This document discusses various aspects of solid dosage processing including: 1) The key stages involve starting materials, processing the active pharmaceutical ingredient and excipients, primary packaging, and secondary packaging to produce the finished dosage form. 2) Processing combines the drug and excipients through various unit operations like wet granulation, blending, drying, and tableting to form the solid dosage. 3) Particle properties are important for processing behavior and product quality, and are influenced by process parameters and the properties of raw materials. Proper selection of unit operations and process conditions can achieve the desired particle properties and product performance.

1. Introduction to Solid Dosage
Processing

2. Stages of pharmaceutical manufacturing
API
Excipients
Primary
Packaging
Secondary
Packaging
API Finished
Product
Starting Materials
(Chemicals)

3. Drug product manufacture
Dosage Form
Wet
granulation
milling
blending
Fluid Bed Dryer
lubrication
tableting
coating
imprinting
Process combines the drug and
excipients into the dosage form
Excipients
API
crystallization
filtration
oven drying
Dry granulation
/ milling
Direct
compression

4. 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

5. 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

6. 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

7. 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

8. 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)

9. 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)

10. 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.

11. 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.

12. Powder flow and tablet weight variations
Hancock, Bruno (2007). Dosage Form Specific Tests. Short course on Material Properties, Purdue University.

13. 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

14. 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)

15. 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

16. Processing routes
Fill die
Coating, Packaging etc..
Compress Tablet
Direct Compression
Drug
Diluent
Glidant
Disintegrant
Lubricant Mixing
Mixing
Dry Granulation
Disintegrant
Glidant
Lubricant
Drug
Diluent
Lubricant
Mixing
Compression
Comminution
Screening
Mixing
Mixing
Wetting
Granulation
Drying
Screening
Mixing
Drug
Diluent
Binder
Solvent
Disintegrant
Glidant
Lubricant
Wet Granulation
Other Routes
Fluidized bed granulation
Extrusion / rotary granulation
Tablet
Compression

17. 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)

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

19. 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

20. 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
Y
T
c


Rumpf (1965), Chem Ing Tech, 37(3), 187-202

21. 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

22. 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

23. 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

24. 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)

25. 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

26. Mill selection
Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648

27. 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 1
P
R R
P F
m t
E C
W x x
 
  
 
 
ln
P F
K K
P
m t x
E C
W x
 
   
 

28. Energy based analysis – ball mill
Kick’s Law
High loading
Low frequency
Rolling attrition
Rittinger’s Law
Low loading
High frequency
Impact fragmentation
1
F
P
R
x
x
k t


exp( )
p F K
x 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

29. Unit operations
• Blending
 Blending equipment
 Impact of size difference
 Radial vs axial mixing

30. Blending – diffusion mixing
• Critical parameters
 Blender load
 Blender speed
 Blending time V-Blender
Cross Flow
Blender
Bin Blender
Double Cone
Blender

31. Blending – convective mixing
Ribbon Blenders Orbiting Screw Blenders
Planetary Blenders
Horizontal Double Arm Blenders
Forberg Blenders
Vertical High Intensity Mixers
Horizontal High Intensity Mixers
Diffusion Mixers with Intensifier/Agitator

32. Size difference and mixing uniformity
Campbell and Bauer (1966), Chem Eng, 73, 179

33. 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)

34. 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)

35. 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

36. 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

37. Johanson’s theory
Slip Region
Nip Region

38. 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

39. Johanson’s theory – nip angle
Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

40. Johanson’s theory - stress profile
Bindhumadhavan et al. (2005), Chem Eng Sci, 60(14), 3891-3897

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

42. Eff. angle of friction and nip angle
(Johanson’s theory)
Eff. Angle of
Friction
Nip Angle

43. Effect of lubrication on friction properties
Yu et al. (2013), Chem Eng Sci, 86, 9-18

44. Effect of lubrication on peak roll pressure
Yu et al. (2013), Chem Eng Sci, 86, 9-18

45. Effect of lubrication on nip angle
Yu et al. (2013), Chem Eng Sci, 86, 9-18

46. 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
H
H
R
R

47. Impact of feed and roll speed on granule properties
Mean particle
size
Hydrous Lactose
H
H
Falzone et al. (1992), Drug Dev Ind Pharm, 18(4), 469-489
V
V
R=4 R=8

48. Effect of entrained air on feeding and discharging
Johanson (1989), Powder Bulk Eng, Februay, 43-46

49. 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

50. 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)

51. 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

52. 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

53. 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

54. Fluid bed drying
Air Flow
Inlet Filter
Condensor
Steam
Damper
Damper Outlet Filter
Air Flow
Product
Temperature
Inlet
Temperature
Outlet
Temperature
From
Granulator
To Mill
Drying Zone
Filter Bag
Air Flow
Retaining
Screein

55. Unit operations
• Tablet compaction
 Relative density and compaction pressure
• Coating
 Objectives
 Critical parameters

56. Rotary tablet press

57. Relative density changes in manufacture of tablets
Hancock et al. (2004), Pharm Tech, April 2003, 64-80

58. Equivalence of tablets made with different presses
Hancock et al. (2004), Pharm Tech, April 2003, 64-80

59. 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 Filter
Steam
Inlet
Temperature
Inlet Air
Outlet Air
Outlet Filter
Outlet
Temperature

60. 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).