All about Tablets (Pharma) - Introduction- Excipients- Tablet Manufacturing Process- Solid Dosage Processing- Unit Operations- Processing Problems

1. Tablets
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2. - Introduction
- Excipients
- Tablet Manufacturing Process
- Solid Dosage Processing
- Unit Operations
- Processing Problems
pharmauptoday@gmail.com Contents

3. Introduction
• Tablets are solid dosage forms consisting of
active ingredient(s) and suitable
pharmaceutical excipients.
• They may vary in size, shape, weight,
hardness, thickness, disintegration and
dissolution characteristics, and in other
aspects.
• They may be classyfied, according to the
method of manufacture, as compressed
tablets or molded tablets.

4. Introduction
Advantages Disadvantages
• Production aspect
 Large scale production at lowest cost
 Easiest and cheapest to package and ship
 High stability
• User aspect (doctor, pharmacist, patient)
 Easy to handling
 Lightest and most compact
 Greatest dose precision & least content
variability
• Some drugs resist compression into dense
compacts
• Drugs with poor wetting, slow dissolution,
intermediate to large dosages may be
difficult or impossible to formulate and
manufacture as a tablet that provide
adequate or full drug bioavailability
• Bitter taste drugs, drugs with an
objectionable odor, or sensitive to oxygen
or moisture may require encapsulation or
entrapment prior to compression or the
tablets may require coating

5. Introduction
• The manufacture of oral solid dosage forms such as tablets is a complex multi-stage
process under which the starting materials change their physical
characteristics a number of times before the final dosage form is produced.
• Traditionally, tablets have been made by granulation, a process that imparts two
primary requisites to formulate: compactibility and fluidity.
• Both wet granulation and dry granulation (slugging and roll compaction) are
used.
• Regardless of weather tablets are made by direct compression or granulation,
the first step, milling and mixing, is the same; subsequent step differ.
• Numerous unit processes are involved in making tablets, including particle size
reduction and sizing, blending, granulation, drying, compaction, and (frequently)
coating.

6. Types of Tablets
• Compressed Tablets
• Sugar coated Tablets
• Film coated Tablets
• Enteric coated Tablets
• Effervescent Tablets
• Chewable Tablets
• Dispersible Tablets
• Sustained release Tablets
• Multilayer Tablets
• Sublingual Tablets
• Troches
• Buccal Tablets
• Implant Tablets
• Hypodermic Tablets
• Solution Tablets
• Vaginal Tablets

7. 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.

8. 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)

9. EXCIPIENTS FOR COMPRESSED TABLETS
• Compressed Tablets or Standard compressed Tablets are uncoated tablets made by
compression and intended to provide rapid disintegration and drug release.
• Compressed tablets usually contain a number of pharmaceutical adjuncts, known as
excipients, in addition to the medicinal substance.
• The use of appropriate excipients is important in the development of the optimum tablets.
• Excipients determine the bulk of the final product in dosage forms such as tablet, capsule,
etc., the speed of disintegration, rate of dissolution,release of drug, protection against
moisture, stability during storage, and compatibility.
• Excipients should have no bioactivity, no reaction with the drug substance, no effect on the
functions of other excipients and no support of microbiological growth in the product .

10. EXCIPIENTS FOR COMPRESSED TABLETS
Conventional oral tablets for ingestion usually contain the same classes of components
in addition to the active ingredient, which are one or more agents functioning as
A. Diluents
B. Binders
C. Lubricants
D. Disintegrators
E. Wetting agents

11. A. DILUENTS
Diluents increase the volume to a formulation to prepare tablets of the desired size.
Widely used fillers are lactose, dextrin, microcrystalline cellulose starch, pre-gelatinized
starch, powdered sucrose, and calcium phosphate.
The diluent is selected based on various factors, such as the experience of the
manufacturer in the preparation of other tablets, its cost, and compatibility with
other formulation ingredients. For example, in the preparation of tablets or
capsules of tetracycline antibiotics, a calcium salt should not be used as a diluent
since calcium interferes with absorption of the antibiotics from the GI tract.

