Anthony O. King

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

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.

Pd-Catalyzed Deoxygenation of Mandelate Esters

A new approach to the synthesis of phenylacetic acids and esters has been developed via the palladium-catalyzed deoxygenation of mandelate esters.

Determination of Vinylmagnesium Halide Reagents by High-performance Liquid Chromatography After Reaction With Anthraldehyde

A reversed-phase HPLC method has been developed for the determination of vinylmagnesium chloride and vinylmagnesium bromide, based on the assay of 1-(9-anthryl)propen-2-ol, the product in the reaction between a vinylmagnesium halide and 9-anthraldehyde. The HPLC system with UV detection and an acetonitrile–water mobile phase containing phosphoric acid buffer was used for the separation and quantification of the reaction product after extraction. The method is selective for 1-(9-anthryl)propen-2-ol and linear response was established at 227 nm in the 0.002 to 0.5 mg ml–1 concentration range. Vinylmagnesium halide concentration was calculated by using benzophenone as an external reference standard to standardize the response of authentic 1-(9-anthryl)propen-2-ol.