PHARMACEUTICAL ENGINEERING

Mixing

Dr. Bhawna Bhatt

Delhi Institute of Pharmaceutical Science and Research Sector – 3, Pushp Vihar

New Delhi

Prof. S.S. Agrawal Principal

Delhi Institute of Pharmaceutical Science and Research Sector – 3, Pushp Vihar

New Delhi

(24-08-2007)

CONTENTS IntroductionObjectivesTypes of MixturesMechanism Rate of MixingTheory of Mixing Liquid mixingLiquid mixersSolid-Solid MixingPowder mixersMixing semi-solidsMixers for semi-solids

Keywords Liquid-liquid mixing, solid-solid mixing, solid-liquid mixing, Propellers, Double cone mixers, Roller mills, Sigma blender, Colloid mill.

1

Introduction Mixing is one of the most common pharmaceutical operations. It is difficult to find a pharmaceutical product in which mixing is not done at one stage or the other during its manufacturing. Mixing may be defined as the process in which two or more than two components in a separate or roughly mixed condition are treated in such a way so that each particle of any one ingredient lies as nearly as possible to the adjacent particles of other ingredients or components. This process may involve the mixing of gases, liquids or solids in any possible combination and in any possible ratio of two or more components. Mixing of a gas with another gas, mixing of miscible low viscosity liquids and mixing of a highly soluble solid with a low viscosity liquid to effect dissolution are relatively simple as compared to the mixing of gases with liquids, mixing of liquids of high viscosity though miscible, mixing of two immiscible liquids such as aqueous and oily solutions to form emulsions, mixing of solids with liquids when the proportion of solids is high and mixing of solids with solids, specialized equipments are required for these operations. Some of the examples of large scale mixing practiced in pharmacy are:

Mixing of powders in varying proportions prior to granulation or tabletting

Dry mixing of the materials for direct compression in tablets

Dry blending of powders in capsules and compound powders (insufflations).

Blending of powders in cosmetics in the preparation of face powders, tooth powders

Dissolution of soluble solids in viscous liquids for dispensing in soft capsules and in the preparation of syrups

Mixing of two immiscible liquids for preparation of emulsions.

Depending on the flow properties of materials, solids are divided into two types:

1. Cohesive materials - These are characterized by their resistance to flow through openings for e.g. wet clay.

2. Noncohesive materials – These materials flow readily such as grain, dry sand, plastic chips etc.

Mixing of cohesive materials is more difficult due to formation of aggregates and lumps. Wet mixing is encountered in pharmacy as an individual operation or as a subsequent step after dry blending. In pharmaceutical practice, solid-solid, solid-liquid and liquid-liquid mixing are generally batch operations where the batch may be as large as one ton. Objectives of mixing Mixing can be done for the following reasons:

• To ensure that there is uniformity of composition between the mixed ingredients which may be determined by taking samples from the bulk material and analyzing them, which should represent overall composition of the mixture.

2

• To initiate or to enhance the physical or chemical reactions e.g. diffusion, dissolution etc. Generally mixing is carried out to obtain following type of products:

• When two or more than two miscible liquids are mixed together, this results in to a solution known as true solution.

• When two immiscible liquids are mixed in the presence of an emulsifying agent, an emulsion is produced.

• When a solid is dissolved in a vehicle, a solution is obtained

• When an insoluble solid is mixed with a vehicle, a suspension is obtained.

• When a solid or liquid is mixed with a semisolid base, an ointment or a suppository is produced.

• When two or more than two solid substances are mixed together, a powder is obtained which when filled into capsule shell is known as capsules and when compressed under heavy pressure is called tablet.

Types of Mixtures Mixtures may be classified as follows:

1. Positive mixtures 2. Negative mixtures 3. Neutral mixtures

I. Positive Mixtures – These types of mixtures are formed when two or more than two gases or miscible liquids are mixed together by means of diffusion process. In this case no energy is required provided the time allowed for solution formation is sufficient. These types of materials do not create any problem in mixing.

II. Negative Mixtures – These types of mixtures are formed when insoluble solids are mixed

with a vehicle to form a suspension or when two immiscible liquids are mixed to form an emulsion. These mixtures are more difficult to prepare and require a higher degree of mixing with external force as there is tendency of the components of these mixtures separate out unless they are continuously stirred.

III. Neutral Mixtures – Many pharmaceutical products such as pastes, ointments and mixed

powders are the examples of neutral mixtures. They are static in their behavior. The components of such products do not have any tendency to mix spontaneously but once mixed, they do not separate out easily.

Many variations occur within the above explained groups owing to the different physical properties of the components of the mixture like viscosity which might change during mixing, the relative densities of the components, particle size, ease of wetting of solids, surface tension of liquids, while other factors such as the proportions of the components and the required order of mixing may exert an influence.

3

Mechanism of Mixing In all type of mixers, mixing is achieved by applying one or more of the following mechanisms:

Convective mixing – During convective mixing transfer of groups of particles in bulk take place from one part of powder bed to another. Convective mixing is referred to as macromixing.

Shear mixing – During shear mixing, shear forces are created within the mass of the material by using agitator arm or a blast of air.