12. B. BINDERS
• Binders promote the adhesion of particles of the formulation. Such adhesion enables
preparation of granules and maintains the integrity of the final tablet.
Carboxymethylcellulose, sodium Karaya gum
Cellulose,microcrystalline(Avicel®) Starch, pregelatinized
Ethylcellulose Tragacanth gum
Hydroxypropyl methylcellulose Poly(acrylic acid)
Methylcellulose Polypvinylpyrrolidone
Acacia gum Gelatin
Agar Dextrin
Algin acid Glucose
Guar gum Molasses

13. C. LUBRICANTS
• Lubricant is a substance capable of reducing or preventing friction, heat, and
wear when introduced as a film between solid surfaces. It works by coating on
the surface of particles, and thus preventing adhesion of the tablet material to
the dies and punches.
Glycerylmonostearate(USP/NFCH2(OH)CH(OH)CH2O2CC17H35) is one
example of a lubricant. Lubricants play more than one role in the preparation of
tablets as described below.
• Commonly used lubricants include: talc, magnesium stearate, calcium stearate,
stearic acid, hydrogenated vegetable oils and (PEG).

14. Lubricants play more than one role in the preparation of tablets
1. Lubricants improve the flow of granules in the hopper to the die cavity.
2. Lubricants prevent sticking of tablet formulation to the punches and dies during
formulation.
3. Lubricants reduce the friction between the tablet and the die wall during the
tablet’s ejection from the tablet machine.
4. Lubricants give a sheen to the finished tablets.

15. D. DISINTEGRATORS
• The breakup of the tablets to smaller particles is important for dissolution of the drug & subsequent
bioavailability. Disintegrators promote such breakup. To rupture or breakup of tablets, disintegrating
agents must swell or expand on exposure to aqueous solution. Thus, the most effective
disintegrating agents in most tablet systems are those with the highest water uptake property. In
general, the more hydrophilic, the better disintegrating agents are therefore highly hydrophilic.

16. E. WETTING AGENTS
• Water molecules attract each other equally in all directions. Water molecules on the surface,
however, can only be pulled into the bulk water by water molecules underneath, since there
are no water molecules to pull in the opposite direction. The surface tension of water is
strong enough to support the weight of tiny insects such as water striders.
• The surface tension in action can be visualized by placing a small drop of alcohol on a thin
layer of water. Alcohol with lower surface tension mixes with water causing reduction in the
surface tension in the local region. Owing to the higher surface tension of water in the
neighbor, water is pulled from the alcohol dropped region into the neighbor, and this leads to
the formation of a dry spot in the middle of the water layer.

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

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

19. Flow Chart
API
Filler Mixing of
granulation blend
Preparation of
binder solution
Binder(s) Granulation
Drying
Milling
LOD
Disintegrant
screening
screening Initial Blending
lubricant screening
Final Blending
Compression
Solvent
Film coating agent Preparation
Film Coating of Tablets
Packaging
and Labelling
Weight
Hardness
Friability

20. Manufacturing Methods
WET GRANULATION DRY GRANULATION DIRECT COMPRESSION
Milling/Screening Milling/Screening Milling/Screening
Pre-blending Pre-blending Blending
Addition of binder Slugging/roller compaction Compression
Screening of wet mass Dry screening
Drying of the wet granules Blending of lubricant
Screening of dry granules Compression
Blending of lubricant (and disintegrant)
Compression

21. 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

22. 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

23. 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

24. Product and process functions
• Product function
Product property = F(particle properties, formulation)
• Product property: Content uniformity, dissolution, flowability, dust formation
• Particle Properties: Particle size, particle shape, surface characteristics
• Process function
Particle properties = F(process parameters, raw material/intermediate properties)
• Process parameters: Type of unit operation, operational parameters

25. 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 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)

26. 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.

27. 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.

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

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

30. Unit operations
• Unit Operation
Every separate manufacturing step.
• Unit Dose Operations
Determined by what manufacturing steps are needed to combine the active ingredient
with other needed ingredients to make a quality finished product.
• Type of unit operation
• Dispensing
• Milling/Screening
• Blending
• Granulation
• Drying
• Compression
• Coating
• Packaging

31. Dispensing

32. Dispensing
• One of the most critical steps in pharmaceutical manufacturing
• manual weighing on a weight scale with material lifting assistance like vacuum transfer
and bag lifters
• automated weighing
• Issues:
• dust control (laminar air flow booths, glove boxes)
• weighing accuracy
• multiple lots of active ingredient with different assays, moisture and residual solvent
content
• cross contamination

33. Dispensing
• Dispensing is the first step in any pharmaceutical manufacturing process.
Dispensing is one of the most critical steps in pharmaceutical manufacturing;
• during this step, the weight of each ingredient in the mixture is determined
according to dose.
Issues like:
• weighing accuracy,
• dust control (laminar air flow booths, glove boxes), during manual handling,
• lot control of each ingredient,
• material movement into and out of dispensary should be considered during
dispensing. 33

