Use to study in 9th semester of Pharmacy in Pharmaceutical technology.

2.  GRANULATION:
The process in which primary
powder particle are made to adhere to form
large multiparticle entitles or agglomerates is
known as granulation.
Why we need granulation?
To control the rate of
drug release, improve flow property and
compression characteristics and increases
density of granules, make hydrophobic surfaces
more hydrophilic and prevent the segregation of
particles.

3.  Rapid release granulation is a technique in
which all those parameters/processes/variables
which cause the rapid release of drug are
applied in the preparation of granules. Most
potential drug candidate which had been
screened to show therapeutic activities could
not be formulated into suitable oral dosage
forms, which are the most preferred form of
drug administration due to poor aqueous
solubility. Rapid release granulation is
expected to benefit the class of compound
where absorption is highly dependent on
dissolution of drug in gastrointestinal tract
termed as Class II compounds under the
Biopharmaceutics Classification system.

4. CLASS Solubility Permeability
I High High
II Low High
III High Low
IV Low Low

5.  Solubility is important because for a drug to
be absorb and be available in systemic
circulation it must have adequate solubility.
To check solubility we have to check its
dissolution because dissolution is a
benchmark to test solubility. The factors may
be classified into patient or dosage form
related factor. Most dosage form related
factor are further divided into formulation
related factor and granulation related factor
are discussed below:

6.  A. Drug
Free Acid, Free Base or Salt Form:
 The use of the appropriate form of drug prior to
granulation is of utmost importance to ensure the
production of rapid release granules. Most of the
drugs are either weak acids or weak bases, so they
are used in pharmaceutical formulations in the form
of the free acid/base or in the form of the salt of
these acids or bases. Sodium salts of weak acids or
hydrochloride salts of weak bases can cause
marked increase in aqueous solubility when
compared to the corresponding free acids or bases.
For example, diclofenac, is the drug in its free acid
form, while diclofenac sodium and diclofenac
potassium are the salts of the drug.

7.  Particle size :
 The solubility of drug is often intrinsically
related to drug particle size; as a particle
becomes smaller, the surface area to volume
ratio increases. The larger surface area
allows greater interaction with the solvent
which causes an increase in solubility. As in
the case of griseofulvin. Griseofulvin
represents a classical example of a drug
where improvement in rate of absorption can
be brought about by an increase in
dissolution rate due to the increase in
surface area by size reduction.

8.  Solution based micronization:
The poorly soluble drug was dissolved in solvent to
make solution and mixed with a core material,
either low-substituted hydroxypropylcellulose or
partly pregelatinized corn starch. The suspension
was subsequently spray dried leaving a thin film of
fine drug crystals on the surface of the core
materials. The rapid solvent evaporation prevented
the growth of large drug crystals. Using disintegrant
as the core material further improved drug release
because the swelling of disintegrant would dislodge
the thin film of fine drug crystals from the core for
better dissolution, thus effectively dispersing the
fine drug crystals.

9.  Interactive mixture :
 The basic mechanism in enhancing the
dissolution rate of a poorly water soluble drug
by reduction of drug aggregates upon mixing
with highly soluble and coarse carrier particles,
thus improving the wettability of the micronized
drug after mixing the solvent is evaporated
resulting in adhesion of drug crystals to
hydrophilic carriers. thereby increasing the
exposed surface area for drug dissolutionThe
adhesion may be due to many factors such as
humidity, adsorption, chemisorption, surface
tension, friction, and electrostatic forces.

10.  Drug can exist in one or more crystalline forms.
But the one crystalline form are stable and other
are megastable. Crystalline forms of a drug can
be further classified into polymorphs and
solvates, also known as pseudopolymorphs.
 Crystalline polymorphs have the same
chemical composition but different crystal
structures. Although the chemical nature of the
drug is similar in the different crystalline forms,
these different crystalline forms can have
substantially different physical properties
including different solubility.

11.  Solvates are crystalline forms containing solvent
molecules in the crystal structures in stoichiometric
or nonstoichiometric proportion.
 On the other hand when the incorporated solvent is
water, the complex is called as “Hydrate”.
 A compound not containing any water within its
crystal structure is termed “Anhydrous”. Aqueous
solubilities of anhydrous forms are higher than the
hydrate forms .
 For Example the use of carbamazepine
polymorphs I and IV, which are the respective
anhydrate and dihydrate forms, gave rise to a
higher dissolution rate than polymorphs II and III,
which are the anhydride forms.

