included case study

1. “Handling of solid”
“Pharmaceutical Granulation ’’
1
Guided By:
Dr. V.B. Pokharkar
Vice-Principal
Poona College of Pharmacy
Pune
Presented By:
Neeraj Rawat
M.Pharmacy 1st
year

2. Contents
• S0lid Handling
• Granulation
• Dispensing of granules
• Purpose of granulation
• Methods of granulation
• Compression
2

3. Solid handling
• Conveying :- the term conveying is applied
to the transportation of solids.
• Objectives :-
1) Decreased product cost and increase
manufacturing capacity.
2) Decrease cost of raw material.
3) Decrease processing time and conservation
4) Minimum contamination and dust formation
3

4. Conveyors are classified into 5 major
group
1. Belt conveyors
2. Screw conveyors
3. Pneumatic conveyors
4. Chain conveyors
5. Bucket conveyors
4

5. 1 Belt conveyors
• For transporting light- and medium-weight loads
between operations, departments, levels, and
buildings
• When an incline or decline is required
• Provides considerable control over the orientation
and placement of the load.
• No smooth accumulation, merging, and sorting on
the belt
• The belt is roller or slider bed supported; the slider
bed is used for small and irregularly shaped items.
5

6. Belt Conveyor
6

7. 2 Screw conveyors
• Consists of a tube or U-shaped stationary trough
through which a shaft-mounted helix revolves to
push loose material forward in a horizontal or
inclined direction
• One of the most widely used conveyors in the
processing industry.
7

8. 3 Pneumatic Conveyoys
• Can be used for both bulk and unit movement of
materials
• Air pressure is used to convey materials through
a system of vertical and horizontal tubes
• Major advantages are that material is completely
enclosed and it is easy to implement turns and
vertical moves.
8

9. 4 Chain Conveyors
• Uses one or more endless chains on which loads
are carried directly
• Parallel chain configuration used to transport
pallets
• Vertical chain conveyor used for continuous
high-frequency vertical transfers.
9

10. 5 Bucket Conveyors
• Used to move bulk materials in a vertical
or inclined path
• Buckets are attached to a cable, chain,
or belt
• Buckets are automatically unloaded at
the end of the conveyor run.
10

11. Granulation
• Granulation is the process in which primary powder
particles are made to adhere to form larger, multi-
particle 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 the
manufacturing of tablets and pellets
11

12. • Granulation may be defined as a size
enlargement process which converts fine or
coarse particles into physically stronger and
larger agglomerates having good flow property,
better compression characteristics and
uniformity.
Granulation Technology
• The art and science for process and production
of granules is known as Granulation
Technology.
12

13. Granules
• Granules are powder particles that have been
aggregated to form a larger particle, which is
usually 0.2 - 4.0 mm in diameter.
• Granules are also prepared as an intermediate in
tablet manufacture. These are smaller in size.
13

14. Dispensing of Granules
• Bulk granules for internal use
• Divided granules (i.e. single preparations) for
internal use
• Insufflations for administration to ear, nose or
throat
• Antibiotic syrups to be reconstituted before use
• Powders for reconstitution into injections
• Dry powder inhalers.
14

15. Why we prepare granules when we have
powders….?
• To prevent segregation of the constituents of the powder
mix.
• To improve the flow properties of the mix.
• To improve the compression characteristics of the mix.
• To reduce caking of hygroscopic materials on storage.
• As granules are denser than the parent powder mix,
occupy less volume per unit weight. Easy for storage.
15

16. Granulation to Prevent Segregation
16

17. Advantages
• It improves flow property and compression
characteristics and increases density of
granules.
• Better distribution of color and soluble drug if
added in the binding solution.
• It reduces dust hazards.
• Prevents segregation of powders.
• Makes hydrophobic surfaces more hydrophilic.
17

18. Disadvantages
• Process is expensive because of labor, space, time
special equipment and energy requirement.
• Loss of material during various stages of
processing.
• Moisture sensitive and thermolabile drugs are poor
candidates.
• Any incompatibility between the formulation
components is aggravated during the processing.
18

19. GRANULATION METHOD
1. Dry granulation
2. Wet granulation
19

20. When To Choose DRY method?
• Drug dose is too high.
• Do not compress well after wet granulation.
• Heat sensitive drugs.
• Moisture sensitive drugs.
e.g. Aspirin , Vitamins
20

21. Dry Granulation
• Dry granulation methods, powder particles are
aggregated under high pressure.
• The dry granulation process is use to form
granules without using liquid solution because
the product to be granulated may be sensitive to
moisture and heat.
• Two method are used for dry granulation.
21