34. Raw Material Dispensing Record
RM
Code
Ingredient Qty
Kg
AR
No
Gross
Wt.
Tare
Wt.
Net Wt. Weighed by Checked
by
Date
API √ √ √ √ √ √
Exp 1 √ √ √ √ √ √
Exp 2 √ √ √ √ √ √
Exp 3 √ √ √ √ √ √
Exp 4 √ √ √ √ √ √
Exp 5 √ √ √ √ √ √

35. Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg
Sr.
No.
AR No. Total available quantity (as
is basis) (Kg)
(A)
Actual
Assay (%)
(B)
Water
content
(% w/w)
(C)
Equivalent
quantity on 100%
assay and nil
water basis (Kg)
(D)
Equivalent
quantity on as is
basis
(Kg)
(E)
1 AP-18 23.50 99.4 0.34 23.28 23.50
2 AP-22 60.00 99.1 0.50 6.72 6.815
ΣE 30.00 ΣE 30.315

36. Milling/Screening

37. • The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit
operation) involved in the tablet manufacturing.
• In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of
pharmaceuticals is easier and more uniform if the ingredients are approximately of same size.
Advantages associated with size reduction in tablet manufacture are as follows:
i) It increases surface area, which may enhance an actives dissolution rate and hence bioavailability.
ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit
weight.
iii) Improved flow properties of raw materials.
iv) Improved colour and/or active ingredient dispersion in tablet excipients.
37
Particle size reduction

38. Particle size reduction
Disadvantages
• 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

39. 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

40. 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

41. Milling equipment – screen mills
• Screen hole size has largest impact on particle size reduction, milling
time and energy requirements
Milling work index= Particle size reduction / Milling work
• 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

42. 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

43. 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)

44. 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

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

46. 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
 

47. 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


xp  xF exp(kKt)
Attrition
Fragmentation
Size Reduction of α–Lactose Monohydrate in a Ball Mill
Chen et al. (2004), J Pharm Sci, 93(4), 113-132

48. Milling/Screening
• Principle: Mixing or blending is more uniform if ingredients are of similar size
Why do it What are the equipment What are the problems
Possible change in polymorphic
form
An increase in surface area may
promote the adsorption of air -
may inhibit wetting of the drug –
could be the limiting factor in
dissolution rate
Fluid energy mill
Comil
Ball mill
Hammer mill
Cutting mill etc.
Increased surface area - may
enhance rate of dissolution
Improved content uniformity due to
increased number of particles per unit
weight
Enhanced flow properties of raw
materials
Uniformly sized wet granules
promotes uniform drying

49. Manufacturing Instructions
screening
Step Instructions Time
start
Time
end
Performed by Verified
by
Date
1.1 API …… Kg
Exp 1 …… Kg
Pass through # 40 screen of Vibratory
sifter and collect material in tared
double PE lined container
√ √ √ √ √
1.2 Exp 2 …… Kg
Exp 3 …… Kg
Pass through # 20 screen of Vibratory
sifter and collect material in tared
double PE lined container
√ √ √ √ √

50. Blending

51. Powder Blending
• The powder/granules blending are involved at stage of pre granulation and/or
post granulation stage of tablet manufacturing.
• Each process of mixing has optimum mixing time and so prolonged mixing may
result in an undesired product.
• So, the optimum mixing time and mixing speed are to be evaluated. Blending
step prior to compression is normally achieved in a simple tumble blender.
• The various blenders used include blender, Oblicone blender, Container blender,
Tumbling blender, Agitated powder blender, etc.
51

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

53. 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

54. Blending
• Blending is the most difficult operation in the manufacturing process since perfect
homogeneity is practically impossible due to differences in size, shape and density of
particles
Why do it What are the equipment What are the problems
Segregation
Possible over mixing of lubricant
Blend uniformity/ Content uniformity
Diffusion Mixers (V,double cone,
bin,drum blenders)
Convection Mixers (ribbon,
planetary blenders)
Pneumatic Mixers
To achieve optimum mixing of
different ingredients in
powder/granules at pre granulation
and/or post granulation stages of
tablet manufacturing

55. Mixer and blender
55 9/2/2014

56. Granulation

57. Dry Granulation
• The dry granulation process is used to form granules without using a liquid solution
because the product to be granulated may be sensitive to moisture and heat.
• Forming granules without moisture requires compacting and densifying the powders.
• In this process the primary powder particles are aggregated under high pressure.
• Dry granulation can be conducted under two processes; either a large tablet (slug) is
produced in a heavy duty tabletting press or the powder is squeezed between two
rollers to produce a sheet of materials (roller compactor, commonly referred to as a
chilsonator).

