MIXING Prepared by ANFAL MOHAMMED M Sc Introduction

MIXING Prepared by ANFAL MOHAMMED M. Sc.

Introduction • The term MIX means to put together in one mass. • The term BLENDING means to mix smoothly together during which a minimum energy is imparted to the bed. • The terms MIXING and BLENDING are commonly used interchangeable in the pharmaceutical industry. Demixing or Segregation is the opposite terms. 03/03/2016 Mixing: Theory and Equipment 2

MIXING ØIt is a process that tends to randomization of dissimilar particles within a system. (Or) ØIt is an operation in which two or more than two components in separate or partially mixed conditions are treated so that each particle lies as nearly as possible in contact with a particle of each other. 03/03/2016 Mixing: Theory and Equipment 3

03/03/2016 Mixing: Theory and Equipment 4

03/03/2016 Mixing: Theory and Equipment 5

Classification of mixing A. B. C. D. 03/03/2016 Mixing of solids Mixing of liquids Mixing of immiscible liquids Mixing of semisolids Mixing: Theory and Equipment 6

A. Mixing of solids • In the manufacture of tablets or granules, normally a number of additives are added. Therefore mixing of powder becomes essential part of the process. • Mixing is considered as a critical factor, especially in case of potent drugs and low dose drugs where high amounts of adjuvants are added. • The diverse characteristics of particles such as size, shape, volume , surface area, density, porosity , flow, and charge contribute to the solid mixing. 03/03/2016 Mixing: Theory and Equipment 7

Mechanism of solid mixing 1. Convective mixing/Macro mixing: Inversion of the powder bed using blades or paddles or screw element, in which large mass of material moves from one place to another. 2. Shear mixing: In this type, forces of attraction are broken down so that each particle moves on its own between regions of different components and parallel to their surface (laminar flow). 3. Diffusive mixing/Micro mixing: Involves the random motion of particle within the powder bed, thereby particles change their position relative to one another. 03/03/2016 Mixing: Theory and Equipment 8

Segregation of particles occurs due to a number of reasons and can be met by the earth's gravitational field, or by centrifugal, electrical or magnetic field that generated during the process. Mixing can prevent it • Poor flow properties. • Particle size, size distribution, density, shape, and charge differences. • Difference in mobilities. It may occur during and after mixing, subsequent handling and Transporting stage. 03/03/2016 Mixing: Theory and Equipment 9

Degree of mixing • Ideal mixing or perfect mixing: • Acceptable mixing: Fig. Different states of powder mixing. (a) Complete segregation. (b) An ideal or ‘perfect’ mix. (c) A random mix. 1. Random mixing: the probability of finding one type of particle at any point in the mixture is equal to its proportion in the mixture. 2. Ordered mixing 03/03/2016 Mixing: Theory and Equipment 10

Factors influencing mixing • • • 03/03/2016 Nature of the surface Density of the particles Particle size Particle shape Particle charge Proportion of materials Mixing: Theory and Equipment 11

EQUIPMENT Criteria: 1. Powder bed should not be filled for more than 60% 2. Particles should be subjected to movement in three directions 3. Shearing force should be sufficient to prevent aggregation 4. There should be no centrifugal effect 5. Forces should not cause breakage of the particles 6. The mixing process should be stopped abruptly 03/03/2016 Mixing: Theory and Equipment 12

Classification of equipment for solid mixing • Based on flow properties: 1. Free flowing solids: e. g. : V shape blender , Double cone blender 2. Cohesive solids: e. g. : Sigma blender, Planetary mixer • Based on scale of mixing: 1. Batch type(small scale): e. g. : Mortar and pestle, V shape blender, Double cone blender, Ribbon blender, Sigma blender, Planetary paddle, Fluidized mixer 2. Continuous type(large scale): e. g. : barrel type, zigzag type 03/03/2016 Mixing: Theory and Equipment 13

