Tablets

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- Introduction
- Excipients
- Tablet Manufacturing Process
- Solid Dosage Processing
- Unit Operations
- Processing Problems

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 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.
 Introduction

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

Compressed Tablets Multilayer Tablets

Sugar coated Tablets Sublingual Tablets

Film coated Tablets Troches

Enteric coated Tablets Buccal Tablets

Effervescent Tablets Implant Tablets

Chewable Tablets Hypodermic Tablets

Dispersible Tablets Solution Tablets

Sustained release Tablets Vaginal Tablets

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.
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 Magnesium stearate
of processing equipment
Surfactants Promotes wetting Sodium lauryl sulfate,
Polysorbate
Modified Release Influences the release of active Hydroxypropyl methylcellulose,
Agents Surelease,

Hlinak (2005)
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 .
 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
 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.
 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
 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).
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
tablets ejection from the tablet machine.

4. Lubricants give a sheen to the finished tablets.

 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.
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.
 Stages of pharmaceutical manufacturing

API Finished
Product

Primary Secondary
API Packaging Packaging

Excipients

Starting Materials
(Chemicals)
 Drug product manufacture
API
Excipients milling

oven drying
blending crystallization

filtration

Direct
compression
lubrication
Wet
granulation Dry granulation
/ milling tableting
coating

Fluid Bed Dryer

Process combines the drug and excipients imprinting

into the dosage form Dosage Form
Flow Chart
API
Filler screening Mixing of
granulation blend

Preparation of Granulation
Binder(s) binder solution

Drying LOD

Milling

Disintegrant screening Initial Blending

lubricant screening
Final Blending

Weight
Compression Hardness
Friability

Film Coating of Tablets

Solvent
Preparation Packaging
Film coating agent
and Labelling
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
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
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, Mixing, classification, granulation, milling
costing

Continuum Flow and handling of powders Granular flow

Particle Particle attributes: composition, size Interparticle forces, breakage
distribution, density, strength, shape

Molecule Enantiomers and polymorphs, material Polymorph prediction, prediction of physical

properties and chemical properties

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

 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

 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)

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.
 Processing routes
Direct Compression Dry Granulation Wet Granulation
Drug
Drug Mixing Drug Mixing Mixing
Diluent
Diluent Diluent
Glidant Lubricant Compression Binder Wetting
Disintegrant
Solvent
Comminution Granulation

Drying
Disintegrant Screening Disintegrant Screening
Glidant Glidant
Lubricant Mixing Lubricant Mixing Lubricant Mixing

Fill die
Tablet Other Routes
Compression
Fluidized bed granulation
Compress Tablet
Extrusion / rotary granulation

Coating, Packaging etc..

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
Dispensing
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
 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

33
dispensing.
Raw Material Dispensing Record

RM Ingredient Qty AR Gross Tare Net Wt. Weighed by Checked Date

Code Kg No Wt. Wt. by
API

Exp 1

Exp 2

Exp 3

Exp 4

Exp 5
Considerations

Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg

Sr. AR No. Total available quantity (as Actual Water Equivalent Equivalent
No. is basis) (Kg) Assay (%) content quantity on 100% quantity on as is
assay and nil basis
(A) (B) (% w/w) water basis (Kg)
(Kg)
(C) (D)
(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

E 30.00 E 30.315
Milling/Screening
 Particle size reduction
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

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
 Forces in milling

Shear (cutting forces)

Compression (crushing forces)

Impact (high velocity collision)

Y
T
c

Griffith theory

T = Tensile stress
Rumpf (1965), Chem Ing Tech, 37(3), 187-202
Y = Youngs modulus

= Surface energy

c = fault length
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= 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
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
Rittingers model
Energy required for particle size reduction is proportional to the area of new surface created

mP t 1 1
ER CR
W xP xF
Kicks model
Energy required to break a particle is proportional to the ratio of the particle volume before reduction
to the volume after reduction
mP t x
EK CK ln F
W xP
Chen et al. (2004), J Pharm Sci, 93(4), 113-132
Energy based analysis ball mill
Kicks Law Attrition
High loading
Low frequency
Rolling attrition

x p xF exp( k K t )