22. 22
Mixing
Compaction of powder
Milling
Screening
Steps in Dry Granulation

23. Dry Granulation methods
1. SLUGGING
• The powders is forced into the dies of a large
capacity tablet press and is compacted by means
flat and faced punches , the compacted mass
called Slugs and the process is called to as a
Slugging.
• The resulting slugs are milled to yield a tablet
granulation.
23

24. 2. Roller compaction
• This method is used for dry granulation on
large scale on a specially designed machine
called roller compactor.
• In this method powders is compressed in a
roller compactor forming a sheet or large pieces
that are broken down into a tablet granulation.
24

25. Roller Compactors
25

26. Chilsonator Roller Compactors
26

27. Advantage of dry granulation
• Increased production capacity.
• Greater control of compaction pressure.
• No need for excessive lubrication.
• Less number of step.
• Less time consuming.
• Useful for moisture and heat sensitive material
27

28. Wet granulation
• Wet granulation involves the massing of a mix of
dry primary powder particles using a
granulating fluid.
• The fluid contain a solvent which must be
volatile so that it can be removed by drying.
• Typically liquid include water, ethanol or
isopropanol either alone or in combination.
• primary advantages of water are that:
• it is non-flammable, which means that
expensive safety precautions not be taken.
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29. 29
1 • Mixing of the drug(s) and excipients
2
• Mixing of binder solution with powder mix.
to form wet mass
3
• Coarse screening of wet mass using a
suitable sieve . (6-12
# screens)
4 • Drying of moist granules.
5
• Screening of dry granules through a suitable
sieve (14-20 # screen).
Steps in wet granulation

30. 30
Granulating
liquid
-Volatile
-Non-toxic
e.g.
Water, Ethanol
,
Isopropanol
Binding
agent-
Natural
Polymers:
Starch,
Pregelatinized
Starch
synthetic binders:
PVP, MC, HPMC,
Maltrodextrins

31. Method of wet granulation
• Mixing :-The first stage in the wet granulation
process is often a dry mixing stage in which the
active component is mixed with a diluents. The
purpose of the mixing stage is to ensure that the
powder blend and hence the resulting tablets are
homogeneous in content.
• Granulation :- Granulation is a unit operation
in which mixed powders are simultaneously
mixed with a suitable fluid, e.g. water,
isopropanol or ethanol.

32. • DRYING :- After the process of granulation, the
product exists as a wet mass from which the liquid
must be removed. Water is usually removed by
evaporation for which energy is needed.
• SEIVING :- When the drying process is
complete, it is likely that the product will have
cohered into relatively large masses, especially if
tray drying has been used. The dried material is
therefore passed through a sieve (usually 250–
700 mm) to break up aggregates and to give a
relatively uniformly sized granules.

33. • MIXING OF ADDITIVES :- A second
mixing stage now follows in which several
important ingredients of the formulation
are added.
 Glidant :- To increase flow of material
during manufacturing processes
 Lubricant :- To avoid sticking with wall
of dyes.
 Disintegrating agent:- To disintegrate in
GIT tract.

34. Wet Granulation Equipment
I. Shear granulators
• Planetary mixer e.g. Hobart, Collette, Beken
34

35. • High shear mixture has been widely used in
Pharmaceutical industries for blending and
granulation.
• Wet agglomeration in a high-shear mixer
involves typically 3 phases:
Dry Powder mixing ( 2-5 mins)
Liquid binder addition (1-2 mins)
Wet massing
Advantages:
Highly cohesive material can be granulated.
Disadvantages:
Mechanical degradation.
35

36. Wet Granulation Equipment
• Oscillating Granulator
36

37. Wet Granulation Equipment
II. High Speed mixers/Granulators
• Little ford Lodige mixer
37

38. Wet Granulation Equipment
• The Gral Mixer-granulator
38

39. Fluidized Bed Granulator
39
Air inlet
Air filter
Air outlet
Spray nozzle
Product
container
Granulating
liquid
Exhaust
filter

40. • The powder particles are fluidized in a stream of
air.
• Granulation fluid is pumped from a reservoir
and sprayed from a nozzle on to the bed of
powders.
• Heated and filtered air is blown through the bed
of unmixed powders to fluidize the particles and
mix the powders.
• The fluid causes the primary powder particles to
adhere when the droplets and powders collide.
40

41. • Sufficient liquid is sprayed to produce granules of
the required size, at which point the spray is turned
off but the fluidizing air continued.
• The wet granules are then dried in the heated
fluidizing air stream.
Advantages
• It reduces product loss.
• It improves worker safety.
Disadvantages
• time consuming.
• Difficulty of assuring reproducibility
41