S. no. Nature of mixer Examples Mechanism of mixing 1 Batch type Mortar pestle Trituration 2 Tumbling mixers or cylindrical mixers with no mixing blade Double cone blender V cone blender Tumbling action 3 Tumbling mixer with a mixing blade V cone blender double cone blender Tumbling action as well as shearing with blade 4 Static mixers Ribbon blender Sigma blender Planetary paddle Stationary shell and rotating blade 5 Air mixers or fluidized mixers Fluidized mixer Air supported blending 6 Continuous type Barrel type Zigzag type Rotating shell with rotating blade 03/03/2016 Mixing: Theory and Equipment 14

Tumblers or Cylindrical blenders with no mixing blade • Meant for dry powders • Equipment consists of a container of any geometric form(cone, drum). • Container is mounted on special roller so that it can be rotated about an axis. • Efficiency of a tumbler mixer highly depends on the speed of rotation. It should be critical and optimum. • Too Slow rotation lead to no intense tumbling, No cascade motion, Not enough shear rates are applied. • Rapid rotation-sufficient centrifugal action to the powder and then goes to the side of the mixer, more dusting and segregation of fines is possible. • Rate of rotation depends upon size , shape of the tumbler and nature of the material to be mixed. Common range is 30 -100 rpm. • Mixing is done by tumbling motion, which is accentuated by the shape of the container. 03/03/2016 Mixing: Theory and Equipment 15

Twin shell or V-shape blender • It is V shaped and made up of stainless steel or transparent plastic. • Material is loaded through shell hatches and emptying is normally done through and apex port. • The material is loaded approximately 50 -60% of the total volume. • As the blender rotates , the material undergoes tumbling motion (bulk transport). • When V is inverted, the material splits into two portions (shearing). This process of dividing and recombining continuously yields ordered mixing by mechanical means. 03/03/2016 Mixing: Theory and Equipment 16

Double cone blender • It consists of double cone on rotating shaft. • It is usually used for small amount of powders. • It is efficient for mixing powders of different densities. • Material is loaded and emptying is done through the same port. • The rate of rotation should be optimum depending upon the size, shape of the tumbler and nature of the material to be mixed. • The rate of rotation commonly ranges from 30 -100 rpm. • Mixing occurs due to tumbling motion. 03/03/2016 Mixing: Theory and Equipment Double cone blender 17

Advantages of V cone blender and double cone blenders: • If fragile granules are to be blended, twin shell blender is suitable because of minimum attrition. • They handle large capacities. • Easy to clean , load, and unload. • This equipment requires minimum maintenance. Disadvantages of V cone blender and double cone blenders: • Twin shell blender needs high headspace for installation. • It is not suitable for fine particulate system or ingredients of large differences in the particle size distribution, because not enough shear is applied. • If powders are free flowing, serial dilution is required for the addition of low dose active ingredients. 03/03/2016 Mixing: Theory and Equipment 18

Tumbling blenders with agitator mixing blades 03/03/2016 Mixing: Theory and Equipment 19

Advantages of tumblers with blades: • Baffles are useful for both wet and dry mixing. • Wide range of shearing force can be applied with agitator bars permitting the intimate mixing of very fine as well as coarse powders. • Serial dilution is not needed when incorporating low-dose active ingredients. Disadvantages of tumblers with blades: • Attrition is large, size reduction of friable particles results. • Cleaning may be a problem, because agitator assembly must be removed and the packing should be replaced for a product changeover • Potential packing (sealing) problems occur. 03/03/2016 Mixing: Theory and Equipment 20

Agitator mixers: 1. Ribbon blender Principle: Mechanism of mixing is shear. Shear is transferred by moving blades. High shear rates are effective in breaking lumps and aggregates. Convective mixing also occurs as the powder bed is lifted and allowed to cascade to the bottom of the container. An equilibrium state of mixing can be achieved. Construction: • Consists of stationary horizontal cylindrical container usually open at the top. It is fitted with two helical blades, which are mounted on the same shaft through the long axis of the container. • Blades have both right and left hand twists. • Blades are connected to fixed speed drive. • It can be loaded by top loading and emptying is done through bottom port. Mixing: Theory and Equipment 03/03/2016 21