Rittingers Law xP
xF
Low loading 1 kRt
High frequency
Impact fragmentation

Fragmentation

Size Reduction of Lactose Monohydrate in a Ball Mill

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

Increased surface area - may Fluid energy mill Possible change in polymorphic
enhance rate of dissolution form
Comil
Improved content uniformity due to An increase in surface area may
increased number of particles per unit Ball mill promote the adsorption of air -
weight may inhibit wetting of the drug
Hammer mill could be the limiting factor in
Enhanced flow properties of raw dissolution rate
materials Cutting mill etc.

Uniformly sized wet granules

promotes uniform drying
Manufacturing Instructions
screening
Step Instructions Time Time Performed by Verified Date
start end by
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
Blending
 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
Blending diffusion mixing

Critical parameters
Blender load

Blender speed
Blending time V-Blender Bin Blender

Cross Flow Double Cone

Blender Blender
Blending convective mixing
Ribbon Blenders Orbiting Screw Blenders

Forberg Blenders

Planetary Blenders

Vertical High Intensity Mixers

Horizontal Double Arm Blenders

Horizontal High Intensity Mixers

Diffusion Mixers with Intensifier/Agitator
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

To achieve optimum mixing of Diffusion Mixers (V,double cone, Segregation

different ingredients in bin,drum blenders)
powder/granules at pre granulation Possible over mixing of lubricant
and/or post granulation stages of Convection Mixers (ribbon,
tablet manufacturing planetary blenders) Blend uniformity/ Content uniformity

Pneumatic Mixers
 Mixer and blender

55 9/2/2014
Granulation
 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).
 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
 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).
 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 slugs 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.
 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.
 Roll compaction

Critical parameters Advantages

Roll speed and pressure
Horizontal and vertical feed speed,
deaeration
Roll diameter and surface
Improve powder flow
Reduce segregation potential
No moisture addition, drying
Johansons theory

Slip Region

Nip Region
 Johansons theory

Slip region

Nip region

Compressibility

Eff. angle of friction Wall angle of friction

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

Eff. angle of friction and peak pressure (Johansons
theory)

Eff. Angle of
Friction
Eff. angle of friction and nip angle (Johansons theory)

Nip Angle

Eff. Angle of Friction

 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

 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 1.051.10
Good 1.111.15
Fair 1.151.20
Passable 1.211.25
Poor 1.261.31
Very Poor 1.321.37
Extremely Poor 1.381.45
 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
 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.
 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.
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
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.

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.
 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).
 High shear wet granulation

Chopper Blade

Mixer Blade

Bowl Discharge

Advantages Critical parameters

Improve flow Amount of binder

Improve uniformity Rate of addition

Increase bulk density Time of granulation

Enhance resistance to segregation Speed

 Wet granulation monitoring liquid addition

(A) 0.24 ml/g (B) 0.36 ml/g (C) 0.47 ml/g (D) 0.53 ml/g
nucleation agglomeration agglomerate growth

Impeller Torque for Lactose Monohydrate/MCC granulation

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

 Wet granulation monitoring liquid addition

(A) 0.24 ml/g (B) 0.36 ml/g

(1 min) (1.5 min)
nucleation

(D) 0.53 ml/g

(C) 0.47 ml/g (2.25 min)
(2 min) agglomerate growth
agglomeration

bar = 500 m
SEM of Lactose Monohydrate/MCC granules

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

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

Provides homogeneity of drug Dry Granulator (roller compactor, Loss of material during various
distribution in blend tabletting machine) stages of processing

Improves flow, compressibility and Wet High-Shear Granulator Multiple processing steps -
hardness of tablets (horizontal, vertical) validation and control difficult

