Industrial Pharmacy I Mixing Milling Drying Filtration Preformulation Reference Theory and practice of Industrial Pharmacy Lachman

MIXING 16-2-2014

Introduction In the vast majority of cases several ingredients are needed so that the required dosage form functions as required and very few Pharmaceutical products contain only one component. Whenever a product contains more than one component, a mixing or blending stage will be required in the manufacturing process. This may be in order to ensure an even distribution of the active component(s), to ensure an even appearance, or to ensure that the dosage form releases the drug at the correct site and at the desired rate. The unit operation of mixing is therefore involved at some stage in the production of practically every pharmaceutical preparation.

Mixing may be defined as a unit operation that aims to treat two or more components, initially in an unmixed or partially mixed state, so that each unit (particle, molecule etc.) of the components lies as nearly as possible in contact with a unit of each of the other components.

Mixing is a critical process because the quality of the final product and its attributes are derived by the quality of the mix. Improper mixing results in a non-homogenous product that lacks consistency with respect to desired attributes like chemical composition, color, texture, flavor, reactivity, and particle size.

The wide variety and ever increasing complexity of mixing processes encountered in industrial applications requires careful selection, design, and scale up to ensure effective and efficient mixing. Today's competitive production lines necessitate robust equipment that are capable of fast blend times, lower power consumption, equipment flexibility, ease of cleaning, and a range of customized features. In addition to blending components, many modern mixers are designed to combine different process steps in a single equipment, e.g. coating, granulation, heat transfer, drying, etc.

Types of mixtures Mixtures may be categorized into three types. 1- Positive mixtures Positive mixtures are formed from materials such as gases or miscible liquids which mix spontaneously and irreversibly by diffusion, and tend to approach a perfect mix. There is no input of energy required with positive mixtures if the time available for mixing is unlimited, although it will shorten the time required to obtain the desired degree of mixing. In general materials that mix by positive mixing present no problems during product manufacture.

Negative mixtures With negative mixtures the components will tend to separate out. If this occurs quickly, then energy must be continuously input to keep the components adequately dispersed, e.g. with a suspension formulation, where there is a dispersion of solids in a liquid of low viscosity. With other negative mixtures the components tend to separate very slowly, e.g. emulsions, creams and viscous suspensions. Negative mixtures are generally more difficult to form and maintain and require a higher degree of mixing efficiency than do positive mixtures.

Neutral mixtures Neutral mixtures are said to be static in behaviour, i.e. the components have no tendency to mix spontaneously or segregate spontaneously once work has been input to mix them. Examples of this type of mixture include mixed powders, pastes and ointments. It should be noted that the type of mixture might change during processing. For example, if the viscosity increases the mixture may change from a negative to a neutral mixture. Similarly, if the particle size, degree of wetting or liquid surface tension changes the mixture type may also change.

Mixing of Fluids The main mechanisms by which liquids are mixed are bulk transport, turbulent flow, laminar flow and molecular diffusion. 1-Bulk transport: The movement of a relatively large portion of the material being mixed from one position in the mix (or system) to another. A simple circulation of material in a mixer, however, does not necessarily result in efficient mixing. For bulk transport to be effective it must result in a rearrangement or transformation of the various portions of the material to be mixed. This is usually 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 It is a direct result of turbulent fluid flow, which is characterized by a random fluctuation of the fluid velocity at any given point within the system. Within a turbulent fluid there are, however, small groups of molecules moving together as a unit, referred to as eddies ( An eddy is the 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 & smaller size until they are no longer distinguishable. Turbulent mixing alone may therefore leave small unmixed areas within eddies and in areas near the container surface which will exhibit streamlined flow.

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 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. An additional characteristic of turbulent flow is its intensity, which is related to the velocities with which the eddies move.

3-Laminar mixing Streamline or laminar flow is frequently encountered when highly viscous fluids 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. This relationship is observed because the rate of increase in interfacial area with time is proportional to the instantaneous interfacial area.

It should be pointed out, however, that by this process alone, an exceedingly long time is required for the layers of the different fluids to reach molecular dimensions. Therefore, good mixing at the molecular level requires a significant contribution by molecular diffusion after the layers have been reduced to a reasonable thickness (several hundred molecules) by laminar flow.

4- Molecular diffusion (analogous to diffusive mixing in powders) The primary mechanism responsible for mixing at the molecular level is diffusion resulting from the thermal motion of the molecules. When it occurs in conjunction with laminar flow, molecular diffusion tends to reduce the sharp discontinuities at the interfaces between the fluid layers, and if allowed to proceed for sufficient time, results in complete mixing. i.e. This will occur with miscible fluids wherever a concentration gradient exists and will eventually produce a well-mixed product, although considerable time may be required if this is the only mixing mechanism. The process is described quantitatively in term of Fick’s first law of diffusion.

Scale and Intensity of Segregation The quality of mixtures must ultimately be judged upon the basis of some measure of the random distribution of their components. Such an evaluation depends on the selection of a quantitative method of expressing the quality of randomness or "goodness of mixing". The intensity of segregation is a measure of the variation in composition among various portions of the mixture. When mixing is complete, the intensity of segregation is zero.