Quantitative 1H NMR method for the routine spectroscopic determination of enantiomeric purity of active pharmaceutical ingredients fenfluramine, sertraline, and paroxetine.

Determining the enantiomeric purity of chiral therapeutic agents is important in the development of active pharmaceutical ingredients (API). A strategy for determining the enantiomeric purity of three APIs was developed using nuclear magnetic resonance (NMR) and the chiral solvating agent (CSA) 1,1-bi-2-naphthyl (1). While chiral chromatography is widely used to evaluate enantiomeric purity, it can sometimes suffer from tedious sample preparation obviating rapid measurements that are sometimes needed during the manufacture of such agents. The techniques described herein provide comparable enantiomeric purity results with those obtained with traditional chiral HPLC and other published methods for these compounds. Chiral analysis of standard samples of methylbenzylamine enantiomeric mixtures using 1 were found to be quantitative to approximately 1% minor enantiomer. Enantiomeric purity determination by NMR utilizing chiral solvating agents do not require special instrumental techniques, chemical derivatization or standards and is therefore ideally suited for rapid routine analysis. As a result, the technique demonstrated is commonly used in our laboratory as a complementary or alternative method to chiral HPLC or optical rotation measurements for routine determination of enantiomeric purity.

Solid-state fluorescence studies of some polymorphs of diflunisal*.

PURPOSE: The solid-state luminescence spectroscopy of organic molecules is strongly affected by the effects of excited state energy transfer, with the fluorescence of solids often differing significantly from the fluorescence of the molecule dissolved in a solution phase. Because the magnitude of these solid-state effects is determined by the crystallography of the system, solid-state fluorescence studies can be used to gain insight into the polymorphism of the system. To this end, the spectroscopic properties of four polymorphs of diflunisal have been obtained, and compared to the properties of the molecule in the solution phase. METHODS: Fluorescence excitation and emission spectra were obtained on four polymorphic forms of diflunisal, and on the compound dissolved in water. RESULTS: It was found that exciton effects dominate the excitation spectra of diflunisal in the four studied polymorphic forms. These phenomena lead to a decrease in the energy of the excitation bands relative to that observed for the free molecule in fluid solution, and in a splitting of the excitation peak into two Davydov components. CONCLUSIONS: The trends in the excitation and emission spectra led to the grouping of diflunisal Forms I, II, and III into one category, and diflunisal Form IV into a separate category. Because other work has established that Form IV is characterized by the highest crystal density and consequent degree of intermolecular interaction, the magnitude of the exciton coupling can be used to estimate the degree of face-to-face overlap of the salicylate-type fluorophores.