MIXING IS FOR DEVELOPMENT OF UNIFORM TABLET

1. MIXING/BLENDING
&
GRANULATION
SUBMITTED BY
SUBMITTED TO ABDUL MUHEEM
DR. YASMEEN M.PHARM II
SULTANA SEMESTER
DOP DOP PHARMACEUTIC

2. DEFINITION
• Mixing may be defined as a unit operation
that aims to treat two or more components,
initially in an unmixed or partially mixed state,
so that each unit (particle, molecule etc.) of
the components lies as nearly as possible in
contact with a unit of each of the other
components.
• Mixing aims at reducing non- uniformity in
one or more of the properties of a material in
bulk.

3. Main aim of the mixing process is the
production of a blend whose sample reflects
exactly, or at least by pre-defined accuracy, the
ratio of the added base materials
Mixing operation may involve:
single phase system (e.g., blending of miscible
solutions or fast chemical parallel reactions.)
multiphase systems (e.g., solid powders,
dispersion/suspension, emulsification)

4. Types of mixtures
• Types of mixtures
Mixtures may be categorized into three types.
• Positive mixtures - Positive mixtures are formed
from materials such as gases or miscible liquids
which mix spontaneously and irreversibly by
diffusion, and tend to approach a perfect mix.
• Negative mixtures- With negative mixtures the
components will tend to separate out. If this
occurs quickly, then energy must be continuously
input to keep the components adequately
dispersed, e.g. with a suspension formulation,
such as calamine lotion.

5. • Neutral mixtures - Neutral mixtures are said
to be static in behaviour, i.e. the components
have no tendency to mix spontaneously or
segregate spontaneously once work has been
input to mix them. Examples of this type of
mixture include mixed powders, pastes and
ointments

7. • Depending upon the relationship between the
shear rate and the applied shear stress, the
fluids may be divided into:
Newtonian Fluids
Non-Newtonian fluids

8. Newtonian flow:
• For it the rate of shear is proportional to the
applied stress.
• Such fluid have a dynamic viscosity
independent of flow rate.

9. Non Newtonian fluid:
• Rate of shear is not proportional to applied
stress.
• These exhibit dynamic viscosity that are a
function of shear stress.

10. Liquid Mixing
mechanisms
Bulk Turbulent Laminar Molecular
transport flow flow diffusion

11. 1.Bulk transport:
•The movement of relatively large portion of the
material being mixed from one location in the
system to another.
•This is usually accomplished by means of paddles,
revolving blades, or other devices within the mixer
arranged so as to move adjacent volumes of fluid
in different direction.

12. 2.Turbulent mixing:
• It is the direct result of turbulent fluid flow which is
characterized by a random fluctuation of the fluid
velocity at any given point within the system.
• The fluid velocity at a given instant may be expressed as
the vector sum of its component in the X,Y,and Z
direction.
• Turbulent flow, the fluid has a different instantaneous
velocities at different location at same instant in time.

13. 3.Laminar mixing:
• Streamline or laminar flow is frequently encountered
when highly viscous fluid are being processed.
• When two dissimilar liquids are mixed through laminar
flow the shear that is generated stretches the interface
between them.
• If the mixer employed forces the layer back upon
themselves ,the number of layer, and hence the
interfacial area increase exponentially with time.

14. 4.Molecular diffusion:
• Primary mechanism responsible for mixing at the
molecular level is diffusion resulting from the thermal
motion of molecules.
• When it occurs in conjugation with laminar flow,
molecular diffusion tends to reduce the sharp
discontinuities at the interface between the fluid layers
• Process if allowed for sufficient time results in complete
mixing

15. EQUIPMENTS.
Equipment Selection, Factors:
 Physical properties of the materials to be
mixed…like density, viscosity, and miscibility.
 Economic considerations regarding processing,
e.g. Time required and power expenditure
necessary, and
 Cost of equipment and its maintenance

16. Equipment's:
Impellers
Distinction between impellers is made on the basis of :
A. Type of flow pattern they produce
• Radial flow
• Axial flow
• Tangential flow
B. Shape and pitch of blades

17. Propellers :
Propellers primary induce axial flow and a very little
tangential flow.
Intense turbulence occurs in the immediate vicinity of
the propellers.
They are most effective when they are run at high speed
in liquids of relatively low viscosity.

18. Turbines:
Blades do not have constant pitch throughout their
length.
When radial and tangential flow is desired blades set at
90-degree angle to their shaft are employed
Tilted blades produce axial flow similar to propellers.
Suitable for viscous fluid( viscosity 1000 times greater
than fluid in which propellers operates.

19. Paddles:
Normally operates at low speeds ( 50 rpm).
Blade have a large surface area in relation to tanks in
which they are employed.
Circulation is primarily tangential.
Effectively mix viscous liquid and semisolids.

