Industrial pharmacy

1. GRANULATION

2. INTRODUCTION
 Granulation can be defined as a size
enlargement process which converts small
particles into physically larger and stronger
agglomerates.
 Granulation is the process of collecting
particles together by creating bonds between
them. Bonds are formed by:
 1] Compression
 2] By using binding agent

3.  GRANULATION is done in order to:
1] Improve flow and compression
2] Reduce segregation
3] Improve content uniformity
4] Eliminate excessive amount of fines
5] Avoid dustiness
6] Increase density of material
Need For Granulation

4.  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 to distribute drug, binder and
moisture.
vi) Drying rate ( Hydrate formation and polymorphism)

5. GRANULATION
WET
GRANULATION
DRY
GRANULATION
DIRECT
COMPRESSION

6. MECHANISM OF GRANULE
FORMATION
Granules are formed in three stages:-
1)Nucleation
2)Transition
3)Ball growth or enlargement of the granule.

8. Important steps involved in wet
granulation
 MIXING OF DRUG AND EXCIPIENTS
For larger quantities of powders following
equipments are employed:
1] Patterson-Kelley twin shell blender and
double cone blender.
2] Planetary mixers-Glen and Hobart mixer.
3] Ribbon and sigma blade blenders.
4] High shear mixers

9.  PREPARATION OF BINDER SOLUTION.
 MIXING OF BINDER SOLUTION WITH
POWDER MIXTURE TO FROM WET MASS.
 COARSE SCREENING OF WET MASS
USING A SUITABLE SIEVE(6-12#
SCREENS)
For larger quantities of powders following mills
can be used for sieving:-
1)Stokes oscillator
2)Colton rotary granulator
3)Stokes tornado oscillating mill

10.  DRYING OF MOIST GRANULES
Following equipments are used for the
purpose:-
1)Tray dryer
2)Fluid bed dryer
3)Microwave drying
4) Infrared drying
5)Rovac dryer system by CIBA/NOVARTIS
 SCREENING OF DRY GRANULES USING A
SUITABLE SIEVE(14-20# SCREEN)
 MIXING OF SCREENED GRANULES WITH
DISINTEGRANT,GLIDANT,LUBRICANT.

11. SPECIAL WET GRANULATION
TECHNIQUES
1]FLUID BED GRANULATION:
Granules are produced by spraying a binder solution
onto fluidized powder bed
2] SPHERONIZATION:
 Formation of spherical particles
 Marumerizer and CF granulator are employed
3] SPRAY-DRYING:
Converts liquid into dry powder
4] HIGH SHEAR MIXTURE GRANULATION:
Very dense granules are formed

12. FLUID BED GRANULATOR

13. SPHERONIZER/MARUMERIZER

14. PROCESSING FLOW CHART
FOR SPHERONIZATION

15. SPRAY-DRYING

16. HIGH SHEAR MIXTURE
GRANULATION
16

17. RAPID MIXTURER
GRANULATOR (RMG)

18. ADVANTAGES OF RMG
 Mixing, massing and granulation are all performed
within a few minutes in the same piece of equipment
 Unit formula maintained
 Forms desired wet granule rapidly
 Less wetting and more rapid drying
 Homogeneously dry mixes quickly: color distribution
is excellent; can eliminate premixes of addition by
geometric progression

19. LIMITATIONS OF WET
GRANULATION
 Its cost
 Loss of material
 Stability problems
 Difficult to validate and control
 Any incompatibility between formulation and
component is aggravated

21. Steps involved 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

22. Dry granulation processes
 Slugging :-
It is the process of compressing dry powder
with tablet press, slugs are produced which
are reduced to appropriate granule size.
 Roller compaction :-
Compaction of powder by means of pressure
roll called chilsonator. Compaction mills
available include :-
1)CHILSONATOR(FITZPATRICK)
2)ROLLER COMPACTOR(VECTOR)
3)COMPACTOR MILL(ALLIS-CHALMERS)

23. Roller compactor

24. LIMITATIONS OF DRY GRANULATION
 Specialized heavy duty press is required.
 Uniform color distribution is not there as can
be achieved with wet granulation.
 Process creates more dust.
 Sometimes results in prolonged
disintegration.

26. INTRODUCTION
 It is the process by which tablets are compressed
directly from powder mixture of API and suitable
excipients.
 No pretreatment by wet or dry granulation is
required.
EVENTS THAT MOTIVATES THE INDUSTRY
PEOPLE TO USE DIRECT COMPRESSION
1)Commercial availability of directly compressible
excipients e.g. spray dried &anhydrous
lactose,starch-1500,mallodextrins etc.
2)Major advances in tablet compression machinery
such as improved positive die filling and
precompression of powder blend.

27. STEPS FOR DIRECT
COMPRESSION
 Milling of drug and excipients
 Mixing of drug and excipients
 Tablet compression

28. MERITS OF DIRECT COMPRESSION
 Efficient and economical
 Suitability of process for thermo labile and
moisture sensitive APIs.
 Particle size uniformity
 Prime particle dissolution
 Batch to batch variation is negligible .Easy to
validate & control.

29. DEMERITS OF DIRECT
COMPRESSION
 EXCIPIENTS RELATED
 PROCESS RELATED

30. ADVANCEMENTS
IN
GRANULATIONS

31. 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.
 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.

32. 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.
 There is no need of drying phase since dried granules are
obtained by cooling it to room temperature.
 It is useful for granulating water sensitive material and
producing SR granulation or solid dispersion.
 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.

33. Moisture Activated Dry
Granulation (MADG)
 It involves minimal moisture addition, distribution
and agglomeration. No drying step is required.
 Water distribution is via high shear mixer, or low-
shear mixer with highly atomized water spray
 Any excess moisture is absorbed by hydrophilic
polymers such as cellulose or silica added to the
moist pre-blend. It produces granules with excellent
flow ability and uniformity, and is applicable to
controlled release.

34. Foam Granulation
 Here liquid binders are added as aqueous foam.
 It has several benefits over spray(wet)
granulation.
1)It requires less binder .
2) Rate of addition of foam is greater
3) No plugging problems since use of spray
nozzles is eliminated .
4) No over wetting.
5) Useful for granulating water sensitive
formulations.
6) Reduces drying time

35. Thermal Adhesion Granulation
Process (TAGP)
 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.