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Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide

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Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine
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Department of Medical Chemistry, National University of Pharmacy, 4 Valentynivska st., 61168 Kharkiv, Ukraine
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Department of Pharmacology, N.I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine
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STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Nauki ave., 61001 Kharkiv, Ukraine
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Department of Inorganic Chemistry, V.N. Karazin Kharkiv National University, 4 Svobody sq., 61077 Kharkiv, Ukraine
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Department of Pharmaceutical Chemistry, Far Eastern State Medical University, 35 Murav’eva-Amurskogo st., 680000 Khabarovsk, Russia
*
Author to whom correspondence should be addressed.
Sci. Pharm. 2020, 88(1), 1; https://doi.org/10.3390/scipharm88010001
Received: 13 November 2019 / Revised: 2 December 2019 / Accepted: 6 December 2019 / Published: 18 December 2019
In order to study polymorphic modifications of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, which is of interest as a promising analgesic, its three colorless crystal forms with different habitus have been obtained: sticks of ethyl acetate, plates of meta-xylene and blocks of ortho-xylene. However, the X-ray diffraction analysis has shown that all the forms studied have the identical molecular and crystal structure in spite of such significant differences in appearance. Moreover, pharmacological tests have revealed significant differences in the analgesic activity in these samples (a total of five experimental models were used: “acetic-acid-induced writhing”, “hot plate”, “thermal irritation of the tail tip” (tail-flick), “tail electric stimulation” and “neuropathic pain”), acute toxicity and the ability to cause gastric damage. As a result, only the plate crystal form of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide is recommended for further studies. Thus, it has been proven that the habitus of crystals is an important characteristic of the drug substance and is able to have a noticeable effect on its biological properties. Changes in habitus should be considered as a guide to the mandatory verification of at least the basic pharmacological parameters of the new form regardless of whether the molecular and crystal structure changes. View Full-Text
Keywords: crystal habitus; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide; 2,1-benzothiazine; crystal structure; analgesic activity crystal habitus; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide; 2,1-benzothiazine; crystal structure; analgesic activity
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Ukrainets, I.V.; Petrushova, L.A.; Fedosov, A.I.; Voloshchuk, N.I.; Bondarenko, P.S.; Shishkina, S.V.; Sidorenko, L.V.; Sim, G. Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide. Sci. Pharm. 2020, 88, 1.

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