Diffusive mixing – During this mixing, the materials are tilted so that the gravitational forces cause the upper layers to slip and diffusion of individual particles take place over newly developed surfaces. Diffusion is also sometimes referred to as micromixing. Rate of Mixing Mixing is the process of achieving uniform randomness of the mixed components, which on subdivision to individual doses contains the correct proportions of each component which depends on the amount of mixing done. In the early stages of mixing, the rate of mixing is very fast because the mixing particles change their path of circulation quickly and find themselves in different environment whereas at the end of the process rate of mixing reaches to almost zero because the particles do not find different environment. Theory of mixing A significant aspect in mixing is to define when a particular batch is mixed. This depends on the method used for examining the samples and its accuracy, the number and location of the samples and the desired properties of the mixture. Diverse criteria like electrical conductivity of the samples, specific gravity of the samples, the amount of a key constituent in the samples, the rate of solution of a soluble solid in the samples etc. have been used to determine the uniformity of a mixed batch. Some of the recent methods of analysis include X-ray fluorescence, emission spectroscopy, flame spectrometry, radioactive tracer methods etc. But these criteria are not all equivalent. For example, if two aqueous solutions or two oily materials or two powders of two specific gravity are mixed, mixing is said to be accomplished when the specific gravity of the mixture is uniform at all points. But if the specific gravity is determined using a hydrometer, the mixture may appear uniform. But if the more accurate pycnometer is employed, the mixture may appear non-uniform. Still the mixture appearing to be uniform by the hydrometer test may be adequate for the user. Therefore the question whether a particular batch is mixed or not is not absolute but only relative. As for the location of the samples, these points could be fixed arbitrary points decided on experience or points where mixing is known to be poorest. Some other criteria such as the method of sampling, location, size, number of samples, method of sample analysis and fraction of batch removed for sampling are important. The theory of mixing should also be able to predict the time in which a given batch is adequately mixed in a given vessel and how much power is used for mixing. Not much is known about the time factor which is largely a function of the characteristics and proportion of the materials being mixed, the size and shape of the container involved, criteria used to determine when mixing is complete and many other factors.

4

In a two-component mixture, perfect or ideal mixing is said to have been achieved when each particle of one material lies as nearly as possible to a particle of another material. In practical degree of mixing is defined by its standard deviation σ which is equal to (xy/N)1/2 where x and y are the proportions of the components and N is the number of particle in the sample taken. Mixing of pharmaceutical powders is continued until the amount of active drug that is required in a dose is within ± 3 standard deviation of that found by assay in a representative number of sample doses. For this N is to be made large by milling the ingredients to a sufficient degree of fineness. I. Liquid mixing Liquid mixing may be divided into following two subgroups:

1. Mixing of liquids and liquids a) Mixing of two miscible liquids b) Mixing of two immiscible liquids

2. Mixing of liquids and solids a) Mixing of liquids and soluble solids b) Mixing of liquids and insoluble solids

1. (a) Mixing of two miscible liquids (homogeneous mixtures e.g. solutions) – mixing of two miscible liquids is quite easy and occur by diffusion. Such type of mixing does not create any problem. Simple shaking or stirring is enough but if the liquids are not readily miscible or if they have very different viscosities then electric stirrer may be used. Sometimes turbulence may be created in the liquids to be mixed. Turbulence is a function of velocity gradient between two adjacent layers of a liquid. Thus if a rapidly moving stream of liquid is in contact with a nearly stationary liquid, there will be high velocity gradient at the boundary which results in tearing off portions of the faster moving stream and sending it off to the slower moving areas as vortexes or eddies. These eddies persists for some time and ultimately dissipate themselves as heat. This results also in drawing in part of the slow moving liquid into a high velocity liquid because of differences in static pressures created as in an ejector. Most of the mixing equipments are designed on the basis of providing high local velocities but directing them in such a manner that they will ultimately carry their own turbulence or the turbulence of the eddies they create, throughout the mass to be mixed 1.(b) Mixing of two immiscible liquids (heterogenous mixtures e.g. emulsions) – two immiscible liquids are mixed to effect transfer of a dissolved substance from one liquid to another an eg. of such type of mixing is the extraction of penicillin in the acid form from aqueous solution into the organic solvent amyl acetate, to promote a chemical reaction after transfer of a component, to allow transfer of heat from one liquid to the other or to prepare emulsion. When two immiscible liquids are mixed together in the presence of an emulsifying agent an emulsion is produced. For the production of a stable emulsion, the mixing must be very efficient i.e. continuous without ceasing because the components tend to separate out if continuous work is not applied on them.

5

Mixing occurs in two stages: (1) Localized mixing in which shear is applied to the particles of the liquid

(2) A general movement sufficient to take all the particles of the materials through the shearing zone so as to produce a uniform product.

On small scale, for the preparation of emulsions, a pestle and mortar is quite suitable. Here, shear forces are produced between the flat head of the pestle and the flat bottom of the mortar whereas a general movement is produced by continuous movement of the pestle along the sides of the mortar by which the sticking material to the sides is returned to the bottom of the mortar. Generally emulsions are prepared in two stages (i) primary emulsion (ii) secondary emulsion. In the primary stage the two immiscible liquids are triturated with an emulsifying agent to get a primary emulsion, which is further diluted by adding more of vehicle. After the preparation of an emulsion which is coarse in nature may be passed through a homogenizer to get a homogeneous emulsion of desired particle size. 2. (a) Mixing of liquids and soluble solids (homogeneous mixtures e.g. solutions)- in this case soluble solids are dissolved in a suitable liquid by means of stirring. It is a physical change i.e. a soluble solid is converted to a solution. 2.(b) Mixing of liquids and insoluble solids (heterogeneous mixtures e.g. suspensions) – when insoluble solids are mixed with a liquid a suspension is produced which is an unstable system. The ingredients of a suspension separate out when allowed to stand for sometime. Thus a suspending agent is required to produce a stable suspension. On small scale, suspensions may be prepared in a pestle and mortar. Table 1 shows classification of mixing equipments.

Table 1: Classification of mixing equipments

S.No. Type of mixing

Name of the mixer Uses

1

Liquid-liquid mixing

Shaker mixers Propeller mixers Paddle mixers Turbine mixers Sonic and

ultrasonic devices such as Rapisonic homogenizer

Used in the preparation of emulsions, antacid suspensions, mixtures such as anti-diarrhoeal bismuth-kaolin mixtures etc. Rapisonic homogenizer is particulary used in the mixing of immiscible liquids i.e. preparation of emulsions.

2

Solid-solid mixing

Agitator mixers Tumbling mixers Double-cone

mixers V-blenders

Used for the mixing of dry powders.

6

3

Semi-solid mixing

Agitator mixers

like sigma mixers and planetary mixers

Shear mixers like

colloidal mills and triple roller mills

These mixers are used for wet granulation process in the manufacture of tablets, in the production of ointments. Sigma mixers can also be used for solid-solid mixing.