Working: in opposite direction Uses: Ø Used for mixing of finely divided solids, wet solid mass, and plastic solids as they not depend on the gravity as tumblers. Ø Uniform size and density materials can be easily mixed. Ø Used for solid – solid and liquid – solid mixing. 03/03/2016 Mixing: Theory and Equipment 22

Advantages of ribbon blender: • High shear can be applied by using perforated baffles, which bring about a rubbing and breakdown aggregates. • Requires less space. Disadvantages of ribbon blender: • It is a poor mixer • Shearing action is less than that in planetary mixer. • Dead spots are observed in the mixer, though they are minimum. • It has fixed speed drive. 03/03/2016 Mixing: Theory and Equipment 23

2. Planetary mixer Principle: Mechanism of mixing is shearing. Shear is applied between moving blade and stationary wall. Mixing arm moves around its own axis and around the central axis so that it reaches every spot of the vessel. The plates in the blades are sloped so that powder makes an upward movement to achieve tumbling action also. Construction: • Consists of vertical cylinder shell which can be removed. • The blade is mounted from the top of the bowl. • Mixing shaft is driven by planetary gear and it is normally built with variable speed drive. 03/03/2016 Mixing: Theory and Equipment 24

Uses : • Break down agglomerates rapidly. • Low speeds are used for dry blending and fast for wet granulation. Advantages: • Speed of rotation can be varied. • More useful for wet granulation process. Disadvantages: • Mechanical heat is buildup within the powder mix. • It requires high power. • It has limited size and is useful for batch work only. 03/03/2016 Mixing: Theory and Equipment 25

Air mixer or Fluidized mixer Principle: The air movement is used for mixing powders. Air is admitted at its base at an angle which gives tumbling action and spiral movements to the powder. Thus mixing is achieved. Construction: • It consists of stationary vessel which may be horizontal or vertical which is made up of stainless steel. • A wire mesh is placed at the bottom of the vessel which acts as support for placing the materials. • Air is allowed from beneath the mesh and circulated by using a fan. 03/03/2016 Mixing: Theory and Equipment 26

Advantages of fluidized mixer: • • Reduced mixing time Mixing is efficient Useful for drying and wet massing. Also useful for coating with some modifications. Processors or Rapid Mixer-Granulator: Diosna mixer-granulator It utilizes: • Bowel mounted in the vertical positions • A high speed mixer blade revolving around the bottom of the bowel • A high speed chopper blade functions as a lump and agglomerate breaker 03/03/2016 Mixing: Theory and Equipment 27

Barrel type continuous mixer Principle: Rotating shell keeps the material under tumbling motion. When the material approach the mid-point of the shell, a set of baffles causes part of the material to move towards the direction of inlet end allowing the remaining part to move forward. This process continuous up to discharge end, while another set of baffles guide the material to the discharge port. Construction: Resembles large cement mixer. Baffles are fitted to the inner surface of the shell. Shell is fixed to a shaft, which is allowed to rotate using electrical power. Side openings are provided on each side for charging and discharging of the material. 03/03/2016 Mixing: Theory and Equipment Barrel Type continuous mi 28

Applications of solid mixing • Involved in the preparation of many types of formulations. • It is also an intermediate stage in the production of several dosage forms. – Wet mixing in the granulation step in the production of tablets and capsules. – Dry mixing of several ingredients ready for direct compression as in tablets. – Dry blending of powders in capsules, compound powders. – Production of pellets for capsules. 03/03/2016 Mixing: Theory and Equipment 29

B. Mixing of Fluids Mechanism: • Bulk transport: Movement of large portion o a material from one location to another location in a given system. Rotating blades and paddles are used. • Turbulent mixing: Highly effective, mixing is due to turbulent flow which results in random fluctuation of the fluid velocity at any given point within the system. • Laminar mixing: Mixing of two dissimilar liquids through laminar flow, the applied shear stretches the interface between them. Frequently encountered for highly viscous fluids. • Molecular diffusion: The primary mech. Responsible for Mixing at molecular level in which molecules diffuse due to thermal motion of it. 03/03/2016 Mixing: Theory and Equipment 30

