Quantitative 1H NMR analysis of a difficult drug substance and its exo-isomer as hydrochloride salts using alkaline deuterated methanol

Abstract

Quantitative NMR is extremely useful for rapid determination of sample purity. Occasionally however, certain ionic compounds (prepared as a salt with a counter ion) may be difficult to accurately quantitate, due to aggregation, solubility, and/or signal drift. Here we describe an example of utilizing alkaline deuterated methanol for quantitative NMR of a problematic endo drug substance and its exo-isomer, as hydrochloride salts, with precision comparable to HPLC. This method allows for in situ neutralization of the HCl salt and subsequent solubilization of the organic free-base for analysis, providing a one-step quantitative sample preparation procedure. The selection of solvent, alkaline concentration, internal standard, instrumental parameters, and assessment of method accuracy are discussed. Overall, the method is simple, cost-effective, and analytically reliable.