UNIT OPERATION

MIXING

Powder mixing is an operation that serves to make two or more components uniformly
distributed in the powder bed.

The aim of mixing is to reducing non-uniformity in one or more of the properties of a material in
bulk

In most cases, solid dosage forms do not only contain one component.

Several ingredients are combined together to contribute to the manufacturing process

For instance, a tablet formulation often consists of the active ingredient (API) and many other
excipients, such as diluents, binders, disintegrants, and lubricants. As a result, the mixing process
is necessary to ensure that the API and other components are homogeneously distributed
throughout the tablet.

Powder mixing processes are involved in every preparation process of pharmaceutical products,
such as tablets, capsules, granules, bulk powders, and dry powder inhalers.

Mixing (blending):

An operation in which two or more ingredients in a separate or roughly mixed condition are
treated so that each particle of any ingredient is as nearly as possible adjacent to a particle of the
other ingredients.

Aim: To bring particles of one component close to that of another component

There are very few pharmaceutical products that contain only one component.

majority of cases contained several ingredients are needed to mix with each other, for example, a
pharmaceutical company wishes to produce a tablet dosage form containing a drug which is
active at a dose of 1 mg, other components (e.g. diluents, binders, disintegrants and lubricants)
will be needed both to enable the product to be manufactured and for it to be handled by the
patient.

This may be in order to ensure an even distribution of the active component, to ensure an even
appearance, or to ensure that the dosage form releases the drug at the correct site and at the
desired.

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The impact of powder mixing:

Powder mixing have important role on:

 Content uniformity
 Dissolution rate
 Tablets, capsules, sachets and dry powder inhalers (mixtures of solid particles)
 Emulsions and creams (mixtures of immiscible liquids)
 Pastes and suspensions (dispersions of solid particles)

Types (Ways) of mixtures:

Mixtures may be categorized into three types (ways):

Positive mixtures

 formed from materials 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.
 In general materials that mix by positive mixing present no problems during product
manufacture.
 Formed from such as gases or miscible liquids.

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, this like suspension formulation, other example of negative
mixtures in which the components tend to separate very slowly, e.g. emulsions, creams.
 Negative mixtures are generally more difficult to form and maintain and require a higher
degree of mixing efficiency than do positive mixtures.

Neutral mixtures

 are said to be static in behavior, i.e. the components have no tendency to mix
spontaneously or segregate spontaneously (de mixed) unless acted upon by an external
system of forces i.e. (once work has been input to mix them).
 Examples of this type of mixture include mixed powders, pastes and ointments.

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Mixing process:

To discuss the principles of the mixing process, a situation will be considered where there are
equal quantities of two powdered components of the same size, shape and density that are
required to be mixed, the only difference between them being their color.

This situation will not of course occur practically, but it will serve to simplify the discussion of
the mixing process and allow some important considerations to be illustrated with the help of
statistical analysis.

Different states of powder mixing:

Completely segregated:

If the components are represented by colored cubes, then a two-dimensional representation of the
initial unmixed or completely segregated state can be produced.

Ideal situation or 'perfect mix:

in this case would be produced when each particle lay adjacent to a particle of the other
component (i.e. each particle lies as closely as possible in contact with a particle of the other
component).

A random mix:

which is defined as a mix where the probability of selecting a particular type of particle is the
same at all positions in the mix, and is equal to the proportion of such particles in the total mix.

Mixing are three types:

1. Solid-solid mixing e.g. (tablet)

2. Liquid-liquid mixing e.g. (solution)
3. Solid-liquid mixing e.g. (suspension)

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Degree of mixing:

 Ideal mixing or perfect mixing

 Acceptable mixing
 Random mixing
 Ordered mixing

The powders may be mixed by following methods:

Spatulation:

Mixing of powder is done by movement of a spatula throughout the powders, it is not suitable for
large quantities of powders or for powders containing potent substances, because homogeneous
blending is not as certain as other methods.

Very little compression or compacting of the powder results from spatulation, which is especially
suited to mixing solid substances that form eutectic mixtures (or liquefy) when in close and
prolonged contact with one another.

Trituration:

This is used both to reduce the particle size and mix powder. A glass mortar-pastel may be
preferred for chemicals.

Sifting:

The powder is mixed by passing through sifters. This processes result in a light fluffy product.
Used for incorporation of potent drugs into a diluent base.

Tumbling:

In this the powder is mixed in a large container rotated by an electric motor. This is employed in
the large industry.

Geometric dilution:

this method may be used to aid in the mixing of potent smaller quantities of active ingredients
into the larger bulk of the mix.

This is achieved by first mixing the active ingredient with an equal amount of diluent; mixing,
then adding an amount of diluent equal to this mix; mixing, etc., until the desired dilution and
mixing has been obtained.

For large-scale industrial pharmaceutical mixing, only the size of the batch has changed. The
same objectives are present.

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 Geometric dilution: This method is used when potent substance is to mixed with a large
amount of diluent. For example: 100 mg potent drug mixed in 900mg of lactose. According to
geometric dilution-

100mg of potent drug + 100mg of lactose = 200mg mixture

200mg of potent drug + 200mg of lactose = 400mg mixture

400mg of potent drug + 400mg of lactose = 800mg mixture

800mg of potent drug + remaining of lactose=1000mg mixture

Solid-solid mixing:

This is the process in which two or more than two solid substances are mixed in a mixer by
continuous movement of the particle.

Mechanism of mixing in solids:

Convective mixing:

The large group of particles are moving together in the mixer, driven by the rotational force
provide by a mixer vessel, paddle, blade, ribbon, or gas flow.

The rotating flow leads to convective motion of particles and mainly contributes to the
macroscopic mixing, rather than microscopic mixing.

The mixing rate of this process is relatively high, however, to achieve a more uniform mixing,
prolonged times are required, because particles within the moving group are not able to mix well.

Shear mixing:

Shear refers to the action that one layer of powder particles moves relative to another layer of
particles.

Shear mixing can be caused by particles from a different powder layer, having different
velocities developed in a rotary vessel or due to the compression force and extension of the
powder bed.

Hence, shear mixing is the movement of a layer of particles, rather than the movement of
individual particles.

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Diffusive mixing:

Diffusion is known as the movement of individual particles, due to random motion of powder
particles.

When the powder bed is placed in a mixer, the volume of that powder bed increases, due to
convection and shear forces, which drive the powder flowing around the mixer.

Therefore, the voids between particles increase, leading to great potential for individual particles
to mix with each other.

The rate of diffusive mixing is relatively low, compared with convection and shear mixing.

For most of the mixing operations, all of these mechanisms are involved, rather than only one or
two of them.