Development of a Method for Determination of Related Impurities in GML-3 Drug Substance: A New Compound with Anxiolytic
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Pharmaceutical Chemistry Journal, Vol. 54, No. 8, November, 2020 (Russian Original Vol. 54, No. 8, August, 2020)
DEVELOPMENT OF A METHOD FOR DETERMINATION OF RELATED IMPURITIES IN GML-3 DRUG SUBSTANCE: A NEW COMPOUND WITH ANXIOLYTIC PROPERTIES L. N. Grushevskaya,1,* M. S. Sergeeva,1 L. M. Gaevaya,1 M. E. Dudenkova,1 E. D. Denisenko,1 N. I. Avdyunina,1 S. V. Minaev,1 and G. V. Mokrov1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 8, pp. 40 – 46, August, 2020.
Original article submitted September 9, 2019. A method for determination of related impurities in the new anxiolytic drug substance GML-3 was developed. HPLC and TLC techniques that could identify starting materials and synthetic intermediates and quantify them and unidentified impurities with contents of 0.05% and less in the drug substance were developed. The proposed techniques could be used further for quality control of GML-3 drug substance. Keywords: GML-3, related impurities, processing impurities, HPLC, TLC, separation, analysis, linearity, accuracy, precision, detection limit.
was required for implementation of the new compound in clinical practice. The most important quality indicators of drug substances are the contents of related impurities, in particular, starting compounds and synthetic intermediates. The aim of the present study was to develop methods for detection and quantitative or semi-quantitative evaluation of the contents of starting compounds and synthetic intermediates in GML-3 drug substance. The chemical structure of GML-3 is derived from pyrrolo[1,2-a]pyrazine. The compound is produced via reaction of pyrrol-2-yl phenyl ketone and 2-azidoacrylic acid
Anxiolytics are currently an important part of the pharmacotherapy of anxiety disorders. Moreover, the incidence and severity of side effects from anxiolytic drugs used in medical practice necessitate further searching for active compounds with a rapid and pronounced effect and without cognitive impairment, habituation, withdrawal syndrome, and other adverse effects typical of existing anxiolytics. One direction of the search is the design of pharmaceuticals with a different mechanism of action involving activation of endogenous neurosteroid generation via regulation of mitochondrial translocator protein (TSPO, 18 kDa) functions. Along these lines, the new compound N-butyl-N-methyl1-phenylpyrrolo[1,2-a]pyrizine-3-carboxamide (GML-3, Fig. 1) was synthesized at V. V. Zakusov Institute of Pharmacology and found to be a TSPO ligand with pronounced anxiolytic activity [1, 2]. This allowed it to be considered a potential pharmaceutical. Pharmaceutical development, one step of which was to create a set of analytical control methods and drug substance quality standards for manufacturing of the pharmaceutical, 1 *
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V. V. Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, 125315 Russia. e-mail: [email protected]
Fig. 1. N-Butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carbo xamide (GML-3).
838 0091-150X/20/5408-0838 © 2020 Springe
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