12.  Second one the amorphous form is the
form where the molecules are arranged in a
random manner drug solubility is usually
higher when the drug exists in the
amorphous form compared to the crystalline
form. This is because the process of drug
solubility involves breaking the
intermolecular bonds that form the crystal
lattice, and these intermolecular bonds are
different for the different forms of the same
chemical entity. However, amorphous solids
are generally not as stable physically and
chemically.

13.  Complexing agent:
The additive is called solubilizing agent and it
must be present at an optimal concentration to
maximize the solubility of a poorly soluble drug.
One commonly used additive is cyclodextrin.
Cyclodextrins are bucket-shaped
oligosaccharides produced from starch.
Cyclodextrin are able to entrap poorly water-
soluble drugs in the hydrophobic cavities
forming watersoluble inclusion complexes with
the poorly water-soluble drugs. This approach
has been used to increase the rate and extent
of absorption of some drugs.

14.  Effervercent Agent:
Effervescence is defined as the evolution of
bubbles of gas from a liquid as the resultof a
chemical reaction. It usually composed of
sodium bicarbonate, citric acid, and tartaric
acid. When added to water, the acids and
the base react to liberate carbon dioxide,
resulting in effervescence. The bioavailability
of aspirin from effervescence tablet was
higher than conventional or enteric coated
tablets. The reasons for this included the
dramatic disintegration rate of the tablets
that enabled rapid release of the drug
particles for dissolution.

15.  Surfactant:
This additive is capable of forming aggregates
called micelles above the critical micelle
concentration. This is the major distinguishing
feature between surface active agent and
complexing agent. The use of surfactants to
improve the dissolution performance of poorly
soluble drug products. Surfactants reduce surface
tension and improve the dissolution of lipophilic
drugs in aqueous medium. Commonly used
nonionic surfactants include polysorbates,
polyoxyethylated castor oil, polyoxyethylated
glycerides, lauryl macroglycerides, and mono- and
di-fatty acid esters of low molecular weight
polyethylene glycols. Sodium lauryl sulfate was
employed in the formulation of ibuprofen tablet to
enhance ibuprofen dissolution.

16.  Super-disintegrent:
A disintegrant is an Excipients, which is
included to a tablet or capsule blend to aid in
the breakup of the compacted mass when it
is put into a fluid environment
.Superdisintegrants represent a subclass of
disintegrants that are associated with
dramatic disintegration rates.
Some of the common superdisintegrants are
crospovidone, croscarmellose sodium, and
sodium starch glycolate.

17.  Hydrophilic Agent:
It is always better to employ more hydrophilic
agents which may be water-soluble or water-
insoluble as binders or fillers in the formulation
so that water penetration into the granules will
not be impeded. Hydrophilic agents commonly
employed include hydroxylpropylcellulose,
hydropropylmethylcellulose, lactose,
microcrystalline cellulose, polyvinylpyrrolidone,
starch, and many others. These additives aid in
wetting the poorly water-soluble drug.
Polyvinylpyrrolidone K30 was able to improve
the wetting of nifedipine complexed with 2-
hydroxypropyl- b-cyclodextrin.

18.  The common steps in dry and wet granulation methods and some
of the factors that may affect the final release of drug from capsules
or tablets made from the granules are mentioned below:

19.  interactive mixing, plays an important part
in improving the dissolution of poorly soluble
drug because the mixing of micronized drug
with the appropriate additives reduces the
cohesiveness of the drug particles, leading
to better dissolution of the drug.

20.  Wet granulation offers an opportunity for the
transformation of crystal forms and the choice of
the liquid binder plays an important role in
determining the final crystal form of the drug in the
granules obtained. Addition of the binder could be
viewed as suspending drug in a mixture of solvent
and additives, hence, encouraging transformation
of anhydrates to solvated forms. If sufficient liquid
binder is added, this could be viewed as a solution
step and subsequent drying of granules as the
recrystallization step. Thus, close attention has to
be paid to polymorph conversion during wet
granulation. The quantity of liquid binder also gives
rise to different dissolution profiles.

21.  The use of the appropriate granulating
equipment also plays an important role in the
release rate of the drug. Acetaminophen beads
made from extrusion/spheronization were
compared to beads made from pan coating.
Beads made from pan coating displayed higher
dissolution rates as compared to those made
from the former method. Thus, the selection of
equipment for wet granulation affects the
hardness of the granules and ultimately
influences drug release.

