Understanding, predicting, and mitigating air entrapment defects in pharmaceutical tablet manufacturing

Principal investigator: Antonios Zavaliangos

University: Drexel University

Industry partners: Merck & Co., Inc.

Solid oral dosages (tablets) represent more than 50% of all pharmaceutical dosage forms in terms of market value and are projected to grow by 6.5% annually for the next decade [1]. They are preferred due to administration convenience, superior stability, and economic advantages in production, transport, and storage. Pharmaceutical manufacturing of solid oral dosages faces several problems that stem from the need to balance the contradicting requirements of mechanical strength and bioavailability. These problems often lead to products with mechanical strength that is below the acceptable limits. The result is anything from cosmetic damage that affects patience’s perception of quality and regiment adherence to complete tablet failure. These issues (a) are especially disruptive in the early stages of drug development when acceptable tablets must be produced from limited and often expensive materials without the benefit of extensive experimentation, (b) may cause significant delays and regulatory stops when they appear during clinical manufacturing and (c) become extremely costly when they appear during full scale manufacturing.

This work focuses on understanding, predicting and mitigating defects that are caused by air entrapment during pharmaceutical tablet manufacturing. This problem has become increasingly common because many new active pharmaceutical ingredients (API) are produce in very fine (~micron) size to address limited solubility and meet bioavailability requirements [2]. The presence of such fine powder in the tablet formulations in high volume percent restricts the displacement of the interstitial air during tablet compaction. The entrapped air is pressurized and upon release of the compaction load the internal pressure is often high enough to damage the tablets.

To address this problem, a collaborative effort between Drexel University and Merck will follow a combined experimental-theoretical-numerical approach to establishing a scientific framework for the processing of tablets under conditions when air entrapment defects is possible.