Content uniformity - Analyses of powders

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Chapter: Pharmaceutical Drugs and Dosage: Powders and granules

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.

Importance of uniform mixing

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.

Factors affecting mixing uniformity

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.

Assessment of content uniformity

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.

Addressing content nonuniformity issues

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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