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Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs

  • Research Article
  • Theme: Integrating In Vitro Systems and Physiologically-Based Pharmacokinetics Modeling to Optimize Drug Product Development
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Abstract

In vivo drug dissolution kinetics of BCS Class 2a IR solid oral drug products remains largely unknown. An understanding to what extent the solubility influences in vivo dissolution is needed to design appropriate in vitro dissolution methods. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to investigate the in vivo dissolution of BCS Class 2a drugs based on numerical deconvolution analyses. The PK data were obtained from published literature or drug applications submitted to the FDA. It has been hypothesized that the in vivo drug dissolution rate would likely correlate to the solubility of NSAIDs in the media at gastrointestinal pH. Our findings show a short lag time of absorption (Tlag), comparable to the liquid gastric emptying time and independent of the solubility and formulation. In Vivo drug dissolution of NSAIDs was generally rapid and complete within the regular drug residence time in the small intestine while multi-phase absorption was observed in some subjects for all the NSAIDs. The comparisons of in vivo drug dissolution rate, which was characterized by in vivo dissolution half-life (Thalf), indicate that solubility has a minimal impact on in vivo drug dissolution rate for NSAIDs. Gastric emptying regulated by migrating motor complex (MMC) under fasted state most likely governs drug dissolution and absorption of NSAIDs. For BCS Class 2a IR solid oral drug products, large variability of gastric emptying and MMC as well as the strong driving force of intestinal absorption probably outweigh the impact of solubility on drug in vivo dissolution.

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Funding

Drs Zhang and Wu were supported in part by the appointments to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education.

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Authors and Affiliations

  1. Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

    Min Li, Xinwen Zhang, Di Wu, Om Anand, Hansong Chen & Kimberly Raines

  2. Biopharmaceutics, Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, New Jersey, USA

    Di Wu

  3. Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Lawrence Yu

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  1. Min Li
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  2. Xinwen Zhang
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All authors were involved in the conceptualization, methodology, data analyses, interpretation and in the development of the manuscript.

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Correspondence to Min Li.

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The findings and conclusions in this work have not been formally disseminated by the United States Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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Li, M., Zhang, X., Wu, D. et al. Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs. AAPS J 23, 113 (2021). https://doi.org/10.1208/s12248-021-00639-0

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