Mixing Apparatus for fluids • A Tank or Container For holding materials • A Mixing Device or Impeller for supplying energy 03/03/2016 Mixing: Theory and Equipment 31

Mixing Device (impellers) • For limited material volume BATCH mixing is used • For large material volume CONTINOUS mixing is preferred • The flow pattern during mixing may be Radial (perpendicular), Axial (parallel ) to the shaft or Tangential ( tangential to the circle of rotation around the shaft) • Based on the flow pattern they produce, on shape and pitch of the blades , the are classified into 3 types: » Propellers » Turbines » Paddles 03/03/2016 Mixing: Theory and Equipment 32

Flow pattern during mixing 03/03/2016 Mixing: Theory and Equipment 33

Propellers • It consists of number of blades, generally 3 bladed design is most common for liquids. Blades may be right or left handed depending upon the slant of their blades. • Two or more propellers are used for deep tank. • Size of propeller is small and may increased up to 0. 5 metres depending upon the size of the tank. • Some tangential flow produced, but the primary effect is due to axial flow. 03/03/2016 Mixing: Theory and Equipment 34

Advantages of propellers: Used when high mixing capacity is required. Effective for liquids which have maximum viscosity of 2. 0 pascals. sec (low viscosity). Effective gas-liquid dispersion is possible at laboratory scale. Disadvantages of propellers: Propellers are not normally effective with liquids of viscosity greater than 5 pascal. second, such as glycerin castor oil, etc. , 03/03/2016 Mixing: Theory and Equipment 35

Turbines • A turbine consists of a circular disc to which a number of short blades are attached. Blades may be straight or curved. • The diameter of the turbine ranges from 30 -50% of the diameter of the vessel. • Turbines rotates at a lower speed than the propellers (50 -200 rpm). • Flat blade turbines produce radial and tangential flow but as the speed increases radial flow dominates. Pitched blade turbine produces axial flow. Near the impeller zone of rapid currents, high turbulence and intense shear is observed. Shear produced by turbines can be further enhanced using a diffuser ring (stationary perforated ring which surrounds the turbine). Diffuser ring increase the shear forces and liquid passes through the perforations reducing rotational swirling and vortexing. 03/03/2016 Mixing: Theory and Equipment 36

Advantages of Turbines: • Turbines give greater shearing forces than propellers. Therefore suitable for emulsification. • Effective for high viscous solutions with a wide range of viscosities up to 7. 0 Pascal. Second. • In low viscous materials of large volumes turbine create a strong currents which spread throughout the tank destroying stagnant pockets. • They can handle slurries with 60% solids. • Turbines are suitable for liquids of large volume and high viscosity, if the tank is baffled. 03/03/2016 Mixing: Theory and Equipment 37

Paddles • A paddle consists of a central hub with long flat blades attached to it vertically. • Two blades or four blades are common. sometimes the blades are pitched and may be dished or hemispherical in shape and have a large surface area in relation to the tank in which they are used. • Paddles rotates at a low speed of 100 rpm. • They push the liquid radially and tangentially with almost no axial action unless blades are pitched. • In deep tanks several paddles are attached one above the other on the same shaft. • At very low speeds it gives mild agitation in unbaffled tank but as for high speeds baffles are necessary. 03/03/2016 Mixing: Theory and Equipment 38

Uses of paddles: Paddles are used in the manufacture of antacid suspensions, agar and pectin related purgatives, antidiarrheal mixtures such as bismuth-kaolin. Advantages of paddles: Vortex formation is not possible with paddle impellers because of low speed mixing. Disadvantages of paddles: Mixing of the suspension is poor therefore baffled tanks are required. 03/03/2016 Mixing: Theory and Equipment 39

Vortex formation • A strong circulatory flow pattern sometimes manifests into formation of a vortex near the impeller shaft. Vortex can be formed when • Shaft is placed symmetrically in the tank. • Blades in the turbines are arranged perpendicular to the central shaft. • At high impeller speeds • In unbaffled tanks 03/03/2016 Mixing: Theory and Equipment 40