58. Dry Granulation
Advantage:
• Avoid exposure of the powder to moisture and heat.
• Used for powders of very low bulk density to ↑ their bulk density.
Disadvantage:
• Tablet disintegration and dissolution may be retarded due to double lubrication
and compaction

59. Steps of Dry Granulation
• The blend of finely divided powders is forced into the dies of a
large capacity tablet press.
• Then, compacted by means of flat faced punches (Compacted
masses are called slugs and the process is slugging) or roll
compactor to produce sticks or sheets.
• Slugs or sheets are then milled/screened to produce granules
(flow more than the original powder mixture).

60. Methods of Dry Granulation
A. Slugging technique
If a tablet press is used for the compaction process, the term slugging is used. But
since particles with a small particle size do not flow well into the die of a tablet press,
the results are weight differences from one tablet (slug) to another.
This in turn causes large fluctuations in the forces applied onto the individual slugs,
with translates in variations of the slug’s mechanical strength. Therefore, the
properties of these granulates obtained by milling the slugs cannot be controlled well
either. This is one of the main reasons why slugging is hardly used any more as a
dry granulation method.

61. Methods of Dry Granulation
B. Roller compaction technique
A Roller compactor generally consist of three major units:
• A feeding system, which conveys the powder to the compaction area between the
rolls
• A compaction unit, where powder is compacted between two counter rotating
rolls to a ribbon by applying a force
• A size reduction unit, for milling the ribbons to the desired particle size.

62. 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

63. Johanson’s theory
Slip Region
Nip Region

64. 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

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

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

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

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

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

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

71. 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

72. 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)

73. Wet Granulation
• In the pharmaceutical industry, granulation refers to the act or process in which
primary powder particles are made to adhere to form larger, multiparticle 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 for the manufacturing of tablets, pellets (or
spheroids).
• The granulation process combines one or more powders and forms a granule that
will allow tableting or spheronization process to be within required limits.

74. Wet Granulation
• Granulation is carried out for various reasons, one of those is to prevent the
segregation of the constituents of powder mix. Segregation is due to differences in
the size or density of the component of the mix.
• Normally, the smaller and/or denser particles tend to concentrate at the base of the
container with the larger and/or less dense ones on the top
• An ideal granulation will contain all the constituents of the mix in the correct
proportion in each granule and segregation of granules will not occur.
• Some powders are difficult to compact even if a readily compactable adhesive is
included in the mix, but granules of the same powders are often more easily
compacted.

75. Wet Granulation
A process of size enlarging a mix of active ingredient and excipient powder particles into stable
aggregates exhibiting desired properties of:
• Compressibility
• Cohesiveness
• Flowability
• Bulk density
Granules may be a final product or an intermediate product that needs further processing

76. Wet Granulation
It involves massing of a mix of dry primary powder particles using a granulating fluid.
• The fluid contain a solvent that must be volatile and non-toxic e.g water, or organic
solvent.
• The granulating solvent may contain a binding agent to ensure particle adhesion
after drying.
• Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used
pharmaceutical binders.
• PVP is dissolved in water or solvent and added to the process.

77. Wet Granulation
Typical liquids include:
1. Water :
• may adversely affect drug stability, causing hydrolysis ,it needs a longer drying time. This
increases the length of the process.
• The advantage :non-flammable and economic.
2. Ethanol, Isopropanol or combination (organic solvents)
• used with water sensitive drugs, alternative to dry granulation or when rapid drying time is
required.

78. Steps of Granule formation
• Agitation of a powder in the presence of
a liquid.
• It forms the granules by binding the
powders together with an adhesive.
• Once the granulating liquid has been
added, mixing continues until uniform
dispersion is attained (15 min. to an
hour).

79. High shear wet granulation
• Advantages
• Improve flow
• Improve uniformity
• Increase bulk density
• Enhance resistance to segregation
Mixer Blade
• Critical parameters
• Amount of binder
• Rate of addition
• Time of granulation
• Speed
Bowl
Chopper Blade
Discharge

80. Wet granulation – monitoring liquid addition
(A) 0.24 ml/g
Impeller Torque for α–Lactose Monohydrate/MCC granulation
Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243
(C) 0.47 ml/g
agglomeration
(B) 0.36 ml/g
nucleation
(D) 0.53 ml/g
agglomerate growth

81. Wet granulation – monitoring liquid addition
(A) 0.24 ml/g
(1 min)
SEM of α–Lactose Monohydrate/MCC granules
(C) 0.47 ml/g
(2 min)
agglomeration
Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243
(B) 0.36 ml/g
(1.5 min)
nucleation
(D) 0.53 ml/g
(2.25 min)
agglomerate growth
bar = 500 μm