20. 2. Air jets:
Subsurface jets of air or less commonly of some other
gas, are effective mixing devices for certain liquids.
Liquid must be of low viscosity, non foaming ,unreactive
with gas, and nonvolatile.
Jets are so arranged that the buoyancy of bubbles lift
liquids from the bottom to the top of the mixing vessel

21. Fluid jets:
When liquids are to be pumped into a tank for mixing,
the power required for pumping often can be used to
accomplish the mixing operation.
Fluid are pumped through nozzles arranged to permit
good circulation of material throughout the tank.
They create somewhat turbulent flow in the direction of
their axis.

23. • Most of the multiparticulate solids as bulk powders or
tablet granules behave somewhat like fluids.
• Well mixed powders are often observed to undergo
substantial segregation during routine handling.
Variables effecting solid mixing:-
 Particle size and particle size distribution are important
since they largely determine the magnitude of
forces, gravitational and inertial.
 The particles having mean particle size less than
100microns are considered to be free flowing.
 The variables like density, elasticity , surface
roughness, and shape also exert their influence on the
bulk properties of powders.

24. Mixing mechanism
Solid mixing proceeds by the combination of
one or more mechanism.
1.Convective mixing
2. Shear mixing
3. Diffusive mixing

25. 1.Convective mixing:
Mechanism is analogous to bulk transport in fluid
mixing.
Convective mixing can occur by
a. An inversion of the powder bed
b. Blades or paddles
c. Revolving screw
d. Any method of moving relatively large mass of
material from one part of the powder bed to
another.

26. 2. Shear mixing:
Depending on flow characteristic these can occur singly
or in such a way to give rise to laminar flow.
When shear occurs between regions of different
composition and parallel to their interface ,it reduce the
scale of segregation by thinning the dissimilar layers.
It thus reduces the scale of segregation.

27. 3.Diffusive mixing:
• Mixing by diffusion is said to occur when random
motion of particles within a powder bed causes them to
change position relative to one another.
• Such an exchange of positions by the single particle
results in reduction of intensity of the segregation.
• It occurs at the interfaces of dissimilar regions that are
undergoing shear and therefore results from shear
mixing.
• It may also be produced by any form of agitation that
results in interparticulate motion.

28. PROBLEMS RELATED TO MIXING.
Segregation
Particles tend to segregate due to differences in the size,
density, shape, and other properties of the particles of
which they are composed.
Powders that are not free-flowing or that exhibit high
forces of cohesion or adhesion b/w particles are difficult
to mix due to agglomeration.
Clumps can be broken by use of mixers that generate
high shear forces.
However these are less susceptible to segregation due
to high interparticulate forces that resist interparticulate
motion leading to unmixing

29. • Problem of segregation is worse when one is working
with free flowing, cohesion less, or nearly cohesion less
particulate matter.
• Segregation has been also attributed by mixers.
• Those that generate principally convective motion have
been classified as non-segregating.
• While those producing shear or diffusive mixing are
classified as segregating.

30. • Two quantities to describe the degree of mixing –namely
the scale of segregation & the intensity of segregation.
• Scale of segregation –analogous to the scale of
turbulence, expressed in two ways-
• The linear scale may be considered to represent an
average value of the diameter of the lumps present.
• Volume scale roughly corresponds to the average lumps
to the average lump volume
• Intensity of segregation is a measure of the
variation in composition among the various
portions of the mixture. When mixing is complete
–intensity of segregation is zero.

31. Equipment for solid mixing
 Most common are mixers which consists of containers
of one or several geometric forms, which are mounted
and can be rotated.
 Resulting tumbling motion is accentuated by means of
baffles or simply by virtue of shape of the container.
TWIN-SHELL BLENDER/TUMBLING MIXERS
 Quite effective because the bulk transport and shear are
accentuated by this design.

32. •Efficiency is dependent on speed of rotation.
•Optimum rotation is 30-100 rpm.

33. STATIONARY CONTAINER TYPE:-
It employs a stationary container to hold the material and
bring about mixing by means of moving screws, paddles,
or blades.
Useful in mixing solids that have been wetted and
therefore are in a sticky or plastic state.
Well known mixers include
1. The Ribbon blender:
• Consists of horizontal cylindrical tank usually opening
at the top and fitted with helical blades.

34. • The blades are mounted on shaft through the long axis
of the tank and have both right and left hand twist

35. HELICAL FLIGHT MIXERS
• Powders are lifted by a centrally located vertical screw
and allowed to cascade to the bottom of the tank.

36. GRANULATION

37. Granulation
• Granules are aggregations of fine particles of
powders in a mass of about spherical shape

38. Why we prepare granules when we have
powders?
1. To avoid powder segregation, if the powder is
composed of particles with different dimensions
& different densities, a separation between
these particles will occur.
2. To enhance the flow of powder, Higher flow
ability gives better filling of the dies or
containers, during a volumetric dosage.

39. 3. Granules have higher porosity than powders,
4. To improve the compressibility of powders.
5. The granulation of toxic materials will reduce
the hazard of generation of toxic dust, which
may arise during the handling of the powders.
6. Materials, which are slightly hygroscope, may
adhere & form a cake if stored as a powder.

