Evaluation of In Vivo Drug Precipitation or Crystallization Potential through a Novel In Vitro Approach for Method Development and Initial Risk Assessment

Evaluation of In Vivo Drug Precipitation or Crystallization Potential Through a Novel In Vitro Approach for Method Development and Initial Risk Assessment

Chenchi Wang¹, Ching Su², and Thanga Mariappan³, et al.

¹Pharmaceutical Manufacturing Science and Technology, Global Manufacturing and Supply, Bristol-Myers Squibb, New Brunswick, New Jersey; ² Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, New Jersey; ³ Biocon-Bristol-Myers Squibb R&D Centre, Syngene International Limited, India.

As poorly water-soluble drug candidates have become prevalent in the discovery and development phases for pharmaceuticals, incidents of in vivo bio-accumulation in animals of drug molecules or related have been reported in some pre-clinical toxicological studies via precipitation or crystallization. These observations could complicate and may prevent further development of these compounds. In the early development of drug substances, it would be beneficial to enable a quick, in vitro assessment to differentiate or screen between multiple drug candidates for their comparative risks of potential precipitation in vivo, using a method with minimum efforts required if possible.

In this work, we explored a novel in vitro precipitation risk assessment concept and designed experimental methods based on measurable characteristics, such as solubility, in vivo exposure, and the levels of supersaturation of related molecules, etc., with assumptions made in order to simplify the working hypothesis. Multiple test compounds have been examined using this approach empirically to monitor and rank order their relative precipitation potentials in deliberately created, precipitation-prone conditions. The resultant indications in vitro are consistent with the observations obtained in vivo in the toxicology studies.