Application of quantitative NMR for purity determination of standard ACE inhibitors

•qNMR method for the calibration of ACE inhibitors were systematically studied.•The reaction between maleic acid and captopril in D2O was first found.•A thiol-Michael addition reaction and new diastereoisomers was first elucidated.•qNMR method has great potential for the quantification of materials.

This study investigated the accuracy of the quantitative NMR method for purity determination of ACE inhibitors reference standards and the discovery of two pairs of new diastereoisomers. Six types of ACE inhibitors, imidapril hydrochloride, benazepril hydrochloride, lisinopril, enalapril maleate, quinapril hydrochloride, and captopril were quantificated and validated for the qNMR method by discussing factors that affect parameters of the qNMR experiment, internal standards, integration, pH-effect, and uncertainty. The results were compared with data obtained by the mass balance method. The study found that maleic acid influenced the quantification of captopril in deuteroxide because of a chemical reaction. The mixtures of the reaction products were isolated by HPLC and structurally elucidated by NMR as two pairs of new diastereoisomers, 1-[(2S,4R)-thio-2-methylpropionyl-5-d-ethanedicarboxylicacid]-l-proline and 1-[(2S,4S)-thio-2-methylpropionyl-5-d-ethanedicarboxylicacid]-l-proline. The results showed that the accuracy and precision of quantitative 1H NMR spectroscopy satisfied the requirements for quantitative analysis of chemical reference standards and provided a simple, rapid, and reliable method for purity determination of ACE inhibitors systematically.

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