If the aim of the mixing process is simply to produce a blend of two liquids that are readily miscible or to form a solution of a solid in liquid then flow alone may be sufficient but flow is unlikely to prove adequate when the aim of mixing is to produce an emulsion from two immiscible liquids, shear forces being essential. Liquid mixing is usually performed with a mixing element, commonly a rotational device, which provides the necessary shear forces, but is of suitable shape to act as an impeller to produce an appropriate pattern in the mixing vessel. The movement of the liquid at any point in the vessel will have three velocity components and the complete flow pattern will depend upon variations in these three components in different parts of the vessel. The three velocity components are;

• Radial components, acting in a direction vertical to the impeller shaft.

• A longitudinal component, acting parallel to the impeller shaft.

• A tangential component, acting in a direction that is a tangent to the circle of rotation round the impeller shaft.

A satisfactory flow pattern will depend on the balance of the components. Assuming that the impeller shaft is vertical, excessive radial movement, especially if solids are present, will take materials to the container wall, where they fall to the bottom and may rotate as a mass beneath the impeller. If the tangential component is dominant, a vortex forms and may deepen until it reaches the impeller, when aeration occurs. If the longitudinal component is inadequate, liquids and solids may rotate in layers without mixing. This stratification may occur even when rotation is rapid and in the presence of vortexing, when it would appear that mixing is vigorous and satisfactory. The flow pattern will be influenced by factors such as the form of the impeller and its position: for example, whether it is high or low in the vessel, whether mounted centrally or to one side, or whether the shaft is vertical or inclined. Container shape and the presence of baffles will have an effect also. The flow characteristics and mixing behaviour of fluids are governed by three primary laws or principles: conservation of mass, conservation of mass, conservation of energy, and the classic laws of motion.

7

Mixing mechanism Mixing mechanisms for fluids fall essentially into four categories: bulk transport, turbulent flow, laminar flow, and molecular diffusion. Usually more than one of these processes is operative in practical mixing situations. 1.Bulk transport – the movement of a relatively large portion of the material being mixed from

one location in the system to another constitutes bulk transport. A simple circulation of material in a mixer may not necessarily result in efficient mixing. For bulk transport to be effective it must result in a rearrangement or permutation of the various portions of the material to be mixed. This can be accomplished by means of paddles, revolving blades, or other devices within the mixer arranged so as to move adjacent volumes of the fluid in different directions, thereby shuffling the system in three dimensions.

2.Turbulent Mixing – the phenomenon of turbulent mixing is a direct result of turbulent fluid

flow, which is characterized by a random fluctuation of the fluid velocity at any given point with in the system. The fluid velocity at a given instant may be expressed as the vector sum of its components in the x, y, and z directions. With turbulence, these directional components fluctuate randomly about their individual mean values, as does the velocity itself. In general, with turbulence, the fluid has different instantaneous velocities at different locations at the same time. This observation is true for both, the direction and the magnitude of the velocity. If the instantaneous velocities at two points in a turbulent flow field are measured simultaneously, they show a degree of similarity provided that the points selected are not too far apart. There is no velocity correlation between the points, however, if they are separated by a sufficient distance.

Turbulent flow can be conveniently visualized as a composite of eddies of various sizes. An eddy is defined as a portion of fluid moving as a unit in a direction often contrary to that of the general flow. Large eddies tend to break up; forming eddies of smaller and smaller sizes until they are no longer distinguishable. The size distribution of eddies within a turbulent region is referred to as the scale of turbulence. It is readily apparent that such temporal and spatial velocity differences, as a result from turbulence within a body of fluid produce a randomization of the fluid particles. For this reason, turbulence is a highly effective mechanism for mixing. Thus, when small eddies are predominant, the scale of turbulence is low. 3.Laminar mixing – Streamline or laminar flow is frequently encountered when highly viscous

liquids are being processed. It can also occur if stirring is relatively gentle and may exist adjacent to stationary surfaces in vessels in which the flow is predominantly turbulent. When two dissimilar liquids are mixed through laminar flow, the shear that is generated stretches the interface between them. If the mixer employed folds the layers back upon themselves, the number of layers, and hence the interfacial area between them, increase exponentially with time.

4.Molecular diffusion – The primary mechanism responsible for mixing at the molecular level

is diffusion resulting from the thermal motion of the molecules. When it comes in conjunction with laminar flow, molecular diffusion tends to reduce the sharp discontinuities at the interface between the fluid layers, and if allowed to proceed for sufficient time, results in complete mixing. The process is described quantitatively in terms of Fick’s law of diffusion:

8

Dm/dt = -DA dc/dx

Where, the rate of transport of mass, dm/dt across an interface of area A is proportional to the concentration gradient, dc/dx, across the interface. The rate of intermingling is governed also by the diffusion coefficient, D, which is a function of variables including fluid viscosity and size of the diffusing molecules. The concentration gradient at the original boundary is a decreasing function of time; approaching zero as mixing approaches completion. Factors influencing mixing

Nature of the product – Rough surface of one of the components does not induce proper mixing. The reason for this is that the active substance may enter into the pores of the other ingredient. A substance that can adsorb on the surface can decrease aggregation, for e.g. addition of colloidal silica to a strongly aggregating zinc oxide can make it a fine dusting powder which can be easily mixed.

Particle size – Variation in particle size leads to separation as the small particles move

downward through the spaces between the bigger particles. As the particle size increases, flow properties also increases due to the influence of gravitational force on the size. It is easier to mix two powders having approximately the same particle size.

Particle shape – For uniform mixing, the particles should be spherical in shape. The

irregular shapes can become inter-locked and there are less chances of separation of particles once these are mixed together.

