MANUFACTURING OF TABLET

WET GRANULATION METHOD

Introduction
Granulation, a well-known technique in the pharmaceutical industry, has
been considered a key unit process for the manufacturing of solid dosage
forms, especially tablets and capsules. It is carried out prior to the tableting
to improve the overall powder properties. Granules possess a wide range of
benefits over simple powders, such as better bulk density, improved
flowability, reduced dustiness, minimized segregation, improved content
uniformity, and increased mechanical strength of tablets.
 METHODS OF TABLET MANUFACTURE

There are three basic methods of preparation of compressed tablets.

Each method has its own advantage, disadvantages and limitations.

Methods of
tablet
Manufacture

Wet Dry Direct

granulation granulation Compression
method method method
 The choice of tablet manufacturing process

The choice of tablet manufacturing process is dependent on several factors, including

▪ The compression properties of the API,

▪ The particle size of the API

▪ The particle size of the excipients

▪ The chemical stability of the API during the manufacturing process and

▪ The strength(dose) of the tablet

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 Wet granulation method

Wet granulation is a pharmaceutical unit operation whereby a liquid or binder solution is

sprayed onto a powder blend to improve the flow, compressibility, and content
uniformity of the blend, prior to tabletting.

The wet granulation method involves dampening or wet massing the tablet powder
mixture with a liquid - adhesive granulating agent followed by wet Screening or
granulation to agglomerate the powder which is then milled and dried.

This is the most widely used and most general method of tablet preparation and also is
the oldest method of tablet manufacture.
 Wet granulation method

Wet granulation method is a process of size enlargement in which fine

powder particles are agglomerated or brought together into larger, strong and
relatively permanent structure called granules using a suitable non-
toxic granulating fluid such as water, isopropanol or ethanol (or mixtures
thereof). The granulating fluid can be used alone or as a solvent containing
binder or granulating agent. The choice of the granulating fluid depends
greatly on the properties of the materials to be granulated. Powder
mixing, in conjunction with the cohesive properties of the granulating agent,
enables the formation of granules. The characteristics and performance of
the final product, greatly depends on the extent to which the powder particles
interact with each other to form aggregates (granules).
Commonly used excipients in wet granulation
Function Excipient Typical Level
(approximate)
Diluent Microcrystalline cellulose, Maize starch 10% - 30%
Lactose monohydrate Up to 90%
Dibasic calcium phosphate Up to 90%
Mannitol Up to 90%
Binder Maize starch, Pregelatinised starch 2% - 5%
Povidone 1% - 3%
Hydroxypropyl cellulose 1% - 3%
Hypromellose 1% - 3%
Disintegrant Maize starch ,Partly pregelatinised starch 5% - 20%
Sodium starch glycolate 2% - 6%
Croscarmellose sodium 2% - 6%
Crospovidone 2% - 6%
Lubricant Magnesium stearate 0.5% - 1%
Sodium stearyl fumarate 0.5% - 1%
Talc / Stearic acid 3% - 5% / 1% - 2%
Glidant Colloidal silicon dioxide 0.1% - 0.3%
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 Factors Affecting High shear Wet Granulation Process

Fig.: Influence of formulation and process variables on high shear wet granulation at
different stages of the process.
 Advantages and Disadvantages

Advantages Disadvantages

▪ Highly popular method ▪ Many separate manuf. Steps

▪ Provide hard granule ▪ Numerous handling operations
▪ Provide good bonding ▪ Not suitable for heat and
▪ Better distribution of color and moisture sensitive materials
▪ Process is time consuming
soluble drugs if added in the binding
▪ Process is costly
solution. ▪ Automation is difficult
▪ Avoid segregation of ingredients ▪ Less validation efficient
▪ Huge involvement of plant and
machineries
▪ Huge involvement of floor
space
▪ Huge involvement of utility costs
 Unit operations involved in wet granulation method

Weighing / Dispensing Drying Dry screening

LOD
Check

Lubrication
Sieving / Milling Wet screening
Lubricants +
Disintegrants

Dry powder mixing

API + Excipients( Wet massing Compression
Diluents, disintegrants
etc.)

