The Co‐Crystal Approach to Improve the Exposure of a Water‐Insoluble Compound: AMG 517 Sorbic Acid Co‐Crystal Characterization and Pharmacokinetics

Abstract Co‐crystals are relatively novel in the pharmaceutical field and are not reported extensively. AMG 517 is an insoluble small molecule VR1 (vanilloid receptor 1) antagonist. In animal studies, good exposure of AMG 517 is seen from a 10% (w/v) Pluronic® F108 in OraPlus® suspension. Investigation of the suspension formulation revealed that AMG 517 forms a co‐crystal with sorbic acid, a preservative in OraPlus®. This co‐crystal of AMG 517 was isolated by coslurrying AMG 517 and sorbic acid; studied by DSC and XRD; and identified by solution NMR, TGA, and HPLC to be a 1:1 association of AMG 517 and sorbic acid. Single crystal structure analysis revealed a 1:1 co‐crystal of AMG 517 and sorbic acid, held together by two hydrogen bonds and other noncovalent, nonionic forces. The co‐crystal has better aqueous solubility initially as compared to AMG 517 free base but does revert back to a form of the free base hydrate during prolonged slurry in FaSIF (fasted simulated intestinal fluid). Pharmacokinetic evaluation of the co‐crystal in rats using 10% (w/v) Pluronic F108® in OraPlus® suspensions revealed that a 30 mg/kg dose in suspension had comparable exposure to a 500 mg/kg dose of the free base. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3942–3956, 2008