Particle charge – Some particles exert attractive forces due to electrostatic charges on

them. This results to separation or segregation. Liquid mixers: Equipments for mixing of miscible liquids, mixing of a soluble solid with a low viscosity liquid Equipments such as shaker mixers, propeller mixers, turbine mixers and paddle mixers are used for liquid mixing. These equipments contain a flat bottomed, unbaffled or baffled cylindrical vessel with tank diameter to liquid ratio usually as 1:1. The vessel is generally made of stainless steel for pharmaceutical operations. Impellers are mixing devices that include paddles, turbines and vaned discs. Shaker mixers – In these mixers, the material present in the containers is agitated either by an oscillatory (for small scale mixing) or by a rotary movement (large scale mixing). Shaker mixers have limited use in industry. Propeller mixers – A device (figure 1-a) comprising a rotating shaft with propeller blades attached, used for mixing relatively low viscosity dispersions (thicker solutions) and maintaining contents in suspension. Propeller mixers are the most widely used form of mixers for liquids of low viscosity. It rotates at a very high speed i.e., up to 8000 r.p.m. due to which mixing is done in a short time. They are much smaller in diameter than paddle and turbine mixers. Uses of propeller mixers: Propellers are used when high mixing capacity is needed. These are effective in handling liquids having a viscosity of about 2.0 Pascals. second.

9

Disadvantages: Propellers are not effective with liquids of viscosity greater than 5 pascals.second for example, glycerin and castor oil.

Figure 1-a Turbine mixer in a baffled tank Figure 1-b A propeller mixer

Paddle mixers – Some of the liquid mixers have paddles which are used as impellers which consist of flat blades attached to a vertical shaft and rotate at low speed of 100 r.p.m. or less. The blades have a large surface area in relation to the container in which they are employed which help them to rotate close to the walls of the container and effectively mix the viscous liquids or semi-solids. A variety of paddle mixers having different shapes and sizes, depending on the nature and viscosity of the product are available for use in industries. Uses of paddle mixers: paddles are used in the manufacture of antacid suspensions, anti-diarroheal mixtures such as bismuth-kaolin mixture. Advantage: Since mixers with paddle-impellers have low speed, vortex formation is not possible with such mixers. Disadvantages: Mixing of the suspensions is poor, thus, baffled tanks are required.

Turbine mixers – turbine mixers (figure 1-b) consist of a circular disc impeller to which a number of short, straight or curved blades are attached. These mixers differ from propellers in that they are rotated at a lower speed than propellers and the ratio of the impeller and container diameter is also low. The former produces greater shear forces than propellers therefore they are used for mixing liquids of high viscosity and has a special application in the preparation of emulsions. Baffles are often used to prevent vortexes.

A mixing vessel is said to be baffled when four vertical strips, each having a width of 1/10 to 1/12 of the tank diameter, are attached to the internal surface of the cylindrical container perpendicularly at 90 degrees position. If solids are present, the baffles are fixed with a gap of about 1 inch between the baffle and the vessel wall. Propellers may be installed in several ways. The central vertical propeller without baffles is not an efficient mixing device since it produces an almost rotary motion of the liquid which leads to the formation of a vortex drawn towards the propeller. When the tip of the vortex touches the propeller, considerable quantities of air will be sucked into the liquid reducing its discharge. Similar rotary liquid circulation patterns and vortexing occur with the other mixing devices as well in an unbaffled system. Vertical or inclined off-centre installation of a propeller reduces the vortex to a considerable extent provided the angle between the vertical and the distance from the centre are properly adjusted. For very large tanks, side entering propellers mounted at an angle to

10

the radius are commonly employed, however in a baffled tank, while a propeller gives an axial liquid circulation pattern, a turbine gives a radial circulation pattern. In some installations when the depth of the liquid is quite large and when the material is difficult to mix, multiple impellers are mounted on the agitator shaft at different positions approximately with one impeller diameter distance between successive impellers. Propellers are used for blending water-thin materials even in large tanks and can handle liquids having a maximum viscosity of about 2,000 cp and slurries up to 10 % solids of fine mesh size. They can also be used for intensive agitation and for emulsifying jobs up to about 1,000 gallons. In contrast turbines are highly efficient. They can bring rapid blending of low viscosity materials of large volumes, produce intense dispersion type agitation in large volumes and can bring about efficient dispersion in multi-liquid phase systems. They can handle slurries containing up to a maximum viscosity of 7, 00,000 cps. They can also handle fibrous slurries containing about 5 % of the dispersion volume. In general it can be said that propeller in a baffled tank is principally a mixing device to handle relatively low volumes of low viscosity liquids while turbine is a very efficient shearing device that can handle very large volumes of liquids of relatively high viscosity. The high shearing at the tip of the blades of a turbine rotating in a baffled vessel is produced due to the radial flow pattern where in the periphery of the blades move in a circular fashion while the liquid is thrown out horizontally towards the surface of the vessel. Uses of turbine mixers: Turbines are effective for high viscous solutions with a wide range of viscosities up to 7,oo pascal.seconds. Advantage: Turbines give greater shearing forces than propellers and thus they are more suitable for preparation of emulsions. Turbo disperser The disperser liquid type of batch mixer uses intense dispersion mixer blades that are lowered into the liquid and then energized for mixing and dispersion of the materials in the solutions. Liquid disperser vertical mixers can approach near emulsification and can handle very thick materials upon completion of the mixing. Liquid disperser mixers are also capable of handling chemical reactions and can be in closed tanks that can maintain an inert gas atmosphere. Figure 2 shows a turbo disperser.

Figure 2 Liquid Disperser Turbo (Courtesy: Frain group, Manufacturer – Scott)

11

Sonic and ultrasonic devices Application of intense vibration by causing equipment producing sonic or ultrasonic frequencies, can effect vibration in some cases causing emulsification and in others resulting in coalescence of an emulsion. While sonic frequencies are from 15 to 20,000 c/s, ultrasonic frequencies are above 20,000 c/s. ultrasonic frequencies break up a liquid into globules by cavitation method i.e., when a liquid is subjected to ultrasonic vibrations alternate regions of compression and rarefaction are produced in the liquid. Cavities are formed in these regions of rarefaction, which subsequently collapses in the regions of compression. This results in the generation of great forces for emulsification. These equipments are widely used for large-scale emulsification and are known as rapisonic homogenizers. In the Rapisonic homogenizer the crude mix of the components of the emulsion is sucked into one end of a long U-tube and ejected at the other end over a blade which vibrates at its natural frequency of about 30 kHz. Pressures of the order of 30,000 pounds per square inch develop within the head so that the liquid is broken into fine particles. The machine is capable of producing particles as small as 1 micron in size and it is therefore claimed that reduced amounts of emulgents are adequate.