82. Granulation
• Principle: A size enlargement process that converts small particles into physically stronger &
larger agglomerates
Why do it What are the equipment What are the problems
Loss of material during various
stages of processing
Multiple processing steps -
validation and control difficult
Incompatibility between formulation
components is aggravated
Dry Granulator (roller compactor,
tabletting machine)
Wet High-Shear Granulator
(horizontal, vertical)
Wet Low-Shear Granulator
(planetary, kneading, screw)
Fluid Bed Granulator, Spray Dry
Granulator, RMG
Provides homogeneity of drug
distribution in blend
Improves flow, compressibility and
hardness of tablets

83. Manufacturing Instructions
blending & granulation
• Mixing SOP No.: Granulation SOP No.:
Step Instructions Time
start
Time
end
Performed
by
Verified
by
Date
2.1 Load material from 1.1 & 1.2 in RMG
Exp 4 ……….Kg
and mix for 5 minutes with following settings:
Impeller speed-fast; Chopper speed-fast
√ √ √ √ √
2.2 Spray purified water into contents of RMG
Impeller speed – fast; Chopper speed - fast
Peristaltic pump atomization press: 0.5-2.5 b Spray
until all purified water is sprayed Ammeter reading
18-22 amps
√ √ √ √ √

84. Manufacturing Instructions
wet milling
• Wet Milling SOP No.:
Step Instructions Time
start
Time
end
Performed by Verified by Date
3.1 Pass wet mass through 1mm screen of
Multi Mill
Speed – fast; Knives - forward
collect in FBD
√ √ √ √ √

85. Recent Advances in Granulation Techniques
• Steam Granulation: Modification of wet granulation; steam is used as
a binder instead of water; granules are more spherical and exhibit
higher rate of dissolution
• Melt Granulation / Thermoplastic Granulation: Granulation is
achieved by the addition of meltable binder i.e. binder is in solid state
at room temperature but melts in the temperature range of 50 – 80˚C
[e.g. PEG (water soluble), stearic acid, cetyl or stearyl alcohol (water
insoluble)] - drying phase unnecessary since dried granules are
obtained by cooling them to room temperature
• Moisture Activated Dry Granulation (MADG): Involves distribution of
moisture to induce agglomeration – drying time is reduced

86. Recent Advances in Granulation Techniques
• Moist Granulation Technique (MGT): A small amount of granulating
fluid is added to activate dry binder and to facilitate agglomeration.
Then a moisture absorbing material like Microcrystalline Cellulose
(MCC) is added to absorb any excess moisture making drying step
unnecessary. Mainly employed for controlled release formulations
• Thermal Adhesion Granulation Process (TAGP): Granules are
prepared by moisturizing excipient mixtures with very little solvent in a
closed system (tumble mixing) with low heating – mainly employed for
preparing direct compression formulations
• Foam Granulation: Binders are added as aqueous foam

87. Drying
Fluid bed dryer Tray dryer

88. Drying
• Drying is a most important step in the formulation and development of
pharmaceutical product.
• It is important to keep the residual moisture low enough to prevent product
deterioration and ensure free flowing properties.
• The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer,
Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc.

89. Drying Process
• A process of evaporating the liquid contained within aggregates produced by
a wet granulation process to a predetermined moisture content
• Accomplished via
1. Tray dryer (direct contact with heating medium)
2. Fluidized bed dryer (indirect contact of the product with the heating medium

90. Drying
• Purpose: To reduce the moisture level of wet granules
Why do it What are the equipment What are the problems
Over drying (bone dry)
Excess fines
Possible fire hazard
Direct Heating Static Solids Bed
Dryers
Direct Heating Moving Solids Bed
Dryers
Fluid Bed Dryer
Indirect Conduction Dryers
To keep the residual moisture low
enough (preferably as a range) to
prevent product deterioration
Ensure free flowing properties

91. Manufacturing Instructions
drying
• Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC)
Time Time end Performed by Verified by Date
start
Step Instructions
√
√
√
√
√
√
√
√
√
√
FBD in let temp 60ºC
Damper 80% open for 15 min
Damper 50% open after 15
minutes ; LOD ……..%
3.2

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

93. Fluid bed drying
• Single machines utilized for both the wet granulation
and drying process in one unit operation.
• Use Fluid Bed Dryer (FBD)
• It is a multiple step process performed in the same
vessel to mix, granulate and dry the powders.
• Combines wetting the powders to for granules &then,
drying them in the same piece of equipment.

