Abstract
Content uniformity (CU) of the active pharmaceutical ingredient is a critical quality attribute of tablets as a dosage form, ensuring reproducible drug potency. Failure to meet the accepted uniformity in the final product may be caused either by suboptimal mixing and insufficient initial blend homogeneity, or may result from further particle segregation during storage, transfer or the compression process itself. This review presents the most relevant powder segregation mechanisms in tablet manufacturing and summarizes the currently available, up-to-date research on segregation and uniformity loss at the various stages of production process—the blend transfer from the bulk container to the tablet press, filling and discharge from the feeding hopper, as well as die filling. Formulation and processing factors affecting the occurrence of segregation and tablets’ CU are reviewed and recommendations for minimizing the risk of content uniformity failure in tablets are considered herein, including the perspective of continuous manufacturing.
Highlights
The safety and efficacy of solid oral drug products, as well as their robust performance, are ensured by meeting the specified values of critical quality attributes (CQAs)
This requirement is important in the case of low-dose, highly potent drugs, where small variations in the active pharmaceutical ingredient (API) amount due to the dosage form may result in a significant impact on safety and efficacy
This review focuses on the latter phenomenon, i.e., demixing and the resulting inhomogeneous distribution of ingredients during various stages of tablet manufacturing, whereas the topic of blending as a unit operation is outside its scope
Summary
The safety and efficacy of solid oral drug products, as well as their robust performance, are ensured by meeting the specified values of critical quality attributes (CQAs). A repeatable unit content of the active pharmaceutical ingredient (API) and a drug potency remaining within the acceptable deviation from the target value (as a general simplification, 85–115% of the label claim for most products) are fundamental for assuring a therapeutic concentration in systemic circulation and for minimizing the risk of adverse events This requirement is important in the case of low-dose, highly potent drugs, where small variations in the API amount due to the dosage form may result in a significant impact on safety and efficacy. A caveat must be made that the diverse reviewed studies use varied measures for assessing CU in terms of responses (e.g., RSD of API content, acceptance value (AV) according to pharmacopeia, etc.) and different, often custom ways of calculating segregation indices Due to this disparity, a direct comparison between the reports in terms of absolute results is not warranted. Focus is placed on the observed trends and relationships between processing parameters, segregation phenomena and content uniformity changes
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