40. • Technologically, granules are used according to
two visions:
1. As a true & proper pharmaceutical dosage form ,
These granules are used to prepare an instant
solution or suspension.
Granules, can be packaged as:
 Bulk granules (Multi-dosage containers),
 Divided granules (Mono-dosage containers ).

41. 2.Semi-finished products for the preparation
of tablets or other dosage forms.
Usually, granules have an excellent
compressibility,

42. Granulation technology on large scale by various techniques

43. GRANULE GROWTH AND CONSOLIDATION
.

44. Mechanisms of Granulation
There are Five Particle Bonding Mechanisms,
 Adhesion and cohesion forces in the immobile liquid films
 Interfacial forces in mobile liquid films within the granules
 Formation of solid bridges after solvent evaporation
 Attractive forces between solid particles
 Mechanical interlocking

45. Mechanisms of Granulation
 Adhesion and cohesion forces in immobile liquid films between
individual primary powder particles.
 Interfacial forces in mobile liquid films
 Solid bridges
Partial mellting, Binder hardening, crystalization of dissolved sub.
 Attractive forces between solid particles
 Mechanism of granule formation

46. Steps to make powder ready for compression
Weighing
Mixing
Granulation
Screening
Drying
Screening
Lubrication
Compression
46

47. Granulation Equipments
(Granulators)
 Dry granulator
47
 Wet granulator

48.  Dry granulators:
 Sluggers
 Roller Compactors
Is used when……
 Effective dose of drug is too high for
direct compression
 Drug is sensitive to heat or moisture or
both.
48

49. Wet granulators
 Shear mixer granulator
49
 High speed granulator
 Fluidized bed granulator
 Spray driers

50. WET GRANULATION: some equipment….
High Shear Littleford Lodige Mixer/Granulator
Granulator Littleford MGT Granulator
Diosna Granulator
Gral Mixer/Granulator
Granulator with Fluidized Bed Granulator
Drying Facility Day Nauta Mixer Processor
Double cone/Twin Shell Processor
Topo Granulator
Special Granulator Roto Granulator
Marumerizer
50

51.  Wet granulation equipment
 shear granulator

52. SOP Of Shear Mixture Granulator:
 Mixed powder are fed in to the bowl
 Granulating liquid is added
 The moist mass has then transferred to a granulator
such as oscillating granulator

53. Disadvantage
 Long duration
 Large number of equipment are needed
 High material loss
Advantage
 Not very sensitive to the material
 End point can be determined by inspection

54. High speed granulator
 Widely used in pharmaceutical
 SS mixing bowl containing a three blade main
impeller, revolves in horizontal plane, and a three blade
auxiliary chopper –revolves vertical or horizontal plane
 Unmixed powder –in the bowl mixed for few minute with
rotating impeller
 Granulation

55. High speed granulator

56. Diosna Mixer / Granulator
 Rapid Mixer Granulator (RMG)
 Gives more normal PSD
with lesser fines.
 Typical Time Sequence
 Mixing – 2 minutes
 Granulation – 8 minutes
 Discharge – 1 minutes
blade chopper 56

57. Rapid Mixing Granulator: (RMG)
57

58.  Advantage
Mixing,Massing,Granulation in a single equipment
within few minutes
 Disadvantage
End point monitor needed

59. Suction Fan
Designs of FB granulators
 Top spray Fabric Filter Bag
 Bottom spray Spray Nozzle
Air Filter
 Rotating disc
granulator
Air Heater Product Bed
Granulating solution

60. Fluidized Bed Granulator

61. Fluidized Bed Granulator
Advantage
 One unit so saving labour cost, transfer loses and time
 2-6 time greater heat transfer than tray dryer
 Uniform drying….prevent mottling.
 Process can be automated once parameters optimized
Disadvantage
 Expensive
 Multiple process variable
 Filter clocking, demixing, electrostatic charge, solvent
explosion

62. Fluidized Bed Granulator
(Industrial Equipment)
62

63. Merumizer (spheronizer)
 Wet mass containing drug, diluents and binder is pass
through extruder to get rod shaped segments.
Screw-feed Extruder Cylinder
 Segments are placed in MERUMIZER where they are shaped into
sphere by centrifugal and frictional forces produced by rotating
plates/blades and form granules
 Advantage
Granules with regular size, shape with lower friability, so
less amount of fines.

64. Other More Specialized Granulators
 Spray Driers

65.  Pelletizers

66. References:
1. Lachman leon, Liberman A. herbeart “The
Theory and Practice of Industrial pharmacy” 3rd
edition, page 3-20
2. Gilber S banker and C.T.Rhodes, Modern
pharmaceutics 2nd edition.
3. Cooper and Guns “tutorial pharmacy” 6th
edition ‘Mixing’.
4. C.V.S Subramanium’’Pharmaceutcal
engineeering” 3rd edition ‘Mixing’.