(T1330-03-19) Using Biorelevant Dissolution to Better Predict Bioavailability Issues

Purpose: Bioavailability is a critical factor in drug development, which must be evaluated early during drug development to avoid failure later on. Traditional dissolution testing methods may not accurately reflect the in vivo performance of a drug: indeed, classical USP methods have been developed for quality control [1]. They require large volume of media and are thus not practical during the early development stages where the amount of available API is scarce. Dissolution tests using small volumes of physiologically relevant media are thus an interesting approach to predict drug dissolution in the gastrointestinal tract and detect early potential bioavailability issues [2]. To do so, multistep in vitro tests where the pH is variated during the dissolution test, or a medium representing gastric or intestinal conditions is added during the dissolution have been developed [3]. Hereafter, two case studies of poorly soluble APIs are presented: the dissolution of Palbociclib, a “brick dust” API (melting point > 200°C, LogP < 2), and the dissolution of Tamoxifen, a “grease ball” API (LogP > 4) [4].

Methods: Dissolution methods were developed in small volumes lower than 80 mL, where the pH was increased progressively during the dissolution process to mimic the pH change of the gastrointestinal tract, from pH 2.0 to pH 7.4. Dissolution methods with addition of FaSSIF (Fasted State Simulated Intestinal Fluid) or FeSSIF (Fed State Simulated Intestinal Fluid) were also developed. Crude APIs were tested. The amount of API chosen for the dissolution was calculated to obtain a maximum concentration equal to the highest dose of the product on the market divided by 250 mL (volume of a glass of water).

Results: Starting volume of the dissolution medium were 40 mL, allowing the use of less than 100 mg of APIs for all three replicates per API. As the pH was variated during a single experiment, more data were obtained using lower amount of APIs, with information on pH-dependency dissolution and precipitation data when switching from low stomach pH to high intestinal pH. Palbociclib dissolution was found to be pH-dependent, the API dissolved readily at pH 2.0, reaching 100% dissolution of the dose after a few minutes. However, when reaching pH 7.4, the solution precipitated out after a few minutes of super-saturation. Differences in dissolution kinetics were found between FaSSIF and FeSSIF medium, showing a food effect caused by pH-change and presence of bile salts. In comparison, Tamoxifen citrate dissolution was slow and limited by the poor solubility of the API from pH 2.0 to 5.5, reaching less than 30% of dissolution after 1h30. A precipitation of the solution was observed over pH 6.5. Dissolution kinetics were also faster in FeSSIF than FaSSIF.

Conclusion: Using biorelevant dissolution testing can enhance our understanding of drug dissolution and absorption, leading to better prediction of potential bioavailability issues. By incorporating physiological conditions into dissolution testing, this approach offers a more accurate representation of in vivo performance of the APIs. The use of small volumes is key to obtain these data early during drug development, to anticipate formulation needs.

References: [1] Otsuka K. et al., Journal of Pharmacy and Pharmacology, 2013
[2] Bhagat N.B. et al., Journal of Drug Delivery and Therapeutics, 2014
[3] Fiolka T. and Dressman J., Journal of Pharmacy and Pharmacology, 2018
[4] Bergström C.A.S., et al., Advanced Drug Delivery Reviews, 2016

Acknowledgements: The authors would like to thank Emilie Bobo and Sofiane Smail for their help with the solid-state characterization of Palbociclib and Tamoxifen citrate and Malik Belmeliani for his help with the dissolution tests. The authors have no conflict of interest to declare.

Scanning Electron Microscopy (SEM) pictures of Palbociclib and Tamoxifen citrate (magnification x3,000)