94. Advantages of Fluid bed drying
A. Reduced product handling
B. Closed process suitable to:
• Gentle product handling.
• Intensive mixing of the solid material.
• Uniform spraying of all particles in the fluid bed.
• Uniform, reproducible product quality.
• Potent compounds
• Minimizing product/operator exposure
• Minimizing cross contamination and product loss
• Reduced cleaning and overall process time
• Reduced equipment and floor space requirements

95. Tablet Compaction

96. Tablet Compaction
Powders intended for compression into tablets must possess two essential
properties:
1. Powder fluidity
The material can be transported through the hopper into the die to produce
tablets of a consistent weight
Powder flow can be improved mechanically by incorporate the glidant.
2. Powder compressibility
The property of forming a stable, intact compact mass when pressure is
applied.

97. Direct compression
• The term “direct compression” is defined as the process by which tablets are
compressed directly from powder mixture of API and suitable excipients.
• It involves only two unite operations powder mixing and tableting.
Advantages of Direct Compaction:
• Reduced production time &cost.
• Product stability can be improved.
• Faster drug dissolution due to fast disintegration into primary particles.
• less number of equipment are required, less process validation
• Elimination of heat and moisture, thus increasing not only the stability but also the
suitability of the process for thermo-labile and moisture sensitive API’s.
• The chances of batch-to-batch variation are negligible, because the unit operations
required for manufacturing processes is fewer.

98. Direct compression
Disadvantages of Direct Compaction
1. Large particles must be used → (acceptable flowability and bulk density)
2. Many active ingredients are not compressible either in crystalline or amorphous
forms.
3. Needs directly compressible filler that is usually expensive, e.g. microcrystalline
cellulose (Avicel), spray dried lactose
4. Problems in the uniform distribution of low dose drugs.
5. High dose drugs having high bulk volume, poor flowability and poor compressibility
are not suitable for direct compression. For example, Aluminium Hydroxide,
Magnesium Hydroxide
6. Non-uniform distribution of colour, especially in tablets of deep colours

99. Tablet Compression Machine
Design:
1. Hopper for holding and feeding granules or powder to be compressed.
2. Dies that define the size and shape of the tablet.
3. Punches for compressing the granules within the dies.
4. Cam tracks for guiding the movement of the punches.
5. A feeding mechanism for moving granules from the hopper into the dies.

100. Stages of Tablet Formation (Compaction Cycle)
1. Die filling
• Gravitational flow of the powder from hopper via the die table into the die. (The die
is closed at its lower end by the lower punch).
2. Tablet formation
• The upper punch descends, enters the die, the powder is compressed until a tablet
is formed.
• after maximum applied force is reached, the upper punch leaves the powder i.e.
compression phase.
3. Tablet ejection
• The lower punch rises until its tip reaches the level of the top of the die.
• The tablet is subsequently removed from the die and die table by a pushing device.

101. Tableting Process
Powders fed into a die
Powder compressed between punches

102. Tablet Presses
• Single Punch
• Rotary Press
• High Speed Rotary Press
• Multi-layer Rotary Press

103. Single Punch press
Single Punch press (Eccentric Press):
• Bench-top models that make one tablet at a
time (single-station presses)
• Disadvantages: Production of small batches
of tablets (200 tablets per minute).
Core components:
1. Die
2. Lower punch
3. Upper punch

104. Rotary Press
Rotary Press( Multi station Press):
• It was developed to increase the output of tablets (10
000 tablets per minute), used for Large scale
production.
• It consists of a number of dies and sets of punches
(from 3 up to 60).
• The dies are mounted in a circle in the die table and
both the die table & the punches rotate together during
operation of the machine.
Rotary Press machine

105. The core components and compression cycle of rotary presses
A: upper punch
B: die cavity
C: die
D: lower punch
The compression is
applied by both the
upper punch and the
lower punch.
The compression cycle of a rotary tablet press

106. Compression cycle of rotary presses

107. Compression cycle of rotary presses
• Stage 1: Top punch is withdrawn from the die by the upper cam, Bottom punch is low in
the die so powder falls in through the hole and fills the die.
• Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some
powder
• Stage 3: Top punch is driven into the die by upper cam; Bottom punch is raised by lower
cam. Both punch heads pass between heavy rollers to compress the powder.
• Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels
the tablet. Tablet is removed from the die surface by surface plate
• Stage 5: Return to stage 1