Some of the factors to be considered in the choice from the wide variety of equipments available are:

• The amount of emulsion to be prepared.

• The rheological characteristics of the final emulsion.

• The need to incorporate ingredients such as powders.

• The operation temperature and

• Whether the processing is batch wise or a continuous operation.

It is easier to produce a fine emulsion with homogenizers.

II Solid-Solid Mixing (Powder mixing) In pharmaceuitical production when the formulation contains an active ingredient, which is toxic or is present in a concentration of about 0.5% of the total mass then the mixing of solids becomes a critically important operation. Product with too low an active ingredient will be ineffective and a product with too high active ingredient may be lethal. To provide good solid mixing the phenomenon to be avoided or overcome is the tendency of the particles to segregate. Segregation occurs when a system contains particles with different sizes, densities, etc. and motion can cause particles to preferentially accumulate into one area over another. Powder mixing is a process in which two or more than two solid substances are intermingled in a mixer by continuous movement of the particles. Mainly, the object of mixing operation is to produce a bulk mixture which when divided into different doses, every unit of dose must contain the correct proportion of each ingredient. The degree of mixing will increase with the length of time for which mixing is done. Powder mixing is a neutral type of mixing. It is one of the most common operations employed in pharmaceutical industries for the preparation of different types of formulations, e.g. powders,

12

capsules and tablets. When grinding and mixing of different substances is to be done simultaneously then two or more than two substances are fed to the mill one at the same time. To obtain good results of powder mixing the following factors and physical properties of drugs must be taken into consideration before undertaking any kind of powder mixing. The ease with which different powders blend to a reasonably homogeneous mix varies considerably, being dependent on various physical properties of the individual components and on their relative proportions. It is easier to mix equal weights of two powders of similar fineness and density than to incorporate a small proportion of a fine powder in a large mass of a coarse denser material. Apart from density and particle size, the stickiness of the components to be mixed is also important. Prolonged mixing becomes necessary to effectively distribute materials like lubricants and wetting agents into tablet granules. Also wide differences among properties such as particle size distribution, shape and surface characteristics such as surface area and electrostatic charges may take blending very difficult. Flow characteristics such as angle of repose and ability to flow, abrasiveness of one ingredient upon the other, state of agglomeration of the ingredients, moisture or liquid content of the solids, density, viscosity and surface tension at operating temperature of any liquid added, are some other significant considerations in mixing and selection of mixing equipments. In fact the properties of the blending ingredients dominate the mixing operation. Mechanism of Powder mixing It has been generally accepted that in all the mixtures, solid mixing is achieved by a combination of one or more of the following mechanisms:

Convective mixing – In convective mixing transfer of groups of particles takes place from one location to another by means of blades or paddles of the machine.

Shear mixing – In shear mixing, slip planes are set up within the mass of material

Diffusive mixing – During this mechanism, mixing occurs by diffusion process by random movement of particles within a powder bed and cause them to change their relative positions. Physical properties affecting mixing Material density: If the components are of different density, the denser material will sink through the lighter one, the effect of which will depend on the relative positions of the material in the mixer. If the denser particles form the lower layer in a mixture at the start of a mixing operation, the degree of mixing will increase gradually until equilibrium is attained, not necessarily complete mixing. If the denser component is above, the degree of mixing increases to a maximum, then dropping to equilibrium as the denser component falls through the lighter one, so that segregation has started. This factor is of practical significance in charging and operating a mixer. Particle size: Variation in particle size can lead to segregation also since smaller particles can fall through the voids between the larger particles. There will be a critical particle size that can just be retained in the mixed condition, which will depend upon the packing. When the bed of the particles is disturbed, dilation occurs and the greater porosity of open packing allows a large size of particle to slip through the voids, leading to segregation.

13

Particle shape: The ideal particle is spherical in shape, and further the particles depart from this theoretical form, the greater the difficulty of mixing. If the particles are of irregular shapes, then they can become interlocked leading to a decrease in the risk of segregation once mixing has been achieved. Particle attraction: Some particles exert attractive forces; this may be due to adsorbed liquid films or electrostatic charges, such particles tending to aggregate. Sine these are surface properties, the effect increases as particle size decreases. Proportions of materials to be mixed The proportions of materials to be mixed play a very important role in powder mixing. It is easy to mix the powders if they are available in equal quantities but it is difficult to mix small quantities of powders with large quantities of other ingredients or diluents. The practical method for mixing such quantities is that the component present in lesser amount is mixed with an equal amount of the diluent, then a further amount of diluent is incorporated which is almost equal to previous quantities and so on until whole of the diluent has been added. This method is followed for mixing potent substances with diluents. When more than two components are to be mixed, they should always be mixed in ascending order of their weights so as to ensure uniform mixing of the ingredients. Conditions for mixing The theory of powder mixing shows four conditions that should be observed in the mixing operation.

Mixer volume: The mixer must allow sufficient space for dilation of the bed. Overfilling reduces the efficiency and may prevent mixing entirely.

Mixing mechanism: The mixer must apply suitable shear forces to bring about local mixing and a convective movement to ensure that the bulk of the material passes through this area.

Mixing time: Mixing must be carried out for an appropriate time, since the degree of mixing will approach its limiting equilibrium value asymptotically. Hence, there is an optimum time for mixing for any particular situation, one should also note that the quilibrium condition may not represent the best mixing if segregation has occurred. Handling the mixed powder When the mixing operation is completed, the mixer should stop and the powder should be handled in such a way that segregation is minimized. The vibration caused by subsequent manipulation, transport, handling or use is likely to cause segregation. Therefore, a bulk powder that has been stored or transported should be re-mixed before removing a part of the contents. Equipment A wide variety of equipment is used in different industries. In some machines the container rotates. In others a device rotates within a stationary container. In some cases, a combination of rotating container and rotating internal device is used. Sometimes baffles or blades are present in the mixer. For mixing of powders or a powder with a small quantity of a liquid where a constituent is cohesive or sticky, the material tends to agglomerate into balls. Under these conditions agitation mixers are more satisfactory than tumbling mixers. They consist essentially

