In pharmaceutical
processing, mixing involves certain heterogeneous components to be manipulated
with the intent to make them more homogeneous. The term mixing is defined as a
process that results in the randomization of dissimilar particles within a
system. Mixing is defined as an operation in which two or more components in a
separate roughly mixed condition are treated so that each particle lies as
nearly as possible in contact with a particle of each of the other ingredients.
Mixing may be performed between any two phases ranging from mobile liquids to
viscous liquids, semi-solids, and solids. It is performed to allow heat and/or
mass transfer to occur between one or more streams, components, or phases. Even
modern industrial processing involves chemical reactors as mixers. Mixing can
be between one component with different particle sizes.
The operation opposite to
the mixing is ‘segregation’. The terms ‘mixing’ and ‘blending’ are often used
synonymously, but technically they are a bit different. Blending is a process
of combining materials but is a relatively gentle process compared to mixing.
In terms of the phase of the material, blending is the process of solid-solid
mixing or mixing of bulk solids with a small quantity of liquid whereas mixing
is more closely associated with liquid-liquid, gas-liquid, and viscous
materials.
Mixing and blending are
the most demanding unit operations in the pharmaceutical, chemical, and food
process industries. For example, chemical process industries involve mixing and
blending specialty chemicals, explosives, fertilizers, dry powdered detergents,
glass or ceramics, and rubber compounds. The pharmaceutical industry employs the
blending of active ingredients of a drug with excipients like starch,
cellulose, or lactose whereas in the food industry preparation of cake mix,
spices, and flavors. In practice, mixing is a critical process because the
quality of the final product and its attributes are derived from the quality of
the mix. Improper mixing results in a non-homogenous product that lacks
consistency concerning desired attributes like chemical composition, color, texture,
flavor, reactivity, and particle size.
With the proper equipment
selection, it is possible to mix a solid, liquid, or gas into another solid,
liquid, or gas. For example, a biofuel fermenter requires mixing of microbes,
gases, and liquid medium for optimal yield; organic nitration requires
concentrated (liquid) nitric and sulfuric acids to be mixed with a hydrophobic
organic phase whereas production of pharmaceutical tablets requires blending of
solid powders. The wide variety and ever-increasing complexity of mixing
processes encountered in industrial applications require careful selection of
design, and scale-up to ensure effective and efficient mixing. Improved mixing
efficiency leads to shorter batch cycle times and operational costs. To
increase productivity and survive in today’s competition there is a need of
selecting robust equipment capable of fast blend times, lower power
consumption, equipment flexibility, ease of cleaning, and other customized
features. In addition to blending components, many modern mixers are designed
to combine different process steps such as coating, granulation, heat transfer,
and drying, in a single equipment, etc.
Agitation is the process
of keeping a mixture that has been mixed in the proper mixed state required for
the 'end' product. Mixing refers to the actual stirring of different liquids
and/or materials to blend them into an end product or mixture. Once this
mixture is 'mixed' it may require agitation to keep the mixture in the proper
'mixed' state.
Generally mixing can lead
to three types of mixtures that are fundamentally different in their
behaviours:
(i) Positive mixtures:
Positive mixtures are formed when two or more components are irreversibly mixed
by a diffusion process. In this case, no energy input is required and the time
allowed for the components to mix is sufficient. In addition, these types of
materials do not create any problems during their mixing process.
(ii) Negative mixtures:
Negative mixtures are formed when components are mixed to form a heterogeneous
system, for example, emulsion or suspension. The components of these mixtures
have a high tendency to separate as they are not continuously being stirred.
Thus, such mixtures are more difficult to prepare as they need a high degree of
mixing with external force.
(iii) Neutral mixtures:
Neutral mixtures are stable in behavior. The components of these mixtures do
not tend to mix spontaneously but once mixed, they do not separate easily.
Pharmaceutical products such as pastes, ointments, and mixed powders are examples
of neutral mixtures.