108. Tablet tooling; punches and dies

109. Caplet Shape Dies
Oval Shapes Dies
Round Shapes Dies
Star Shapes Dies
Tablet tooling; punches and dies

110. Compression
• Principle: Powder/granules are pressed inside a die and compressed by two punches into
required size, shape and embossing
Why do it What are the equipment What are the problems
Poor flow in hopper
Inadequate lubrication
Capping, chipping, cracking,
lamination, sticking, picking, binding,
mottling
Double compression
Multiple Stations (Rotary) and High
Speed Tablet Presses
To compress powder into tablets

111. Manufacturing Instructions
compression
• Balance no.: Vernier Caliper no.:
• Hardness tester no.: Friability tester no.:
• Disintegration tester no.:
Tooling No. of units Checked by Verified by
Upper punch: …mm x …mm oval shaped concave
55
embossed…….
Lower punch: …mm x …mm oval shaped concave
embossed…….
55
Dies: …mm x ….mm oval shaped 1

112. Manufacturing Instructions
compression
Parameter Limit Results
Machine speed 20 rpm (15-25 rpm)
Wt. of 20 tabs 12.00g +2 (11.76-12.24g)
Theoretical weight/tab 600mg
Hardness 25Kg (20-30 Kg)
Thickness (av. of 10 tabs) 4.10mm +0.15mm (3.95 – 4.25mm)
Length 10mm + 0.1 mm (9.9 – 10.1 mm)
Width 5 mm + 0.1mm (4.9 – 5.1 mm)
Disintegration time NMT 15 mins
Wt. variation + 3% of Av. Wt.
Friability (10 tabs) NMT 1.0% w/w

113. In-process Checks
Parameter Frequency
Wt. of 20 tabs Every hour by production and every two hours by QA
Hardness, thickness, length, width Every hour by production, every two hours by QA
Wt. variation Every half hour by production and every hour by QA
DT Every half hour by production, every hour by QA

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

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

116. Coating

117. Coating
Once a good tablet is made, we often
need to add a coating. The coating can
serve many purposes; it makes the
tablet stronger and tougher, improves
taste, adds color, and makes the tablet
easy to handle and package.

118. Tablet coating
The reasons for tablet coating
• to protect the medicinal agent against destructive exposure to air and/or humidity;
• to mask the taste of the drug;
• to provide special characteristics of drug release;
• to provide aesthetics or distinction to the product;
• to prevent inadvertent contact by non patients with the drug substance

119. Tablet coating
The general methods involved in coating tablets are as follows
1) Sugarcoating tablets
2) Film-coating tablets
3) Enteric coating
4) Pan coating
5) Fluid-bed or air suspension coating
6) Compression coating

120. Tablet coating
The sugarcoating of tablets may be divided into the following steps:
1) Waterproofing and sealing (if needed)
2) Subcoating
3) Smoothing and final rounding
4) Finishing and coloring (if desired)
5) Polishing

121. Tablet coating
1) Waterproofing and sealing (if needed)
Aim: to prevent the components from being adversely affected by moisture; one or more coats;
shellac, zein or a polymer as cellulose acetate phthalate
2) Subcoating
Aim: to bond the sugar coating to the tablet and provide rounding
• 3 to 5 subcoats of a sugar-based syrup are applied. The sucrose and water syrup also contains
gelatin, acacia, or PVP.
• When the tablets are partially dry they are sprinkled with a dusting powder, usually a mixture of
powdered sugar and starch but sometimes talc, acacia, or precipitated chalk as well.
• Then drying the tablets. Repetition (15 to 18 times) the subcoating process until the tablets are of
the desired shape and size.

122. Tablet coating
3) Smoothing and final rounding (Aim: to complete the rounding and smooth the coatings)
5 to 10 additional coatings of a thick syrup; This syrup is sucrose-based with or without additional
components as starch and calcium carbonate.
4) Finishing and coloring (Aim: to attain final smoothness and the appropriate color)
Several coats of a thin syrup containing the desired colorant
5) Imprinting (Aim: to impart identification codes and other distinctive symbols to the product.)
The imprint may be debossed, embossed, engraved, or printed on the surface with ink.
6) Polishing (Aim: to render the tablets the desired sheen/gloss/luster)
a) pans lined with canvas cloth impregnated with carnauba waxand/or beeswax
b) Pieces of wax may be placed in a polishing pan
c) light-spraying of the tablets. with wax dissolved in a nonaqueous solvent

