A Deeper Investigation of Drug Degradation Mixtures Using a Combination of MS and NMR Data: Application to Indapamide.

Cécile Palaric,François Mesnard,Alain Petit,Dominique Cailleu,Jean-Xavier Fontaine,Yoann Gut,Serge Pilard,Tristan Renaud,Roland Molinié,David Mathiron

doi:10.3390/molecules24091764

Abstract

A global approach that is based on a combination of mass spectrometry (MS) and nuclear magnetic resonance (NMR) data has been developed for a complete and rapid understanding of drug degradation mixtures. We proposed a workflow based on a sample preparation protocol that is compatible to MS and NMR, the selection of the most appropriate experiments for each technique, and the implementation of prediction software and multivariable analysis method for a better interpretation and correlation of MS and NMR spectra. We have demonstrated the efficient quantification of the remaining active pharmaceutical ingredient (API). The unambiguous characterization of degradation products (DPs) was reached while using the potential of ion mobility-mass spectrometry (IM-MS) for fragment ions filtering (HDMSE) and the implementation of two-dimensional (2D) NMR experiments with the non-uniform sampling (NUS) method. We have demonstrated the potential of quantitative NMR (qNMR) for the estimation of low level DPs. Finally, in order to simultaneously monitor multi-samples, the contribution of partial least squares (PLS) regression was evaluated. Our methodology was tested on three indapamide forced degradation conditions (acidic, basic, and oxidative) and it could be easily transposed in the drug development field to assist in the interpretation of complex mixtures (stability studies, impurities profiling, and biotransformation screening).

Highlights

The stability testing of new drug substances and products guidelines Q1A(R2) that are issued by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [1] suggests that stress studies should be carried out on an active pharmaceutical ingredient (API) to establish its inherent stability characteristics, such as the degradation pathways, which lead to the identification of degradation products (DPs) and support the suitability of the proposed analytical procedures.A lot of analytical techniques are used in order to assess the quality of drugs [2]
Our objective is to offer a global tool to the pharmaceutical industry for a deeper investigation of complex mixtures containing API and numerous other compounds
We have investigated the benefit of partial least squares (PLS) regression to establish a rapid correlation between mass spectrometric (MS) and nuclear magnetic resonance (NMR) data set when several degradation conditions need to be simultaneously analyzed and processed

Summary

Introduction

The stability testing of new drug substances and products guidelines Q1A(R2) that are issued by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [1] suggests that stress studies should be carried out on an active pharmaceutical ingredient (API) to establish its inherent stability characteristics, such as the degradation pathways, which lead to the identification of degradation products (DPs) and support the suitability of the proposed analytical procedures.A lot of analytical techniques are used in order to assess the quality of drugs [2]. The use of nuclear magnetic resonance (NMR) spectroscopy is the other way to access unambiguous structural and quantification data [5,6]. This technique lacks sensitivity and suffers from signal overlapping when analyzing mixtures. New approaches that involve the combination of MS and NMR data have been recently developed for metabolomics studies [9,10] and food control [11]. They include specific sample preparation and dedicated experiments (MS/MS, two-dimensional (2D) NMR)

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