42. Spray Dryer
42
suspension
Fluidization air
screen

43. • Granular product is made from a solution or a
suspension rather than initially dry primary powder
particles.
• The resultant granules are free-flowing hollow
spheres and the distribution of the binder in such
granules results in good compaction properties.
Advantages
• 1. Rapid and continuous process.
• 2. Reduces overall cost
• 3. Offers minimal product handling and operator
exposure to dust.
• 4. Suitable for heat sensitive product.
43

44. Mechanisms of Granule Formation
• Three stages :
1. Nucleation-
Particle-particle contact adhesion due to
liquid bridges form the pendular state
agitation densities the pendular bodies bodies
act as nuclei for granule growth.
44

45. Mechanisms of Granule Formation
2. Transition
Nuclei Growth
single particles two or more nuclei
added to the nuclei may combine
by pendular bridges
• Here presence of a large number of small granules
with a wide size distribution can be seen.
• This is a suitable end-point for granules used in
capsule and tablet manufacture to have uniform
tablet die or capsule fill.
45

46. Mechanisms of Granule Formation
3. Ball growth
Further granule growth large, spherical
granules mean particle size will increase with
time.
• Ball growth seen in planetary mixers
essential feature of some spheronizing
equipment
46

47. Advantage Disadvantage
Excellent cohesiveness and
compressibility due to added binder
High labour and equipment cost.
Excellent flow properties High space and time requirement.
Good distribution and uniform
content for low dose drugs.
Large no. of steps.
Prevention of segregation. Migration of soluble dyes.
Improve the dissolution rates for
hydrophobic drugs
Aggravation of incompatibilities
between formulation components
47

48. Compression
48
“External mechanical force applied to a
powder mass reduction in bulk volume’’
• After preparation of granules they are
compressed to get final product.
• The compression is done either by single
punch machine or by multi station
machine (rotary press)

49. • Consolidation
“Increase in mechanical strength of material due
to particle-particle interaction”
• Compaction
“It is the compression & consolidation of two
phases (solid & gas) system due to applied force”
49

50. Effect of Compression
When external mechanical forces applied to a
powder mass there is reduction in bulk volume
as follows:
Particles deformation
1) Elastic deformation eg. Acetyl salicylic acid
2) Plastic deformation -at yield point of elastic.
 Brittle fracture eg. Sucrose
50

51. Sequence of events involved in
formation of tablets
51

52. Compression Stages
• Particle rearrangement
• Deformation
• Fragmentation
• Bonding
• Decompression
• Ejection
52

53. 1) Particle Rearrangement
• During initial stage of compression particles are
subjected to low pressure during this particles
moves with respect to each other.
• Small particles enter voids bet larger particles as
a result volume decreases and density increases.
53

54. 54

55. 2) Deformation
• Elastic – When force is applied deformation
occurs and deformation disappears when release
of stress.
• Plastic – The deformation which doesn’t
completely recover after removal of stress.
• Yield strength – Force required to initiate
plastic deformation.
55

56. 3) Fragmentation
• As compression force increases deformed
particles start undergoing fragmentation due to
high load particles breaks into smaller fragments
leading to formation of new bonding areas.
• Some particles undergo structural break down
called as brittle fracture.
56

57. 5) Decompression
As the upper punch is withdrawn from the die the
tablet is confined in die cavity by radial pressure
consequently any radial change during
decompression must occur in axial direction.
4) Bonding
• When particles approach each other close enough
the unsatisfied forces present on their surface lead
to formation of strong attractive forces/bonding
formation of strong attractive forces.
57

58. 6) Ejection
• As lower punch rises and push tablet upward
there is continuous residual die wall pressure
and energy may be expanded due to die wall
friction.
• As the tablet is removed from die pressure is
released.
58

59. CASE STUDY
A COMPARATIVE EVALUATION OF DIRECT
COMPRESSION AND WET GRANULATION
METHODS FOR FORMULATION OF
STAVUDINE TABLETS.
By Prof. Sunil Kumar
Prof. K. P. R. Chowdary
Prof. P. Suresh
59

60. ABSTRACT
• The objective of the present study is to make a
comparative evaluation of direct compression
and wet granulation methods for formulation of
stavudine tablets.
• Stavudine is a widely prescribed antiretroviral
drug used for treating HIV infections.
60

61. EXPERIMENTAL
Materials:
• Stavudine
• Acacia, PVP K30,
• Crospovidone, Lactose, Lubritose AN, Lubritose
SD,
• Lubritose MCC, Talc and Magnesium stearate
• PGS-MCC, PGSPVP,
• Starch phosphate and starch citrate
61