123. Film-coating machine

124. Pan coating
• Benefits
• Mask taste
• Chemical barrier
• Controlled release
• Appearance
Air+Moisture
• Critical Parameters
• Air flow
• Spray
• Drum dynamics
• Rotational speed
• Fill fraction
Dry Air
Rotation
Baffle
Spray Nozzle
Air Flow
Inlet Filter
Inlet Steam
Temperature
Inlet Air
Outlet Air
Outlet Filter
Outlet
Temperature

125. Coating/Polishing
• Principle: Application of coating solution to a moving bed of tablets with concurrent use of
heated air to facilitate evaporation of solvent
Why do it What are the equipment What are the problems
Blistering, chipping, cratering,
picking, pitting
Color variation
Roughness
Pan (standard/perforated) Coating
Machines
Fluidized Bed Coating Machines
Spray Coating Machines
Vacuum, Dip & Electrostatic Coating
Machines
Enhance appearance and colour
Mask taste and odour (film/sugar)
Improve patient compliance
Improve stability
Impart enteric, delayed, controlled
release properties

126. Manufacturing Instructions
coating
Step Instructions Time
start
Time
end
Performed by Verified by Date
6.1 Introduce compressed tablets into Auto
Coater and spray coating solution
Inlet air temp …….ºC (30-60ºC)
Pan speed……..rpm (2-8 rpm)
Solution rate …..ml/min (20-60 ml/min)
Distance of gun from tablet bed……cm
(20-40cm)
√ √ √ √ √

127. Packaging

128. Packaging
• Pharmaceutical manufacturers have to pack their medicines before they can be sent
out for distribution.
• The type of packaging will depend on the formulation of the medicine.
• 'Blister packs' are a common form of packaging used for a wide variety of products.
• They are safe and easy to use and they allow the consumer to see the contents
without opening the pack.

129. Packaging Types
• Primary packaging is the material that first envelops the product and holds it. This
usually is the smallest unit of distribution or use and is the package which is in direct
contact with the contents.
• Secondary packaging is outside the primary packaging – perhaps used to group
primary packages together
• Tertiary packaging is used for bulk handling, warehouse storage and transport
shipping. The most common form is a palletized unit load that packs tightly into
containers.

130. Tablet Defects & Processing Problems

131. Sources of Tablet Defects
• Moisture
• Improper drying
• High speed machines
• Tools setting problem
• Excess use of binders
• Lack of proper lubricant selection
• Air interaction
• Lack of knowledge
• Improper training
• Abnormal ratio of excipients
• Temperature adjustment
• Size, shape

132. Processing Problems
• Binding
• Sticking,
• Picking and Filming
• Capping
• Lamination
• Chipping
• Mottling
• Weight Variation
• Poor flow
• Hardness variation
• Double impression
• Cracking

133. Binding
It is the adhesion of the granules to the die wall and this cause the resistance of the tablet
to eject from the die, it is usually due to insufficient lubrication, which produce tablets with
rough and vertical score marks on the edges.
Can be improved by:
1. Increasing lubrication.
2. Improve lubricant distribution.
3. Increasing the moisture content of the granulation

134. Sticking, Picking & Filming
Adhesion of the material to the punch faces.
Sticking : (whole adhesion)
• is usually due to improperly dried or lubricated granulation
causing the whole tablet surface to stick to the punch faces →
dull, scratched, or rough tablet faces.
Picking : (localized adhesion)
• is a form of sticking in which a small portion of granulation
sticks to the punch face & a portion of the tablet surface is
missed.
Filming: is a slow form of sticking and is largely due to excess
moisture in the granulation

135. Capping & Laminating
Capping occurs when the upper segment of the tablet separates from
the main portion of the tablet & comes off as a cap.
• Can appear immediately after compression, or hours, even days after
preparation.
• It is usually due to air entrapped in the granulation which is
compressed in the die during the compression & then expands when
the pressure is released.
Reasons of capping :
1. large amount of fines in the granulation &/or the lack of sufficient clearance between the punch and
the die wall.
2. In new punches and dies that are tight fitting.
3. Too dry granules
Lamination is due to the same causes as capping except that the tablet splits at the sides into two or
more parts. If tablets laminate only at certain stations, the tooling is usually the cause.

136. Capping & Laminating
Solutions for capping & laminating:
• Increasing the binder.
• Adding dry binder such as gum acacia polyvinylpyrrolidone (PVP).
• Decreasing the upper punch diameter.
• Certain degree of moisture in the granules

137. Mottling
It is an unequal distribution of color on the surface of the tablet.
Cause :
• A drug that differs in color from its excipients or whose degradation products are highly
colored.
• Migration of a dye during drying of a granulation (change the solvent system, reduce
the drying temperature, or grind to a smaller particle size).

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