Objectives of Mixing
Mixing aims to ensure
that there is uniformity of composition between the mixed ingredients that
represent the overall composition of the mixture. The primary objective of
mixing is to make a homogeneous product using the minimum amount of energy and
time. The other objectives are as follows:
(i) To produce a single
physical mixture: This may be simply the production of a
blend of two or more miscible liquids or two or more uniformly divided solids.
In pharmaceutical practice, the degree of mixing must commonly be of a high
order as many of such mixtures are dilutions of active substances and must be the
inaccurate amount for dose uniformity in dosage forms.
(ii) To produce physical
change: Mixing can be performed to produce physical as well
as chemical change, for example, solution of a soluble substance. In such cases,
lower efficiency of mixing is often acceptable because mixing merely
accelerates a dissolution and diffusion process that could occur by simply
agitation.
(iii) To produce
dispersion: Mixing is also aimed to include the dispersion
of two immiscible liquids to form an emulsion or dispersion of a solid in
liquid to give a suspension or paste. Usually, good mixing is required to
ensure stability and effectiveness.
(iv) To promote chemical
reaction: Mixing encourages and at the same time control a
chemical reaction. Mixing ensures a uniform product such as reactions where
accurate adjustment to pH is required and the degree of mixing will decide the
possibility of reaction.
Mixing fulfills many
objectives beyond a simple combination of raw ingredients. These include
preparing fine emulsions, reducing particle size, carrying out chemical
reactions, manipulating rheology, dissolving components, facilitating heat
transfer, etc. So even within a single pharmaceutical product line, it is a
common practice to employ several different style mixers to process raw
ingredients, handle intermediates and prepare the finished product.
Applications of Mixing
(i) Dry mixing:
Mixing helps various powders to be mixed in varying proportions before
granulation or tableting. Dry mixing of the materials makes them suitable for
direct compression into tablets.
(ii) Product features:
The mixing helps to deliver an accurate dosage that has an acceptable
appearance and texture, or to maintain formulation stability for the
appropriate length of time. The importance of proper mixer selection and its
optimal operation can hardly be over-estimated.
(iii) Dry blending:
Mixing is used for dry blending in the manufacture of many vitamins, dietary
supplements, and drugs in powders (insufflations, face powders, and tooth
powders), capsules, and tablets. Dry blending operation combines the active
ingredient with other solid excipients in the most appropriate way. Sometimes
relatively small amounts of liquid may be added to the solids to coat or absorb
coloring and flavoring agents, oils, or other solutions.
(iv) Emulsions:
Throughout the pharmaceutical industry, high shear mixing is widely used in the
preparation of emulsions such as creams and medicated lotions.
(v) Heterogeneous
mixtures: Mixing is used when different powders behave
differently when added into liquid, and some require more coaxing to dissolve,
hydrate or disperse completely than others. The ‘easier’ ones need only gentle
agitation but more challenging powders need higher speed devices that generate
a powerful vortex into which the powders are added for faster wet-out.
(vi) Tough agglomerates:
It is used to deal with solids that tend to form tough agglomerates which do
not easily break apart. A high shear mixer is often used to resolve such issues
and many solutions and dispersions are made. For example, tablet coatings,
vaccines, and disinfectants.
(vii) Fluid blending:
Mixing is used for continuous blending of fluid streams, emulsification, and
dispersion of gases into liquid, pH control, dilution, and heat exchange. A
static mixer is unique with no moving part that relies on external pumps to
move the fluids through it. For example, dissolution of soluble solids in
viscous liquids for dispensing in soft capsules and the preparation of syrups.
(viii) Viscous fluids:
Mixing is used for batch mixing of viscous formulations. Mixers are used in the
pharmaceutical industry for batch manufacturing of moderate to relatively high
viscosity applications such as syrups, suspensions, pastes, creams, ointments,
and gels.
(ix) Uniformity in size
distribution: Mixing helps in particle size
distribution and other related parameters which depend on cycle time and mixer
design. Thus the selection of a proper mixer along with product chemistry,
operating temperature, pressure/vacuum conditions, quality of raw materials,
presence of additives, etc. help to obtain appropriate product features.
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