Several types of high-temperature calorimeters are compared in this paper. The calorimetry methods reviewed are drop, adiabatic, pulse, differential scanning, and, the newest method, high-temperature differential scanning.
Several active pharmaceutical ingredients are currently being developed as pharmaceutical cocrystals as these systems often have superior properties compared to traditional pharmaceutical forms. Pharmaceutical cocrystal formers typically used are polar, small molecule acids or bases which often lack a UV chromophore. Their polar nature results in almost no reversed phase retention and their detection typically cannot be done with UV. Here we discuss approaches for the analysis of pharmaceutical cocrystals using HPLC columns designed for polar retention, ion pairing chromatography (IPC), and hydrophilic interaction chromatography (HILIC) using model cocrystal formers. Corona charged aerosol detection (CAD) was used to monitor the cocrystal formers. L-alanine was used as a model basic cocrystal former, and succinic acid and glutaric acid were used as model acidic cocrystal formers. The acidic cocrystal formers were adequately retained on a C18 column. Heptafluorobutyric acid was used as the ionpairing reagent for L-alanine as it was unretained without the ion-pairing reagent. HILIC, a newer approach for polar compound retention, was also investigated. Using the HILIC mode, all three model cocrystal formers were retained adequately. Of all the approaches studied for the analysis of the cocrystal formers, HILIC appears to be the best choice as the same column can be used for both acidic and basic cocrystal formers. With IPC, the ion-pairing reagent permanently alters the column chemistry and dedicated columns are required for each ion-pairing reagent used. CAD detection provided a linear response in the 80-100% test concentration range for the analytes studied here.
A reversed-phase high-performance liquid chromatographic method (HPLC) with diode-array detection (DAD) has been evaluated for monitoring trace levels of impurities, such as 4-amino-2-ethoxy-cinnamic acid (impurity A), hydrochloride salt of 4-amino-2-ethoxy-ethyl cinnamate (impurity B), and 4-bromo-3-ethoxy-nitrobenzene (impurity C), in drug substance and 3 different formulation prototypes. These compounds have been highlighted as potential genotoxins and 2-ethoxy-4-amino-cinnamic acid (impurity A) as possible degradant isolated during the synthesis of BI drug substance. HPLC-UV-DAD was found to be more promising, and limits of quantification were between 0.09 and 0.6 microg/mL, which enabled detection limits in drug substance at 2-15 ppm for a 15 mg/mL solution. All three genotoxic impurities are completely resolved from each other as well as from diluent peaks, drug substance, and other related impurities within 40 min. The retention times of impurities A, B, and C were 3.4, 13.1, and 21.3 min. The results demonstrating the specificity, assay precision, recovery, linearity, and range achieved during the method validation experiments are presented in this paper.
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