22.  Wet massing was found to play an important
factor in the dissolution rate.Increasing the
time during wet massing results in an
increase in bulk density of the granules. The
maximum bulk density value confirmed with
the minimum dissolution rate indicating that
the dissolution of drug required the diffusion
of dissolution medium into granules via
pores to dissolve the drug .Thus, the
duration of wet massing affects the hardness
of granules and ultimately, dissolution of the
drug.

23.  The dissolution rate is affected by the type of
blending equipment employed, the duration of
blending of granules with disintegrant, glidant, and
lubricant. It was found that the type of blender
affected the distribution of magnesium stearate and
hence, drug dissolution. High-speed blender was
employed to mix interactive mixture of theophylline
with magnesium stearate before tableting. It was
found that a 15 min duration was sufficient to impair
theophylline dissolution whereas an impairment of
dissolution was not observed for a lower-speed
blender. The impairment to drug dissolution
increased with an increase in the duration of
blending.

24.  The term, solid dispersion, refers to a composite solid of
one or more drugs in a water soluble carrier or matrix
prepared by melt (fusion), solvent, or melt–solvent method.
Solid dispersions have been traditionally employed to
enhance the dissolution rate of drug, with a view to
improve bioavailability. The common approach to achieve
rapid drug dissolution is to use inert but water-soluble
carriers such as polyethylene glycol or polyvinyl
pyrrolidone. Solid dispersion enhances the dissolution of
drugs by the formationof fine drug crystals via the eutectic
or monotectic systems. The drug particles in solid
dispersions were released as fine or amorphous colloidal
entities upon dissolution of the matrix, enhancing drug
dissolution rate.

25.  Melt/fusion method:
The main advantages of this direct melting
method is its simplicity and economy. In this
method, the physical mixture of a drug and a
water-soluble carrier are heated directly until
the two melts. The melted mixture is then
cooled and solidified rapidly in an ice bath with
rigorous stirring. The final solid mass is then
crushed, pulverized, and sieved, which can be
compressed into tablets with the help of
tableting agents.

26.  Solvent Evaporation Method:
Firstly dissolve both the drug and the carrier
in a common solvent and then evaporate the
solvent under vacuum to produce a solid
solution. This enabled them to produce a
solid solution of the highly lipophilic the
highly water soluble carrier.

27.  Melt-Solvent Method:
This is a hybrid of the two methods
discussed. The drug is dissolved in a
suitable organic solvent and the solution is
incorporated directly into a molten carrier.
Subsequently, the organic solvent is
evaporated off.

28.  Melt granulation:
Melt granulation is a process by which powders are
agglomerated with the aid of a binder, in either a
molten state or solid state that melts during the
process. The apparatus of choice is a high-shear
mixer, where the temperature of a powder can be
raised above the melting point of a meltable binder
by either a heating jacket or frictional forces
generated by the impeller blades. Liquid binding is
possible by the molten binder, thus melt granulation
does not require the use of solvents. The choice of
the meltable binder plays an important role in the
process. It has to melt at a relatively low
temperature of 50–80_C.

29.  The use of hydrophilic binder that melts at a
low temperature will aid in the rapid release
of drugs. Ethylene glycol and propylene
glycol use as the surface active agent, to
achieve fast release ibuprofen granules.

30.  Melt Extrusion:
This process originated from the plastic industry and it
entails conversion of a raw material into a product of
uniform shape and density. The drug and additives are
usually mixed followed by forcing the powder mass
through a die under controlled conditions. The extruded
mixtures always exhibited more rapid release of drug
versus the corresponding physical mixtures. This
technique is used to produce hydrochlorothiazide tablets
by directly extruding the melt into a tablet-shaped cavity.
The molded tablet thus formed displayed higher in vitro
dissolution and relative bioavailability in healthy
volunteers. The improvement in dissolution rate is drug
specific. A possible modification of this process is the
extrusion/spheronization

31.  1-RECENT ADVANCES IN GRANULATION TECHNOLOGY
Himanshu.K.Solanki*, Tarashankar Basuri, Jalaram H.Thakkar,
Chirag A. Patel
 2-Handbook of Pharmaceutical Granulation Technology Second
Edition Dilip M. Parikh page number 407,409,412,414,416,418,421
 3- Basic pharmacokinetics 2nd edition by Mohsen A. Hedaya page
number 99,100
 4-Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems 9th edition page number 196,198
 5-Review Article, Drug Solubility: Importance and Enhancement
Techniques by Ketan T. Savjani, Anuradha K. Gajjar, and Jignasa
K. Savjani