Tablet:Manufacturing methods/Granulation
Introduction
Granulation may be defined as a size enlargement process
which converts small particles into physically stronger & larger agglomerates.
Granulation method can be broadly classified into two types:
Wet granulation and Dry granulation
Ideal characteristics of granules
The ideal characteristics of granules include spherical
shape, smaller particle size distribution with sufficient fines to fill void
spaces between granules, adequate moisture (between 1-2%), good flow, good
compressibility and sufficient hardness.
The effectiveness of granulation depends on the following
properties
i) Particle size of the drug and excipients
ii) Type of binder (strong or weak)
iii) Volume of binder (less or more)
iv) Wet massing time ( less or more)
v) Amount of shear applied
vi) Drying rate ( Hydrate formation and polymorphism)
Wet granulation
Introduction
The most widely used process of agglomeration in
pharmaceutical industry is wet granulation. Wet granulation process simply
involves wet massing of the powder blend with a granulating liquid, wet sizing
and drying.
Important steps involved in the wet granulation
i) Mixing of the drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form
wet mass.
iv) Coarse screening of wet mass using a suitable sieve
(6-12 screens).
v) Drying of moist granules.
vi) Screening of dry granules through a suitable sieve
(14-20 screen).
vii) Mixing of screened granules with disintegrant, glidant,
and lubricant.
Limitation of wet granulation
i)The greatest disadvantage of wet granulation is its cost.
It is an expensive process because of labor, time, equipment, energy and space
requirements.
ii)Loss of material during various stages of processing
iii)Stability may be major concern for moisture sensitive or
thermo labile drugs
iv)Multiple processing steps add complexity and make
validation and control difficult
v)An inherent limitation of wet granulation is that any
incompatibility between formulation components is aggravated.
Special wet granulation techniques
i) High shear mixture granulation
ii) Fluid bed granulation
iii) Extrusion-spheronization
iv) Spray drying
1.High shear mixture granulation
High shear mixture has been widely used in Pharmaceutical
industries for blending and granulation. Blending and wet massing is
accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification
and agglomeration are achieved through shear and compaction force exerted by
the impeller.
Advantages:
i) Short processing time
ii) Less amount of liquid binders required compared with
fluid bed.
iii) Highly cohesive material can be granulated.
2.Fluid bed granulation
Fluidization is the operation by which fine solids are
transformed into a fluid like state through contact with a gas. At certain gas
velocity the fluid will support the particles giving them free mobility without
entrapment.
Fluid bed granulation is a process by which granules are
produced in a single equipment by spraying a binder solution onto a fluidized
powder bed. The material processed by fluid bed granulation are finer, free
flowing and homogeneous.
3.Extrusion and Spheronization
It is a multiple step process capable of making uniform
sized spherical particles. It is primarily used as a method to produce
multi-particulates for controlled release application.
Advantages:
i) Ability to incorporate higher levels of active components
without producing excessively larger particles.
ii) Applicable to both immediate and controlled release
dosage form.
4.Spray drying granulation
It is a unique granulation technique that directly converts
liquids into dry powder in a single step. This method removes moisture
instantly and converts pumpable liquids into a dry powder.
Advantages:
i) Rapid process
ii) Ability to be operated continuously
iii) Suitable for heat sensitive product
Lists of equipments for wet granulation
High Shear granulation:
i)Little ford Lodgie granulator
ii)Little ford MGT granulator
iii)Diosna granulator
iv)Gral mixer
Granulator with drying facility:
i) Fluidized bed granulator
ii) Day nauta mixer processor
iii) Double cone or twin shell processor
iv) Topo granulator
Special granulator:
i) Roto granulator
ii) Marumerizer
Current topics related to wet granulation
I.Hydrate formation
For example, theophylline anhydrous during high shear wet
granulation transfers to theophylline monohydrate. The midpoint conversion
occurs in three minutes after the binder solution is added.
For online monitoring of the transformation from one form to
another, Raman spectroscopy is most widely used.
II.Polymorphic transformation
The drying phase of wet granulation plays a vital role for
conversion of one form to another.
For example, glycine which exist in three polymorphs that is
α β γ . γ is the most stable form and αis the metastable form. The stable
Glycine polymorph (γ) converts to metastable form (α) when wet granulated with
microcrystalline cellulose.
Dry granulation
Introduction
In dry granulation process the powder mixture is compressed
without the use of heat and solvent. It is the least desirable of all methods
of granulation. The two basic procedures are to form a compact of material by
compression and then to mill the compact to obtain a granules. Two methods are
used for dry granulation. The more widely used method is slugging, where the
powder is precompressed and the resulting tablet or slug are milled to yield
the granules. The other method is to precompress the powder with pressure rolls
using a machine such as Chilosonator.
Advantages
The main advantages of dry granulation or slugging are that
it uses less equipments and space. It eliminates the need for binder solution,
heavy mixing equipment and the costly and time consuming drying step required
for wet granulation. Slugging can be used for advantages in the following
situations:
i) For moisture sensitive material
ii) For heat sensitive material
iii) For improved disintegration since powder particles are
not bonded together by a binder
Disadvantages
i) It requires a specialized heavy duty tablet press to form
slug
ii) It does not permit uniform colour distribution as can be
iii) Achieved with wet granulation where the dye can be
incorporated into binder liquid.
iv) The process tends to create more dust than wet
granulation, increasing the potential contamination.
