- DRx.Deepak Badode Patel college of pharmacy bhopal

 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 can be done for the following reasons:-  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.

 Mixtures may be classified as follows: 1. Positive mixtures 2. Negative mixtures 3. Neutral 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.

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.

 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.

 In all type of mixers, mixing is achieved by applying one or more of the following mechanisms: - 1) 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.

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

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.

 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

S.NoType of mixerName 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. 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.

 Equipments for mixing of miscible liquids, mixing of a soluble solid with a low viscosity liquid :- 1) 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. 2) 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. 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.

3) 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. Uses of paddle mixers: paddles are used in the manufacture of antacid suspensions, antidiarroheal mixtures such as bismuth-kaolin mixture 4)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. Uses of turbine mixers: Turbines are effective for high viscous solutions with a wide range of viscosities up to 7,oo pascal.seconds

 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

 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: 1) 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. 2) Shear mixing – In shear mixing, slip planes are set up within the mass of material. 3) 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.

 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.

Mixing an insoluble powder with a liquid, a number of stages can be observed as the liquid content is increased 1) 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. 2) 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

3) 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. 4) 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 may be divided into: 1) Agitator mixers – Sigma mixers and planetary mixers. 2) Shear mixers - Colloidal mill and triple roller mill.

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.  Sigma mixer :- 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. The mixed product can be easily discharged by tilting the container by hand lever manually either by system of gears manually operated or motorized.

 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.  Advantages :- Sigma blade mixer creates a minimum dead space during mixing. There is close tolerance betw een the blades and the sidewalls as well as the bottom of the mixer shell.  Disadvantage:- Sigma mixers work at a fixed speed.

P lanetary 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.

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

 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 r.p.m. and the clearance can be adjusted between 50 and 500 micrometers.

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. 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 inch to inch depending on the size of the equipment.  Advantages :- 1) Extremely fine particle distribution through optimal shear force. 2) High capacity with minimal space requirements. 3) Rapid ha ndling and easy cleaning. 4) Virtually unlimited application due to highly flexible homogenization system.