Surface Energy Bulk Density Pore Size Internal Friction Wall Friction Hygroscopicity Hlinak et al, Journal of Pharmaceutical Innovation, 1 (2006)
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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.
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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.
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Powder flow and tablet weight variations
Hancock, Bruno (2007). Dosage Form Specific Tests. Short course on Material Properties, Purdue University.
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Excipients 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: 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. USP, General Information Chapter <1078>, Good Manufacturing Practices for Bulk Pharmaceutical Excipients
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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)
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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,
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Processing routes Direct Compression Dry Granulation Wet Granulation
Drug Diluent Drug Diluent Glidant Disintegrant Drug Diluent Lubricant Mixing Mixing Mixing Compression Binder Solvent Wetting Comminution Granulation Drying Disintegrant Glidant Lubricant Screening Disintegrant Glidant Lubricant Screening Lubricant Mixing Mixing Fill die Other Routes Tablet Compression Fluidized bed granulation Extrusion / rotary granulation Compress Tablet Coating, Packaging etc..
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Unit operations Process function Type of unit operation
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)
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Unit operations Size reduction (milling) Advantages and disadvantages
Forces in milling Milling equipment (dry milling) Media mills (wet milling) Mill selection Energy requirements
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Particle size reduction
Benefits 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 Disadvantages
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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 Rumpf (1965), Chem Ing Tech, 37(3),
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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),
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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 Milling work index= Particle size reduction / Milling work Byers, Peck (1990), Drug Dev Ind Pharm, 16(11),
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Milling equipment – impact mills
Significant wear on surfaces Hammer mills Medium to coarse size reduction Peripheral speed m/sec Pin mills Peripheral speed up to 200 m/sec Capable of fine grinding Can be used to mill sticky materials
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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)
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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
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Mill selection Wibowo and Ng (1999), AIChE Journal 45 (8)
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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),
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Energy based analysis – ball mill
Kick’s Law High loading Low frequency Rolling attrition Rittinger’s Law Low loading High frequency Impact fragmentation Attrition Fragmentation Size Reduction of α–Lactose Monohydrate in a Ball Mill Chen et al. (2004), J Pharm Sci, 93(4),
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Unit operations Blending Blending equipment Impact of size difference
Radial vs axial mixing
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Blending – diffusion mixing
Critical parameters Blender load Blender speed Blending time V-Blender Cross Flow Blender Bin Blender Double Cone
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Blending – convective mixing
Orbiting Screw Blenders Ribbon Blenders Forberg Blenders Planetary Blenders Vertical High Intensity Mixers Horizontal Double Arm Blenders Horizontal High Intensity Mixers Diffusion Mixers with Intensifier/Agitator
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Size difference and mixing uniformity
Campbell and Bauer (1966), Chem Eng, 73, 179
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Mixing in a bin blender – axial mixing
Composition after 30 revolutions (10rpm, 60%fill, w/o baffle) Sudah et al. (2002), Powder Technology, 126,
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Mixing in a bin blender – radial mixing
Composition after 30 revolutions (10rpm, 60%fill, w/o baffle) Sudah et al. (2002), Powder Technology, 126,
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Unit operations Dry granulation (roll compaction) Wet granulation
Critical parameters Johanson’s theory Feed system Impact of granulation on flow properties Wet granulation Monitoring liquid addition Drying Fluidised bed dryer
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Roll compaction Critical parameters Advantages 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
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Johanson’s theory Slip Region Nip Region
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Johanson’s theory Slip region Nip region Compressibility
Eff. angle of friction Wall angle of friction Yu et al. (2013), Chem Eng Sci, 86, 9-18
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Johanson’s theory – nip angle
Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14),
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Johanson’s theory - stress profile
Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14),
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Eff. angle of friction and peak pressure (Johanson’s theory)
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Eff. angle of friction and nip angle (Johanson’s theory)
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Effect of lubrication on friction properties
Yu et al. (2013), Chem Eng Sci, 86, 9-18
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Effect of lubrication on peak roll pressure
Yu et al. (2013), Chem Eng Sci, 86, 9-18
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Effect of lubrication on nip angle
Yu et al. (2013), Chem Eng Sci, 86, 9-18
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Impact of feed and roll speed on granule properties
Avicel PH 101 Compressibility Mean particle size R R H H Falzone et al. (1992), Drug Dev Ind Pharm, 18(4),
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Impact of feed and roll speed on granule properties
Hydrous Lactose R=4 R=8 Mean particle size V V H H Falzone et al. (1992), Drug Dev Ind Pharm, 18(4),
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Effect of entrained air on feeding and discharging
Johanson (1989), Powder Bulk Eng, Februay, 43-46
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Characterization of flowability
Hausner ratio = tapped density / bulk density Excellent –1.10 Good –1.15 Fair –1.20 Passable –1.25 Poor –1.31 Very Poor –1.37 Extremely Poor –1.45
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Roll compaction and flow properties
Before Compaction (poor) After Compaction (excellent) Soares et al. (2005), Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech
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High shear wet granulation
Mixer Blade Bowl Chopper Blade Discharge Advantages Improve flow Improve uniformity Increase bulk density Enhance resistance to segregation Critical parameters Amount of binder Rate of addition Time of granulation Speed
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Wet granulation – monitoring liquid addition
0.24 ml/g (B) 0.36 ml/g nucleation (C) 0.47 ml/g agglomeration (D) 0.53 ml/g agglomerate growth Impeller Torque for α–Lactose Monohydrate/MCC granulation Jorgensen et al. (2004), J Pharm Sci, 93(9),
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Wet granulation – monitoring liquid addition
0.24 ml/g (1 min) (B) 0.36 ml/g (1.5 min) nucleation (D) 0.53 ml/g (2.25 min) agglomerate growth (C) 0.47 ml/g (2 min) agglomeration bar = 500 μm SEM of α–Lactose Monohydrate/MCC granules Jorgensen et al. (2004), J Pharm Sci, 93(9),
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Fluid bed drying Outlet Outlet Filter Filter Bag From Granulator
Air Flow Inlet Filter Condensor Steam Damper Outlet Filter Product Temperature Inlet Outlet From Granulator To Mill Drying Zone Filter Bag Retaining Screein
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Unit operations Tablet compaction Coating
Relative density and compaction pressure Coating Objectives Critical parameters
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Rotary tablet press
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Relative density changes in manufacture of tablets
Hancock et al. (2004), Pharm Tech, April 2003, 64-80
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Equivalence of tablets made with different presses
Hancock et al. (2004), Pharm Tech, April 2003, 64-80
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Pan coating Dry Air Rotation Baffle Spray Nozzle Air+Moisture Benefits
Air Flow Inlet Filter Steam Inlet Temperature Inlet Air Outlet Air Outlet Filter Outlet Air+Moisture Benefits Mask taste Chemical barrier Controlled release Appearance Critical Parameters Air flow Spray Drum dynamics Rotational speed Fill fraction
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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).
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