62. Methods:
Preparation of Tablets by Direct
Compression Method:
• All the materials required as per the formulae
were blended in a closed polyethylene bag.
• The blends were compressed into tablets on a
tablet punching machine to a hardness of 6
kg/cm sq. using 9 mm concave punches.
62

63. 63

64. Preparation of Tablets by Wet
Granulation Method:
• Drug (stavudine), acacia, PVP K30 and lactose were
thoroughly blended in a dry mortar and granulated with
water (q.s.). The water (q.s.) was added and mixed
thoroughly to form dough mass.
• The mass was passed through mesh No. 12 to obtain wet
granules. The wet granules were dried at 600°C for 2 h.
• The dried granules were passed through mesh No. 16 to
break the aggregates. Crospovidone and the lubricants
(talc and magnesium stearate) were passed through
mesh No 100 on to dry granules and blended in a closed
polyethylene bag.
• The tablet granules were compressed into tablets on a
tablet punching machine to a hardness of 6 kg/cm 2
using 9 mm round and flat punches.
64

65. 65

66. Evaluation of Tablets:
• All the tablets prepared were evaluated for
content of active ingredient, hardness, friability,
and disintegration time and dissolution rate.
• Hardness of the tablets was tested using
Monsanto Hardness tester.
• Friability of the tablets was determined in a
Roche friabilator.
• Disintegration time was determined in a
Labindia tablet disintegration test machine
(Model: DT 1000) using water as test fluid.
66

67. Estimation of Drug Content in the
Tablets
• From each batch of tablets prepared 20 tablets
were accurately weighed and powdered.
• Tablet powder equivalent to 50 mg of drug was
taken for assay into a 100 ml conical flask and
extracted with 3x20 ml quantities of methanol.
• The methanolic extracts were filtered and
collected into a 100 ml volumetric flask and the
volume was made up to 100 ml with methanol.
67

68. • The solution was then suitably diluted with 0.01
M hydrochloric acid.
• The absorbance of the solution was measured at
266 nm.
• Drug content of the tablets was calculated using
the standard calibration curve.
68

69. Dissolution Rate Study:
• Dissolution rate of the tablets prepared was
studied employing USP 8 station Dissolution
Rate Test Apparatus with a paddle stirrer at 50
rpm. Hydrochloric acid, 0.01 M (900 ml) was
used as dissolution fluid as prescribed for
stavudine tablets in I.P 2010.
• One tablet was used in each test. A temperature
37±1°C was maintained throughout.
• Samples of dissolution medium (5 ml) were
withdrawn through a filter (0.45μ) at different
time intervals and assayed for stavudine at 266
nm.
69

70. RESULTS AND DISCUSSION
• Hardness of the tablets was in the range 5. 0–6.5
Kg / sq. cm.
• Weight loss in the friability test was in the range
0.65 – 1.65 %.
• The drug content of the tablets was within 100 ±
3%
• Lubritose MCC, Starch citrate and Starch
phosphate gave very rapid disintegration of the
tablets within 1 min.
70

71. 71

72. • Co-processed excipients, PGS-MCC and PGS-
PVP also gave rapid disintegration within 2-3
min.
• Lubritose MCC, starch phosphate and starch
citrate gave relatively higher dissolution than the
others.
• Tablets prepared using PVP as binder gave
higher dissolution than those prepared using
acacia as binder.
72

73. 73

74. CONCLUSIONS
• Tablets of good quality fulfilling the official
specifications with regard to drug content,
hardness, friability and disintegration time could
be prepared by both the methods.
• The tablets prepared by direct compression
method disintegrated very rapidly when
compared to those prepared by wet granulation
method.
74

75. • Tablets prepared by direct compression method
gave very rapid dissolution of the contained
drug, 100% within 20 min.
• In the case of wet granulation method, the
tablets gave relatively low dissolution. When
compared to those prepared by direct
compression method. The dissolution was
complete (100%) in 60 min.
75

76. References
1. Pharmaceutics : The Science of Dosage Form Design, edited
by M. E. Aulton, 2nd edition, Churchill Livingstone
Publications.
2. Eichie, F. E. and Kudehinbu, A. O., Effect of particle size of
granules on some mechanical properties of paracetamol
tablets, African Journal of Biotechnology Vol. 8 (21), pp.
5913-5916, 2 November, 2009 Available online at
http://www.academicjournals.org/AJB
3. Garett Jonathan Morin, The Effects of Lubrication on
Pharmaceutical Granules, 2012
4. Remington : The Science and Practice of Pharmacy, Vol 1,
20th edition, Lippincott Williams and Wilkins, 2001
5. Lachman L., Liberman H. A., Kanig J. L., The Theory and
Practice of Pharmacy, 3rd edition, Indian edition, Varghese
Publishing House, 1987
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