14

of a stationary shell with a horizontal or vertical agitator moving inside it. The agitator may take the form of blades, paddles or screw. Sometimes agglomerates are desired as in the case of some foods and pharmaceuticals. Mixing is sometimes achieved by feeding two or more materials simultaneously to a mill, such as ball mill, if both require grinding. For fine, dry powders the use of a screw conveyor often gives satisfactory mixing while transporting the material and hence no additional equipment or power is needed for mixing. Powder mixers Dry mixer (stationary container): For batch work the dry mixer which is the stationary shell type is often used. This consists of a semi-cylindrical trough, usually covered and provided with two or more ribbon spirals. One spiral is right-handed and the other left-handed (as shown in figure 3) so that the material is worked back and forth in the trough. Ribbon cross section and pitch and number of spirals on the ribbon are varied for different materials varying from low density, finely divided materials to fibrous or sticky materials. It may be centre discharge or end discharge. Another variation is the mounting of cutting blades on the central shaft. A broad ribbon lifts and conveys the materials while a narrow one will cut through the materials while conveying. Ribbon blenders are often used on the large scale and may be adapted for continuous mixing.

Figure 3: Dry Mixer

The paddle mixer has a stationary outer vessel and the powders are agitated by paddles rotating within. The equipment is suitable to heating, by jacketing the vessel, and also permits a kneading effect by the use of appropriately shaped paddles or beaters. In the bowl mixer the paddle is mounted vertically and in the trough mixer (e.g., dry mixer) a number of vanes are mounted horizontally. Vertical screw mixer: In these types of mixers, the screw rotates about its own axis while orbiting around the centre axis of the conical tank (as shown in figure 4). In another variation, the screw does not orbit but remains in the centre of the conical tank and is tapered so that the swept area steadily increases with increasing height. This type of mixer is mainly used for free flowing solids.

Figure 4 Vertical screw mixer (orbiting type)

15

Agitator mixers: Agitator mixers for powders can take a similar form to paddle mixers for

umbling mixers (Rotating containers) el imparts movement to the materials by tilting the

ouble cone mixer

liquids, but their efficiency is low. Planetary motion mixers are more effective, these are most commonly in the form of trough in which an arm rotates and transmits shearing action to the particles. General mixing requires an end-to-end movement which can be obtained by fitting helical blades to the agitator. In these mixers shear forces are not high, so that aggregates may remain unbroken and the movement may encourage segregation due to density or size differences. This type of mixer is most suitable for blending free-flowing materials, with components that are of uniform size and density. Special designs have been developed with modified agitators and vessels to overcome these limitations. TIn tumbling mixers, rotation of the vesspowder until the angle of the surface exceeds the angle of repose when the surface layers of the particles go into a slide. Simple forms use a cylindrical vessel rotating on its horizontal axis, but shear forces are low and end-to-end movement is slight. This may be overcome by including flights (a form of baffles), or the shape of the vessel may be altered to avoid symmetry. A number of different designs are used, such as a cylinder rotating about its mid-point on an axis at right angles to the longitudinal axis, a cube rotating about a diagonal and double-cone, V-shape, Y-shape or diamond shaped vessels, together with baffles where appropriate. These shapes give effective three-dimensional movement and shearing takes place as the charge flows. In addition, the particles hit against the wall and are deflected, causing considerable velocity and acceleration gradients. The repeated reversal of the direction of flow makes the tumbling mixer preferable where differences in density for particle size occur. D (Rotating containers): A variety of equipment is available in which the container rotates. This may consist of horizontal rotating cylindrical drum with deep or cupped flights on the inside. When drum is rotated slowly, the powders cascade over one another. With a plain drum, the mixing is not efficient when the proportions and characteristics of the powders vary widely. A double cone mixer consists of a vessel with two cones base to base, with or without a cylindrical section in between as shown in figure 5-a and 5-b. It is so mounted that it can be rotated about an axis at right angles to the line joining the points of the cones. Tumblers of this type are available plain or with an agglomerate-breaking device or with a spray nozzle or with both of these devices. Mechanism of mixing in a double cone mixer is illustrated in figure 5-c.

igure 5-a Double cone blender Figure 5-c Mechanism of mixing of a double cone mixer

F(Courtesy: Bombay Pharma equipments)

16

Figure 5-b Another view of Double cone mixer

ouble cone mixer

(Courtesy: Mill powder tech solutions, www.mill.com.tw) D is an efficient mixer for mixing dry powder and granulates homogeneously.

eatures e mixing barrel and blades are made of stainless steel, always keeping clean and away

les uniform mixing and easy discharge. nd motor

be

dle types baffles can be provided on the shaft for better

-Blender

are used for dry mixing. They are totally enclosed to prevent any foreign particles to

All the contact parts are made up of stainless steel. Two-third of the volume of the cone blender is filled to ensure proper mixing. F

Thfrom dirt. The mixing barrel can be tilted freely at the angle of 0°~360° degrees for discharging and cleaning purpose. The conical shape at both ends enab

The cone is statically balanced to avoid any excessive load on the gear box a While the powder can be loaded into the cone through a wider opening, it can

discharged through a side valve. Depending upon the product, padmixing.

VV- blenders enter into the chamber. Modifications such as the addition of baffles to increase mixing shear can be done to these type of mixers. Figure 6 shows v-blender.

Figure 6 V-Blender (Courtesy: S.S. Engineers, Mumbai)

17

Features • Minimal attrition when blending fragile granules. • Large-capacity equipment available. • It is easier to clean and unload the blender • Minimal maintenance is required • Available in various capacities from 25 litres to 1000 litres.