Disadvantages of vortex formation • Vortex formation reduces mixing intensity by reducing velocity of the impeller relative to the surrounding fluid. • When vortex reaches the impeller, air from the surface of the liquid are drawn and air bubbles are produced. • Air bubbles in the fluid can create uneven loading of the impeller blades. • Entrapped air causes oxidation of the substances in certain cases. 03/03/2016 Mixing: Theory and Equipment 41

Prevention of vortex formation 1. Impeller should in any one of the position that can avoid symmetry such as off central, inclined, side entering, etc. , and should be deep in the liquid. 2. Baffled containers should be used. In such case impeller can be mounted vertically at the center. 03/03/2016 Mixing: Theory and Equipment 42

3. Two or more impellers are mounted on the same shaft where greater depth is required. This system is known as push and pull mechanism. The bottom impeller is placed about one impeller diameter above the bottom of the tank. It creates zone of high turbulence. 03/03/2016 Mixing: Theory and Equipment 43

4. Tank other than cylindrical in shape are used to prevent vortex formation. However, such shapes may facilitate the formation of dead spots 03/03/2016 Mixing: Theory and Equipment 44

Factors influencing mixing of liquids in tanks Ø Material related factors– Properties of liquids: physical properties of materials to be mixed. e. g. : Density, Viscosity and miscibility. Ø Equipment related factors- – Shape of impeller: Propeller type, straight, vertical, curved, or pitched. – Position of impeller: Central, off-center, side entry, vertical or inclined etc. , – Shape and size of the container: cylindrical or other geometric forms. Presence or absence of baffles. – Cost of equipment and its maintenance. Ø Process related factors– – – Speed of rotation of the impeller. Time required for mixing. Amount of power that can be expended. Ease of operation. Batch size. 03/03/2016 Mixing: Theory and Equipment 45

Equipment for Liquid mixing 1. Air jet mixer 2. Fluid Jet mixer 3. Flow mixer or line mixer or pipe mixer 03/03/2016 Mixing: Theory and Equipment 46

1. Air jet mixer Principle: When compressed air jets are passes from the bottom of a vessel, air bubbles are formed in the liquid phase. The buoyancy of the bubbles lifts the liquids (LOW VISCOSITY, NONFOAMING, NONREACTIVE, NONVOLATILE), which are confines to the central portion due to the presence of draft tubes. The liquids flow down from the periphery of the vessel and enter from the bottom due to suction effect. Construction: Compresses air or suitable gas is allowed to pass at high pressure from the inlet provided at the bottom of the tank. This causes buoyancy of the bubbles which lifts the liquid rom bottom to the top of the vessel. 03/03/2016 Mixing: Theory and Equipment 47

2. Fluid jet mixer • It utilize liquids pumped at high pressure through nozzles arranged to permit a good circulation of the material throughout the tank. 03/03/2016 Mixing: Theory and Equipment 48

3. Flow mixer or line mixer or pipe mixer • It may consist a baffled pipe or an empty chamber. • Liquids to be mixed are passed through the pipe/ chamber. • Mixing takes place through bulk transport in the direction of flow. • The power supplied to pump the liquid itself accomplishes mixing. Baffled pipe • For effective mixing, controlling the feed rate is essential. • If the input rate is difficult to control and fluctuations in the added proportions of the liquids are unavoidable, continuous mixing equipment of tank type is preferable, because hold-up of the liquids and back flow or recirculation is possible. 03/03/2016 Mixing: Theory and Equipment 49

Applications of pipe line mixer • Used when large volume of liquids are to be mixed. • Used for continuous mixing. 03/03/2016 Mixing: Theory and Equipment 50

Advantages of liquid mixing • Liquid mixing promotes heat transfer between liquid and a heating source. This step is essential in the crystallization of drug substances. Uniform heat transfer in the solution yields crystals of same size. • Liquid mixing is essential in the manufacture of number of dosage forms. E. g. : – – Suspensions Emulsions Solutions Aerosols 03/03/2016 Mixing: Theory and Equipment 51

