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

Abstract

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.

Analytical methodologies for the determination of sertraline

“…Further chemical derivatization of the molecule may be necessary to observe the enantiomers by chromatographic detectors and/or to obtain separation. Salsbury and Isbester [34] presented a nuclear magnetic resonance (NMR) and chiral solvating agent (CSA, 1,1-bi-2-naphthyl) technique for the routine determination of enantiomeric purity. The technique was applied to three common active pharmaceutical ingredients (APIs: SRT, PAR and fenfluramine), to demonstrate that NMR is a useful and convenient technique to complement or provide an alternative to optical rotation and chiral HPLC for evaluation of enantiomeric purity.…”

Use of (S)‐BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs

“…25 More in general, (R)-BINOL has been recently applied as NMR CSA for some nonsulfoxide important drugs. 26 In this work, we report the results of the application of this NMR method to the enantiodiscrimination of omeprazole and three structurally related analogs (lansoprazole, y Omeprazole presents tautomerism in the benzimidazole group. Therefore, both tautomers must be considered when using the systematic nomenclature.…”

Characterization of Chemical Weapons Convention Schedule 3 Compounds by Quantitative 13C NMR Spectroscopy

“…Quantitative NMR analyses are typically reported for 'H, 4 -6 13 C 7-9 and 3 1p0-12 spectroscopy, however, quantitative spectroscopy for other nuclei 1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] can also be found. Further, the accuracy and precision of NMR signal intensity measurements have recently been reviewed, 20 and more recently, Maniara et al 2 reported a systematic validation of the quantitative NMR method.…”