Considerations while choosing solids mixing equipments A number of performance characteristics have to be considered carefully before making a choice of a solid-solid mixing device. Since a wide variety of equipment is available for mixing varieties of materials, the proper type of mixer should be chosen to give the desired degree of homogeneity for mixing the materials on hand. Too long a mixing may result in a proper blend. A quantitative relationship between degrees of mixing vs time is worth determining. Except in a few cases, in general, mixing should be over in a few minutes to about 15 minutes if proper equipment is chosen. Some other aspects to be considered are the charging and discharging of the materials, power required for mixing, ease, frequency and thoroughness of cleaning particularly when different types of batches are to be mixed at different times in the same machine, agglomerate breakdown and attrition requirements, dust formation (loss of dust particularly that of vital minor ingredients can seriously effect the composition of the mixture). Steps should be taken to prevent or minimize dust formation by using less density but equally effective ingredients or a pellety form of the dusty ingredient, by using dust tight arrangements for loading and unloading the mixer, by addition of liquids like water (where tolerated) along with a trace of surface active agent etc. Other aspects to be considered are the electrostatic charge, equipment area, contamination of product (from lubricants and repair materials), heating and cooling requirements of the mixer for the problem on hand, flexibility to operate different sized batches, (the effect of percent volume occupied by the batch on the adequacy of mixing is to be borne in mind), provision for vacuum or pressure, method of adding liquids, proper ventilation and discharge enclosures, provisions for relief of internal explosion, noise during operation etc. III Mixing semi-solids Mixing solids with liquids – If the solid is not too coarse, the liquid is not too viscous and the percentage of solids is not too great, solids can be suspended in liquids by the use of a propellers or a flat-bladed turbine in a cylindrical container. The mechanism involved in mixing semi-solids depends on the character of the material, which may show considerable variation. There is very little difference between liquids at the upper end of the viscosity range and semi-solids capable of flow. Also, when a powder and liquid are mixed, at first they are likely to resemble closely the mixing of powders. Theory of mixing of semi-solids Mixing an insoluble powder with a liquid, a number of stages can be observed as the liquid content is increased.

18

Pellet and Powder state: Addition of a small amount of liquid to a bulk of dry powder causes the solid to ball up and form small pellets. The pellets are embedded in a matrix of dry powder, which has a cushioning effect and makes the pellets difficult to break up. From the overall point of view, the solid is free-flowing and the rate of homogenization is low. Pellet state: Further addition of liquid results in the conversion of more dry powder to pellets until, eventually, all the material is in the state. The mass has a coarse granular appearance, but the pellets do not cohere and agitation will cause aggregates to break down into smaller granules. The rate of attainment of homogenization is even lower than in the pellet and powder stage and it is the state aimed at in moistening powders for tablet granulation. Plastic state: As the liquid content is increased further, the character of the mixture changes markedly, aggregates of the material adhere, the granular appearance is lost, the mixture becomes more or less homogeneous and of clay like consistency. Plastic properties are shown, the mixture being difficult to shear, flowing at low stresses but breaking under high stresses. Homogenization can be achieved much more rapidly than in the previous cases. This is the state obtained when making a pill-mass, for example. Sticky state: Continual incorporation of liquid causes the mixture to attain the sticky state, the appearance becomes paste-like, the surface is shiny, and the mass adheres to solid surfaces. The mass flows easily, even under low stresses, but homogeneity is attained only slowly. Liquid state: Eventually, the addition of liquid results in a decrease of consistency until a fluid state is reached. In this state, the mixture flows under its own weight and will drain off vertical surfaces. Mixers for semi-solids Mixers for semi-solids may be divided into:

Agitator mixers: Sigma mixers and planetary mixers Shear mixers: Colloidal mill and triple roller mill.

Agitator mixers: These are similar in principle to the agitator mixers used for liquids and for powders, indeed the planetary motion mixer is often used for semi-solids. Mixers designed specifically for semi-solids are usually of heavier construction to handle materials of greater consistency. The agitator arms are designed to give a pulling and kneading action and the shape and movement is such that material is cleared from all sides and corners of the mixing vessel. One form in common use for handling semi-solids of plastic consistency is known as the sigma-arm mixer, since the mixer uses two mixer blades, the shape of which resembles the Greek letter, sigma. The two blades rotate towards each other and operate in a mixing vessel which has a double trough shape, each blade fitting into a trough. The two blades rotate at different speeds, one usually about twice the speed of the other, resulting in a lateral pulling of the material and division into the two troughs, while the blade shape and difference into the two troughs, while the blade shape and difference in speed causes end-to-end movement. Being of sturdy construction and higher power, this form of mixer can handle even the heaviest plastic materials, and products such as pill masses, tablet granule masses, and ointments are mixed readily. One of

19

the problems encountered in the mixing of semi-solids is the entrainment of air. The sigma arm mixer can be enclosed and operated under reduced pressure, which is an excellent method for avoiding entrainment of air and may assist in minimizing decomposition of oxidisable materials, but it must be used with caution if the mix contains volatile ingredients. Shear mixers: Machines designed for size reduction can be used for mixing e.g. roller mills but although the shear forces are good, the general mixing efficiency is poor. Rotary forms may be used and the colloid mill has a stator and a rotor with conical working surfaces. The rotor works at a speed of the order of 3000 to 15000 r.p.m. and the clearance can be adjusted between 50 and 500 micrometers. A roughly mixed suspension or dispersion is introduced through a funnel and is thrown out between the working surfaces by centrifugal force. Ultrasonic mixers: An effective method for dealing with certain forms of mixing problems is to subject the material to ultrasonic vibration. This has a special application in mixing in the preparation of emulsions. Colloid Mill - The colloid mill is useful for milling, dispersing, homogenizing and breaking down of agglomerates in the manufacture of food pastes, emulsions, coatings, ointments, creams, pulps, grease, etc. The main function of the colloid mill is to ensure a breakdown of agglomerates or in the case of emulsions to produce droplets of fine size around 1 micron. The material to be processed is fed by gravity to the hopper or pumped so as to pass between the rotor and stator elements where it is subjected to high shearing and hydraulic forces. Material is discharged through a hopper whereby it can be recirculated for a second pass. For materials having higher solid and fibre contents conical grooved discs are preferred. Sometimes cooling and heating arrangements are also provided in theses mills depending on the type of material being processed. Rotational speed of the rotor varies from 3,000-20,000 r.p.m. with the spacing between the rotor and stator capable of very fine adjustment varying from 0.001 inch to 0.005 inch depending on the size of the equipment. Colloid mills require a flooded feed, the liquid being forced through the narrow clearance by centrifugal action and taking a spiral path. In these mills almost all the energy supplied is converted to heat and the shear forces can unduly increase the temperature of the product. Hence, most colloid mills are fitted with water jackets and it is also necessary to cool the material before and after passing through the mill. Figure 7-b Colloid mill (stepped grinding surface) Figure 7-a Premier Colloid mill (conical grinding surface)