D. Mixing of semisolids • Semi solids dosage forms include ointments, pastes, creams, jellies, etc. , The mixing action include combination of low speed shear, smearing, wiping, folding, stretching and compressing • Mixing steps: 1. Initial powder (powder state)with small amount of liquid to form pellets (pellet state) 2. Additional liquid added to form homogenous mixture (plastic state) 3. Additional liquid added with application of shear forces to attain a paste like appearance (sticky state) 4. Further addition of the liquid results in a decrease in consistency till a fluid state is reached (fluid state), in this state the rate of homogenization is rabid and the mixture behave like liquid (liquid mixing) 03/03/2016 Mixing: Theory and Equipment 52

Classification of equipment • kneaders: e. g. : - Sigma-blade and Planetary mixers. • Mills: e. g. : - Triple roller mill and Colloidal mill. Selection of mixing equipment for semi solids • Physical properties of the materials – density, viscosity and miscibility. • Economic considerations regarding processing – time required for mixing and power consumption. • The cost of equipment and its maintenance. 03/03/2016 Mixing: Theory and Equipment 53

Sigma blade mixer Principle – shear. Inter meshing of sigma blades creates high shear and kneading action. Construction and working: • It consists of double tough shaped stationary bowl. • Two sigma shaped blades are fitted horizontally in each tough of the bowl. • These blades are connected to a fixed speed drive. • Mixer is loaded from top and unloaded by tilting the entire bowl. • The blades move at different speeds and opposite direction , one about twice than the other, which allows movement of powder from sides to centers. • The material also moves top to downwards and gets sheared between the blades and the wall of the container resulting cascading action. • Perforated blades can be used to break lumps and aggregates which creates high shear forces. • The final stage of mix represents an equilibrium state. 03/03/2016 Mixing: Theory and Equipment Sigma blade mixer 54

Uses of sigma blade mixer: • Used in the wet granulation process in the manufacture of tablets, pill masses and ointments, • It is primarily used for liquid – solid mixing, although it can be used for solid – solid mixing. Advantages of sigma blade mixer: • Sigma blade mixer creates a minimum dead space during mixing. • It has close tolerances between the blades and the sidewalls as well as bottom of the mixer shell. Disadvantages of sigma blade mixer: • Sigma blade mixer works at a fixed speed. 03/03/2016 Mixing: Theory and Equipment 55

COLLOIDAL MILL Principle: Mechanism of mixing is “shearing”. Construction: high speed rotor, a stator with conical milling surfaces Uses: Used for preparation of colloidal dispersions like emulsions, suspensions, ointments. Particles of 3 µm can be obtained. Advantages: Used in production of sterile products Disadvantages: Heat is generated Not used for dry milling.

Triple roller mill Principle: - High shear , which causes crushing of aggregates, particles and also distributes the drug uniformly throughout the semi solid base. • It consists of 3 parallel rollers of equal diameters made up of stainless steel. • These are mounted on rigid frame work horizontally. • The gap between the first 2 rollers is more than that of the gap between the last two. • A hopper is placed in between the first two rollers. • A scrapper is attached to the last roller. • First roller rotates at lower speed compared to the 2 nd similarly 2 nd roller speed is less than the 3 rd roller. 03/03/2016 Mixing: Theory and Equipment 57

Advantages of triple roller mill • From the small to the large batch - Three roll mills are ideally suited for processing the smallest and also very large quantities • Excellent temperature control - Three roll mills enable excellent control of the product temperature, since the product is processed as a thin film on the roller. This way, the product can be warmed or cooled off depending on your requirements • Avoid contamination - Through the selection of materials for the rollers and scraper knives, which are available in a broad spectrum of chromeplated steel, aluminium oxide, zirconium oxide, and silicon carbide, it is possible to avoid product contamination due to metal abrasion. • Extremely uniform dispersion is obtained. • low material loss. • easy cleaning. 03/03/2016 Mixing: Theory and Equipment 58

03/03/2016 Mixing: Theory and Equipment 59