MIXING/BLENDING

& GRANULATION

SUBMITTED TO DR. YASMEEN

SULTANA DOP

PHARMACEUTICS

FACULTY OF PHARMACY

SUBMITTED BYABDUL MUHEEM

M.PHARM II SEMESTER

DOP PHARMACEUTICSJAMIA HAMDARD

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.

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)

Types of mixtures• Types of mixturesMixtures 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.

• 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

FLUID MIXING AND THEIR MECHANISMS.

• Depending upon the relationship between the shear rate and the applied shear stress, the fluids may be divided into:

Newtonian Fluids

Non-Newtonian fluids

Newtonian flow:• For it the rate of shear is proportional to the

applied stress.• Such fluid have a dynamic viscosity

independent of flow rate.

Non Newtonian fluid:• Rate of shear is not proportional to applied

stress.• These exhibit dynamic viscosity that are a

function of shear stress.

Liquid Mixing

mechanisms

Bulk transport

Turbulent flow

Laminar flow

Molecular diffusion

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.

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.

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.

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

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

Equipment's:

ImpellersDistinction 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

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.

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 employedTilted blades produce axial flow similar to propellers.Suitable for viscous fluid( viscosity 1000 times greater

than fluid in which propellers operates.

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.

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

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.

SOLID MIXING AND THEIR MECHANISMS.

• 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.

Mixing mechanism

Solid mixing proceeds by the combination of one or more mechanism.

1.Convective mixing2. Shear mixing3. Diffusive mixing

1.Convective mixing:Mechanism is analogous to bulk transport in fluid

mixing.Convective mixing can occur by a. An inversion of the powder bedb. Blades or paddlesc. Revolving screwd. Any method of moving relatively large mass of

material from one part of the powder bed to another.

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.

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.

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

• 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.

• 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.

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.

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

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 include1. The Ribbon blender:• Consists of horizontal cylindrical tank usually opening

at the top and fitted with helical blades.

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

HELICAL FLIGHT MIXERS

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

GRANULATION

Granulation

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

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.

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.

• 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 ).

2.Semi-finished products for the preparation of tablets or other dosage forms.

Usually, granules have an excellent compressibility,

Granulation technology on large scale by various techniques

GRANULE GROWTH AND CONSOLIDATION

.

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

Adhesion and cohesion forces in immobile liquid films between individual primary powder particles.

Interfacial forces in mobile liquid films

Solid bridgesPartial mellting, Binder hardening, crystalization of dissolved sub. Attractive forces between solid particles Mechanism of granule formation

Mechanisms of Granulation

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Steps to make powder ready for compression

Weighing

Mixing

Granulation

Screening

Drying

Screening

Lubrication

Compression

Granulation Equipments (Granulators)4

7 Dry granulator

Wet granulator

48

Effective dose of drug is too high for

direct compression

Drug is sensitive to heat or moisture or

both.

Dry granulators: Sluggers

Roller Compactors

Is used when……

Wet granulators4

9

Shear mixer granulator

High speed granulator

Fluidized bed granulator

Spray driers

WET GRANULATION: some equipment….

High Shear Granulator

Littleford Lodige Mixer/Granulator Littleford MGT GranulatorDiosna GranulatorGral Mixer/Granulator

Granulator with Drying Facility

Fluidized Bed GranulatorDay Nauta Mixer Processor Double cone/Twin Shell ProcessorTopo Granulator

Special Granulator

Roto GranulatorMarumerizer

50

Wet granulation equipment shear granulator

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

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

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

High speed granulator

56

Typical Time Sequence

Mixing – 2 minutes

Granulation – 8 minutes

Discharge – 1 minutes

Gives more normal PSD

with lesser fines.

Diosna Mixer / Granulator

Rapid Mixer Granulator (RMG)

blade chopper

57

Rapid Mixing Granulator: (RMG)

Advantage

Mixing,Massing,Granulation in a single equipment

within few minutes

Disadvantage

End point monitor needed

Designs of FB granulators

Top spray

Bottom spray

Rotating disc

granulator

Suction Fan

Fabric Filter Bag

Granulating solution

Product Bed

Spray Nozzle

Air Filter

Air Heater

Fluidized Bed Granulator

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)

Merumizer (spheronizer) Wet mass containing drug, diluents and binder is pass through extruder to get rod shaped segments.

CylinderScrew-feed Extruder

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.

Other More Specialized Granulators Spray Driers

Pelletizers

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’.