20

In the Premier colloid mill as shown in figures 7-a and 7-b, intense shearing action is produced between the rotor running at several thousand rpm with its working surface in close proximity to the stator. A 5-inch diameter rotor runs at 9000 r.p.m. and has an output of 40-60 gallons depending on the viscosity of the liquid. The gap between the two surfaces is adjustable from 0.3-0.002 inch. Crude mix is fed via the hopper to the centre of the rotor. The material is flung outward and after homogenization across the shearing surfaces, it is discharged. If the feed is very slow, many hundreds of revolutions will take place while the contents of the gap traverse the working faces and consequently the globules will be subjected to a greater shearing action than effected at the maximum rate of feed. The materials must be supplied at such a rate that the space between the rotor and stator is kept entirely filled with liquid. Colloid Mills are used in the production of ointment, cream, gels and high viscous fluids for grinding, dispersing and homogenizing in one operation. Advantages

Extremely fine particle distribution through optimal shear force. High capacity with minimal space requirements.

Rapid handling and easy cleaning.

Virtually unlimited application due to highly flexible homogenization system.

Sigma mixers Sigma mixer contains mixing element (Blades) of Sigma type two in numbers which contra rotates inward to achieve end to end circulation and thorough and uniform mixing at close or specified clearance with the container (figure 8). The mixed product can be easily discharged by tilting the container by hand lever manually either by system of gears manually operated or motorized. The complete mixer is mounted on steel fabricated stand of suitable strength to withstand the vibration and give noise free performance.

Figure 8 Sigma blender (Courtesy: S.S. Engineers, Mumbai)

Uses of sigma mixers: sigma mixers are used for wet granulation process in the manufacture of tablets, pill masses and ointments. It is primarily used for solid-liquid mixing although it can be used for solid-solid mixing also.

21

Advantages Sigma blade mixer creates a minimum dead space during mixing. There is close tolerance between the blades and the sidewalls as well as the bottom of the

mixer shell.

Disadvantage: Sigma mixers work at a fixed speed.

Triple Roller mill Various types of roller mills consisting of one or more rollers are commonly used but triple roller mill is preferred. It is fitted with three rollers which are composed of a hard abrasion-resistant material. They are fitted in such a way that they come in close contact with each other and rotate at different speeds. The material which comes in-between the rollers is crushed and reduced in particle size. The reduction in particle size depends on the gap between the rollers and difference in their speeds. As shown in figure 9, the material is allowed to pass through hopper A, in-between the rollers B and C where it is reduced in size. Then the material is passed between the rollers C and D where it is further reduced in size and a smooth mixture is obtained. The gap between rollers C and D is usually less than the gap between B and C, after passing the material between rollers C and D the smoothened material is continuously removed from roller D by means of scraper E, from where it is collected in a receiver.

Figure 9 Triple-Roller mill

On large scale, mechanical ointment roller mills are used to obtain an ointment of smooth and uniform texture. The performed coarse ointments are forced to pass through moving stainless steel rollers where it is reduced in particle size and a smooth product which is uniform in composition and texture is obtained. For small-scale work, small ointment mills are available.

Advantages: The triple roller mill produces very uniform dispersion and is suitable for continuous processes.

Planatory Mixer Planetary mixers are used for mixing and beating for viscous and pasty materials, the planetary mixer is still often used for basic operations of mixing and blending in pharmaceutical industry. Figure 10-a and 10-b shows planetary mixer and its different blade attachment.

Uses of planetary mixers: Low speeds are used for dry blending and faster speeds for the kneading action required in wet granulation.

Advantage: Planetary mixers work at varying speeds. This is more useful for wet granulation and is advantageous over sigma mixers.

22

Figure 10-a Planatory Mixer Figure 10-b Different blade attachment available for planetary mixer (Courtesy: Frigmaires Engineers, Mumbai) Disadvantages

1. Planetary mixers require high power. 2. Mechanical heat is built up within the powder mix. 3. Use is limited to batch work only

Double planetary mixers The double planetary mixer includes two blades that rotate at their own axis, while they orbit the mix vessel on a common axis. The blades continuously advance along the periphery of the vessel, removing material from the vessel wall and transporting it to the interior. After one revolution the blades have passed through the entire vessel.

Contrary to conventional planetary mixers, the two blade configurations sweep the wall of the vessel clockwise and rotate in opposite directions at about three times the speed of travel. The shear blades displace the material from the walls of the vessel and by their overlapping action the center carry the particles towards the agitator shafts, therefore producing a large field of shear forces. By this means even highly viscous and cohesive material can be efficiently mixed.

Material of construction of mixers Materials having sufficient strength and corrosion resistance may be used for the construction of mixers, but stainless steel is favored more for most pharmaceutical applications. Monel metal can be used as an alternative if ferrous metals are to be avoided. Thus, one can conclude that the process of mixing is one of the most commonly used operations in daily life. A wide variety of materials like liquids, semi-solids and solids require mixing during their formulation into a dosage form, therefore, a proper selection of the mixing equipment is required keeping in mind the physical properties of the materials like density, viscosity, economic considerations regarding processing i.e. time required for mixing and power requirement and also the cost of the equipment and its maintenance. References

1. Remington – The Science and Practice of Pharmacy, 20th Edition, Volume – 1. 2. The Theory and Practice of Industrial Pharmacy by Leon Lachman. 3. A textbook of Pharmaceutical Engineering by K. Sambhamurthy. 4. Introduction to Chemical Engineering by Walter L. Badger. 5. Tutorial Pharmacy by Cooper and Gunn, Sixth Edition.

23

6. Unit operations in Food processing (1983) by R.L. Earle. 7. Website – www.spxprocessequipment.com 8. Website - www.mill.com.tw

Suggested reading Cooper and Gunn’s Tutorial Pharmacy

24