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J Pharm Sci. 2014 Oct;103(10):3007-21. doi: 10.1002/jps.24088. Epub 2014 Jul 29.

Physicochemical properties, form, and formulation selection strategy for a biopharmaceutical classification system class II preclinical drug candidate.

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Department of Discovery Pharmaceutical Sciences, Merck and Company, Inc., Rahway, New Jersey, 07065.


This work summarizes the pharmaceutical evaluation of a preclinical drug candidate with poor physicochemical properties. Compound 1 is a weakly basic, GPR-119 agonist designated to Biopharmaceutics Classification System Class II because of good permeability in a Caco-2 cell line model and poor solubility. Compound 1 showed good oral bioavailability from a solution formulation at low doses and oral exposure sufficient for toxicological evaluation at high doses from a nanosuspension of Form A-the only known polymorph of 1 during drug discovery. The identification of the thermodynamically stable polymorph, Form B, during early development adversely affected the bioperformance of the nanosuspension. The poor solubility of Form B resulted in a significant reduction in the oral exposure from a nanosuspension to a level that was insufficient for toxicological evaluation of compound 1. Subsequent to the discovery of Form B, multiple form and formulation engineering strategies were evaluated for their ability to enhance the oral exposure of 1. Formulations based on cocrystals and amorphous solid dispersions showed a statistically significant increase in exposure, sixfold and sevenfold, respectively, over the benchmark formulation, a suspension of Form B. The physicochemical characterization of 1, and the solid form and formulation engineering approaches explored to address the insufficient oral exposure of Form B are discussed along with insights on improving the physicochemical properties of the follow-on drug candidates in discovery.


BCS Class II; bioavailability; cocrystal; physicochemical properties; polymorphism; solid dispersion; solubility

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