Preparation and
addition of GF
 Disintegrants addition
Disintegrants can be added to formulations before
compression by three different methods:

▪ Intragranular addition: The disintegrant is mixed

with other powders before granulation (i.e.
disintegrants are added during dry powder mixing)

▪ Extragranular addition: The disintegrant is added

to the granules before compression (i.e.
disintegrants are added and mixed just before
compression).

▪ Combination method: Both intra and extra granular

additions of disintegrants are used. This is the most
efficient way of adding a disintegrant to a tablet
formulation before compression. These agents swell
when exposed to gastric fluids and exert sufficient
mechanical pressure from within the tablet to cause
it to break apart into small segments.
 Unit operations involved in wet granulation method

Weighing / Dispensing Drying Dry screening

LOD
Check

Lubrication Extragra
nular
Sieving / Milling Wet screening addition
Lubricants +
Disintegrants

Intragra
nular Dry powder mixing
addition API + Excipients( Wet massing Compression
Diluents, disintegrants
etc.)

Preparation and
addition of GF
 Weighing Drying Dry screening

Sieving or milling Wet screening Lubrication

Preparation of GF Dry powder mixing and wet massing Compression

 Weighing Drying Dry screening

Sieving or milling Wet screening Lubrication

Preparation of GF Dry powder mixing and wet massing Compression

WET GRANULATION PARAMETER

Wet Granulation

HSMG FBP/FBD Mass Mixer

▪ Capacity of HSMG ▪ Capacity of FBP ▪ Capacity of Mass Mixer

▪ Mixer speed /Chopper ▪ CFM OF Blower ▪ Binder addition time
speed ▪ Product Temperature ▪ Mixing Time
▪ Binder addition time ▪ Peristaltic Pump RPM ▪ Mixer Speed
▪ Effective wet massing ▪ Flow rate/Spray Pattern
time ▪ Atomizing air pressure
▪ Amperage load of ▪ Inlet Air Temperature
mixer/Chopper

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• Flow characteristics, bulk density etc
Control parameters of granules
• Granulation end-point
• Homegeneity of granule
• Moisture content
• Particle size

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Fig.: High shear mixer granulator or Rapid mixer granulator
Fig: Mass mixer Planetary Mixer
Milling
 Blending
Homogeneity of powder blend
(on-line NIR, at-line HPLC or
UV-visible and/or imaging
techniques)

Moisture content (on-line near

infra-red and/or ERH probes)

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The choice of mixing equipment and blending protocol can affect the uniformity of content.
For example:
▪ The type of blending equipment. For example, a V-shaped blender tends to produce
better mixing than a bin-blender.
▪ In terms of the blending protocol, minor (lower quantity) components of the powder
mixture are often “sandwiched” between the major components by controlling the
sequence of addition of the components to the blender. This is particularly important for
critical excipients that have a tendency to segregate, such as magnesium stearate.
▪ In addition, components that have atypical particle characteristics, such as the very low
BD of colloidal silicon dioxide, are often pre-mixed with a small quantity of another
component before addition to the blender.
▪ Mixing time plays a key role. Although a minimum amount of time is required to achieve
desired content uniformity, quite counterintuitively, prolonged mixing does not
necessarily result in better uniformity of content. In fact, prolonged mixing can
compromise the uniformity. Therefore, optimum mixing time is carefully determined and
controlled.
Uniformity of a powder mixture can be compromised post-mixing during storage and
handling of powders. For example, vibration in the storage bins due to the operation of
large scale equipment can lead to segregation of a uniform mixture of components with
differences in particle size and/or density.
Segregation can also happen during material transfer. For example, flow of a powder blend
through the hopper from a closed chamber can result in a countercurrent flow of air, which
can partially fluidize the powder leading to segregation based on fluidization potential of
different components.
CRITICAL PARAMETERS DURING BLENDING
/MIXING

Blending/Mixing
• Type of blender/Mixer
• Capacity of Blender/Mixer
• Blender RPM
• Blending time

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