Wet Low-Shear Granulator Incompatibility between formulation

(planetary, kneading, screw) components is aggravated

Fluid Bed Granulator, Spray Dry

Granulator, RMG
Manufacturing Instructions
blending & granulation
Mixing SOP No.: Granulation SOP No.:
Step Instructions Time Time Performed Verified Date
start end by by
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
Manufacturing Instructions
wet milling

Wet Milling SOP No.:

Step Instructions Time Time Performed by Verified by Date

start end
3.1 Pass wet mass through 1mm screen of
Multi Mill

Speed fast; Knives - forward

collect in FBD
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 80C
[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
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

 Fluid bed dryer Tray dryer

Drying
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.
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
Drying

Purpose: To reduce the moisture level of wet granules

Why do it What are the equipment What are the problems

To keep the residual moisture low
enough (preferably as a range) to
prevent product deterioration
Ensure free flowing properties
Direct Heating Static Solids Bed
Dryers
Direct Heating Moving Solids Bed
Dryers
Over drying (bone dry)
Excess fines
Possible fire hazard

Fluid Bed Dryer

Indirect Conduction Dryers

Manufacturing Instructions
drying
Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105C)

Step Instructions Time Time end Performed by Verified by Date

start

3.2 FBD in let temp 60C

Damper 80% open for 15 min

Damper 50% open after 15

minutes ; LOD ..%
 Fluid bed drying

Damper Outlet Outlet Filter

Temperature

From Filter Bag Air Flow

Granulator
Drying Zone

Air Flow Product

Temperature Air Flow
Retaining
Screein
Damper Inlet Steam Condensor Inlet Filter
To Mill Temperature
 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.
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
Tablet Compaction
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.
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 APIs.
The chances of batch-to-batch variation are negligible, because the unit operations
required for manufacturing processes is fewer.
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
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.
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.
Tableting Process

Powders fed into a die

Powder compressed between punches
Tablet Presses

Single Punch

Rotary Press

High Speed Rotary Press

Multi-layer Rotary Press

 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
 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

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

Compression cycle of rotary presses
 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

Tablet tooling; punches and dies
Tablet tooling; punches and dies

Caplet Shape Dies Star Shapes Dies

Oval Shapes Dies

Round Shapes Dies

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

To compress powder into tablets Multiple Stations (Rotary) and High Poor flow in hopper
Speed Tablet Presses
Inadequate lubrication

Capping, chipping, cracking,

lamination, sticking, picking, binding,
mottling

Double compression
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 55

embossed.

Dies: mm x .mm oval shaped 1

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
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

 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

Coating
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.
 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

 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
 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
 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.
 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
Film-coating machine
 Pan coating
Rotation Spray Nozzle
Outlet
Outlet Air
Temperature
Dry Air
Outlet Filter

Air Flow

Inlet Air Baffle

Inlet Steam
Temperature
Inlet Filter

Air+Moisture
Benefits Critical Parameters
Mask taste Air flow
Chemical barrier Spray
Controlled release Drum dynamics
Appearance Rotational speed
Fill fraction
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

Enhance appearance and colour
Mask taste and odour (film/sugar)
Improve patient compliance
Improve stability
Impart enteric, delayed, controlled
release properties
Pan (standard/perforated) Coating Blistering, chipping, cratering,
Machines picking, pitting
Fluidized Bed Coating Machines Color variation
Spray Coating Machines Roughness
Vacuum, Dip & Electrostatic Coating
Machines
Manufacturing Instructions
coating
Step Instructions Time Time Performed by Verified by Date
start end

6.1 Introduce compressed tablets into Auto

Coater and spray coating solution

Inlet air temp .C (30-60C)

Pan speed..rpm (2-8 rpm)

Solution rate ..ml/min (20-60 ml/min)

Distance of gun from tablet bedcm
(20-40cm)
Packaging
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.
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.
Tablet Defects & Processing Problems
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
Processing Problems
Binding
Sticking,
Picking and Filming
Capping
Lamination
Chipping
Mottling
Weight Variation
Poor flow
Hardness variation
Double impression
Cracking
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
 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
 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.
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

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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