Rapid quantification of isomeric and dehalogenated impurities in pharmaceutical raw materials using MRR spectroscopy

• Published in: Journal of pharmaceutical and biomedical analysis 2020-09, Vol.189, p.113474-113474, Article 113474
• Main Authors: Neill, Justin L., Mikhonin, Alexander V., Chen, Ted, Sonstrom, Reilly E., Pate, Brooks H.
• Format: Article
• Language: English
• Subjects: Chiral analysis; Molecular rotational resonance spectroscopy; MRR Spectroscopy; Pharmaceutical impurities; Raw materials
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2020.113474

[Display omitted] •MRR demonstrated to be useful for purity characterization of two raw materials.•Regioisomeric, dehalogenated, and enantiomeric impurities were quantified by MRR.•No sample preparation, purification, or derivatization was required.•Measurements performed in cycle times of less than 20 min. We demonstrate the application of molecular rotational resonance (MRR) spectroscopy to quantify regioisomeric, dehalogenated, and enantiomeric impurities in two raw materials used in the synthesis of a HIV integrase inhibitor, cabotegravir. Characterization of these raw material impurities is important due to their ability to introduce structurally similar impurities into the final drug product. MRR, due to its high resolution and selectivity to small changes in molecular structure, can perform these measurements rapidly and without the need for developing a chromatographic separation method. For 2,4-difluorobenzylamine, four impurities were quantified (benzylamine, 2-fluorobenzylamine, 4-fluorobenzylamine, and 2,6-difluorobenzylamine), while for (S)-alaninol (2-amino-1-propanol), its enantiomer, (R)-alaninol, was measured using a chiral tagging method. For both samples, the resonance frequencies of each compound of interest were first determined using a broadband spectrometer before evaluating analytical performance metrics on a faster targeted spectrometer. For the fluorobenzylamines, quantitative performance was demonstrated over the range 0.05–5 % (v/v) for each impurity, while for alaninol, measurements were performed over the range of 70–99 % enantiomeric excess. This study suggests that MRR can be useful for validating the purity of pharmaceutical raw materials.