The powder or granulation used in pharmacy or pharmaceutical industry is commonly a mixture of two or more distinct components.
Content uniformity
- Analyses of powders
The
powder or granulation used in pharmacy or pharmaceutical industry is commonly
a mixture of two or more distinct components. Adequate performance of the
powder blend at different stages of manufacturing or use depends on the
uniformity of distribution of the different component materials throughout the
powder.
Uniform
distribution of each component in a powder mixture is desired to assure uniform
subdivision of the individual components when the powder mixture is subdivided.
For example, compression of granules of a combina-tion drug product, containing
two different drugs, requires good content uniformity of both drugs in the
granulation so that each tablet would have both drugs at the desired dose
level.
Uniform
distribution of components is also critical for the excipients used in the drug
product manufacture. For example, magnesium stearate as a lubricant can
function effectively only when it is uniformly distributed throughout the
granulation. Any lack of uniformity distribution of magne-sium stearate can
lead to overlubrication and underlubrication of portions of the granulation,
which can lead to potential drug dissolution and pro-cessability issues, respectively.
Uniformity
of mixing of two or more components is affected by the simi-larity of particle
characteristics of the components. Components having similar particle size,
shape, density, and size distribution tend to produce uniform powder mixtures.
Uniformity of content of a drug in a dosage form is usually good if the drug
loading in the dosage form is high (e.g., 50% w/w or more of the dosage form
weight is attributable to the drug weight) and the drug particles exhibit good
flow, have a shape that is close to spherical, and possess density that is
comparable to other ingredients used in the dosage form.
In
addition, the choice of mixing equipment and blending protocol can affect the
uniformity of content. For example,
·
A V-shaped blender tends to produce better mixing than a bin
blender.
·
In terms of the blending protocol, minor (lower quantity)
components of the powder mixture are often sandwiched
between the major com-ponents by controlling the sequence of addition of the
components to the blender. This is particularly important for critical
excipients that have a tendency to segregate, such as magnesium stearate.
·
Components that have atypical particle characteristics, such
as the very low BD of colloidal silicon dioxide, are often premixed with a
small quantity of another component before addition to the blender.
·
Mixing time plays a key role. Although a minimum amount of
time is required to achieve desired content uniformity, prolonged mixing does
not necessarily result in better uniformity of content. In fact, prolonged
mixing can compromise the uniformity. Therefore, opti-mum time of mixing is
carefully determined and controlled.
Uniformity
of a powder mixture can get compromised after mixing, such as during the storage
and handling of powders. For example, vibration in the storage bins due to the
operation of large-scale equipment can lead to segregation of a uniform mixture
of components especially if they differ in particle size and/or density.
Segregation can also happen during material transfer. For example, flow of a
powder blend through the hopper from a closed chamber can result in a
counter-current flow of air, which can par-tially fluidize the powder leading
to segregation based on differences in the fluidization potential of particles
of different components.
Uniformity
of content of the APIs in the finished drug product is an impor-tant criterion
to ensure consistency of the dose delivered to the patient. The USP and other
compendia define the acceptance criterion for determining the uniformity of
content. This criterion is based on statistical probability considerations and
is based on the requirement that the potency of each individual dosage unit
must be within a given range, and no more than a given number of dosage units
may exceed a narrower range.
To
ensure the uniformity of content of the API in the finished drug prod-uct,
pharmaceutical manufacturing also typically tests the content unifor-mity of
the powder blend at the end of certain unit operations, such as blending and
granulation. These may also provide a prospective guidance to adjust the
operating parameters of such unit operations. The testing of content uniformity
in powders and granules typically involves sampling a fixed quantity of the
powder from several different, predefined locations in the storage container or
process equipment and testing them for the content of the APIs. The acceptance
criteria for the uniformity of content on these powder samples are typically
same as the compendial criteria for finished drug products.
Selection
of appropriate manufacturing process and its parameters plays a key role in
ensuring good content uniformity of the drug in the final dos-age form. For
example, wet granulation or roller compaction-based dry granulation processes
can improve the uniformity of distribution of seg-regation prone drugs, such as
due to low drug loading or atypical particle shape or density. Granulation adds
an additional mixing step and leads to the aggregation of drug particles with
those of excipients, thus changing both particle size and shape. The selection
of drug loading in the dosage form also plays a key role. Higher the drug
loading, lower the chances of segregation of the drug.
Content
uniformity issues arising from segregation in powder blends can also be
addressed by engineering considerations in the design and opera-tion of
large-scale equipment. These include the handling operations that minimize
vibration on the equipment and material transfers. For example, conventional
tablet manufacturing processes involved preparation of the powder blends for
compression and their storage in drums, which were then transferred to bins for
loading on the tablet press for compression. In the redesigned process, the
powder blend is prepared in a modified bin that can be used on the tablet
press, thus minimizing two transfer operations. Another example of equipment
redesign is designing a vent for air inlet in closed powder transfer processes
to minimize fluidization of powder.
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