Steps in dry granulation
i) Milling of drugs and excipients
ii) Mixing of milled powders
iii) Compression into large, hard tablets to make slug
iv) Screening of slugs
v) Mixing with lubricant and disintegrating agent
vi) Tablet compression
Two main dry granulation processes
1.Slugging process
Granulation by slugging is the process of compressing dry
powder of tablet formulation with tablet press having die cavity large enough
in diameter to fill quickly. The accuracy or condition of slug is not too
important. Only sufficient pressure to compact the powder into uniform slugs
should be used. Once slugs are produced they are reduced to appropriate granule
size for final compression by screening and milling.
Factors which determine how well a material may slug
i) Compressibility or cohesiveness of the mater
ii) Compression ratio of powder
iii) Density of the powder
iv) Machine type
v) Punch and die size
vi) Slug thickness
vii) Speed of compression
viii) Pressure used to produce slug
2.Roller compaction
The compaction of powder by means of pressure roll can also
be accomplished by a machine called chilsonator. Unlike tablet machine, the
chilsonator turns out a compacted mass in a steady continuous flow. The powder
is fed down between the rollers from the hopper which contains a spiral auger
to feed the powder into the compaction zone. Like slugs, the aggregates are
screened or milled for production into granules.
Formulation for dry granulation
The excipients used for dry granulation are basically same
as that of wet granulation or that of direct compression. With dry granulation
it is often possible to compact the active ingredient with a minor addition of
lubricant and disintegrating agent. Fillers that are used in dry granulation
include the following examples: Lactose, dextrose, sucrose, MCC, calcium
sulphate, Sta-Rx® etc.
Examples of some tablet formulation prepared by dry
granulation
Advancement in Granulations
Steam Granulation
It is modification of wet granulation. Here steam is used as
a binder instead of water. Its several benefits includes higher distribution
uniformity, higher diffusion rate into powders, more favourable thermal balance
during drying step, steam granules are more spherical, have large surface area
hence increased dissolution rate of the drug from granules, processing time is
shorter therefore more number of tablets are produced per batch, compared to
the use of organic solvent water vapour is environmentally friendly, no health
hazards to operators, no restriction by ICH on traces left in the granules,
freshly distilled steam is sterile and therefore the total count can be kept
under control, lowers dissolution rate so can be used for preparation of taste
masked granules without modifying availability of the drug. But the limitation
is that it is unsuitable for thermolabile drugs. Moreover special equipments
are required and are unsuitable for binders that cannot be later activated by
contact with water vapour.
Melt Granulation / Thermoplastic Granulation
Here granulation is achieved by the addition of meltable
binder. That is binder is in solid state at room temperature but melts in the
temperature range of 50 – 80˚C. Melted binder then acts like a binding liquid.
There is no need of drying phase since dried granules are obtained by cooling
it to room temperature. Moreover, amount of liquid binder can be controlled
precisely and the production and equipment costs are reduced. It is useful for
granulating water sensitive material and producing SR granulation or solid
dispersion. But this method is not suitable for thermolabile substances. When
water soluble binders are needed, Polyethylene Glycol (PEG) is used as melting
binders. When water insoluble binders are needed, Stearic acid, cetyl or
stearyl alcohol, various waxes and mono-, di-, & triglycerides are used as
melting binders.
Moisture Activated Dry Granulation (MADG)
It involves moisture distribution and agglomeration. Tablets
prepared using MADG method has better content uniformity. This method utilizes
very little granulating fluid. It decreases drying time and produces granules
with excellent flowability.
Moist Granulation Technique (MGT)
A small amount 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. By
adding MCC in this way drying step is not necessary. It is applicable for
developing a controlled release formulation.
Thermal Adhesion Granulation Process (TAGP)
It is applicable for preparing direct tableting
formulations. TAGP is performed under low moisture content or low content of
pharmaceutically acceptable solvent by subjecting a mixture containing
excipients to heating at a temperature in the range from about 30ºC to about
130ºC in a closed system under mixing by tumble rotation until the formation of
granules. This method utilizes less water or solvent than traditional wet
granulation method. It provides granules with good flow properties and binding
capacity to form tablets of low friability, adequate hardness and have a high
uptake capacity for active substances whose tableting is poor.
Foam Granulation
Here liquid binders are added as aqueous foam. It has
several benefits over spray(wet) granulation such as it requires less binder
than Spray Granulation, requires less water to wet granulate, rate of addition
of foam is greater than rate of addition of sprayed liquids, no detrimental
effects on granulate, tablet, or invitro drug dissolution properties, no
plugging problems since use of spray nozzles is eliminated, no overwetting,
useful for granulating water sensitive formulations, reduces drying time,
uniform distribution of binder throughout the powder bed, reduce manufacturing
time, less binder required for Immediate Release (IR) and Controlled Release
(CR) formulations
