David Michael Remick

Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine

The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.

Novel Method for the Determination of Piperazine in Pharmaceutical Drug Substances Using Hydrophilic Interaction Chromatography and Evaporative Light Scattering Detection

Abstract A novel method for the determination of piperazine in pharmaceutical drug substances was developed using high performance liquid chromatography (HPLC) with evaporative light scattering detection (ELSD). This method uses the hydrophilic interaction chromatography (HILIC) mode on a cyanopropyl (CN) bonded stationary phase. Optimization of organic modifier and acid composition in the mobile phase resulted in robust chromatography conditions with excellent resolution, peak shape, and retention time for the piperazine peak. The method was further evaluated with respect to linearity, precision, selectivity, limit of detection (LOD), and reproducibility. Based on the data provided, this HPLC–ELSD method demonstrated acceptable levels of linearity, precision, LOD, and selectivity for determination of piperazine.

Isolation and Physical Property Optimization of an Amorphous Drug Substance Utilizing a High Surface Area Magnesium Aluminometasilicate (Neusilin® US2)

Control and optimization of the physical properties of a drug substance (DS) are critical to the development of robust drug product manufacturing processes and performance. A lack of isolatable, for example, crystalline, DS solid forms can present challenges to achieving this control. In this study, an isolation scheme for an amorphous DS was developed and integrated into the synthetic route producing DS with optimized properties. An inert absorbent excipient (Neusilin® US2) was used to isolate the DS via a novel antisolvent scheme as the final step of the route. Isolation was executed at kilogram scale utilizing conventional equipment. The resulting 50 wt% DS:Neusilin complex had improved physical stability and exceptional micromeritic and tableting properties. Improved dissolution was observed and attributed to enhanced dispersion and increased surface area. Characterization data suggest a high degree of penetration of the DS into the Neusilin, with DS occupying 70% of mesopore and 12% of macropore volume. This approach has application in the isolation and particle engineering of difficult to isolate DS without additional unit operation, such as spray drying, and has the potential for a high degree of optimization and control of physical properties over the course of DS development.