Mitigating Cocrystal Physical Stability Liabilities in Preclinical Formulations.
Poor aqueous solubility of a majority of new small molecule chemical entities is a significant challenge in drug discovery since considerably high exposures are often required to enable pharmacokinetic, pharmacology, and toxicology studies. Pharmaceutical cocrystals have received considerable attention in recent years owing to their potential to improve the physicochemical properties and in vivo performance of poorly soluble drugs. However, physical instability in supersaturated solution/suspension formulations is a major concern for their use in preclinical studies. This review will present an overview of the thermodynamic and kinetic contributions impacting physical stability of cocrystals in preclinical formulations with a focus on the role of surfactants, polymeric excipients, and pH. Finally, the in vivo performance of cocrystals will be discussed. The article will conclude with a perspective on strategies to develop physically stable preclinical cocrystal formulations.
Discovery Pharmaceutical Sciences, Merck & Co., Kenilworth, New Jersey 07033. Electronic address: sunny.bhardwaj2@merck.com.
Sunny
S
Bhardwaj
Discovery Pharmaceutical Sciences, Merck & Co., West Point, Pennsylvania 19486.
Maya
M
Lipert
Discovery Pharmaceutical Sciences, Merck & Co., Kenilworth, New Jersey 07033.
Annette
A
Bak
D000818:Animals; D003460:Crystallization; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010599:Pharmacokinetics; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D013816:Thermodynamics
D005079:Excipients; D004364:Pharmaceutical Preparations; D013501:Surface-Active Agents
cocrystals; formulation; oral drug delivery; physical stability; solubility