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Crystals 2017, 7(12), 365;

Structural Characterization of Febuxostat/l-Pyroglutamic Acid Cocrystal Using Solid-State 13C-NMR and Investigational Study of Its Water Solubility

College of Pharmacy, CHA University, Sungnam 13844, Korea
R&D Center, J2H biotech, Ansan 15426, Korea
College of Pharmacy, Kyungpook National University, Daegu 41566, Korea
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Srinivasulu Aitipamula and Reginald Tan
Received: 31 October 2017 / Revised: 4 December 2017 / Accepted: 5 December 2017 / Published: 8 December 2017
(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)
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Febuxostat (FB) is a poorly water-soluble drug that belongs to BCS class II. The drug is employed for the treatment of inflammatory disease arthritis urica (gout), and the free base, FB form-A, is most preferred for drug formulation. In order to achieve a goal of improving the water solubility of FB form-A, this study was carried out using the cocrystallization technique called the liquid-assisted grinding method to produce FB cocrystals. Here, five amino acids containing amine (NH), oxygen (O), and hydroxyl (OH) functional groups, and possessing difference of pKa less than 3 with FB, were selected as coformers. Then, solvents including methanol, ethanol, isopropyl alcohol, n-hexane, dichloromethane, and acetone were used for the cocrystal screening. As a result, a cocrystal was obtained when acetone and l-pyroglutamic acid (PG) of 0.5 eq. were employed as solvent and coformer, respectively. The ratio of 2:1, which is the ratio of FB to PG within FB-PG cocrystal, was predicted by means of solid-state CP/MAS 13C-NMR, solution-state NMR (1H, 13C, and 2D) and FT-IR. Moreover, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA) were used to investigate the characteristics of FB-PG cocrystal. In addition, comparative solubility tests between FB-PG cocrystal and FB form-A were conducted in deionized water and under simulated gastrointestinal pH (1.2, 4, and 6.8) conditions. The result revealed that FB-PG cocrystal has a solubility of four-fold higher than FB form-A in deionized water and two-fold and five-fold greater than FB form-A at simulated gastrointestinal pH 1.2 and pH 4, respectively. Besides, solubilities of FB-PG cocrystal and FB form-A at pH 6.8 were similar to the results measured in deionized water. Therefore, it is postulated that FB-PG cocrystal has a potential overcoming the limitations related to the low aqueous solubility of FB form-A. Accordingly, FB-PG cocrystal is suggested as an alternative active pharmaceutical ingredient of the currently used FB form-A. View Full-Text
Keywords: Febuxostat; cocrystal; solid-state NMR; solubility; active pharmaceutical ingredient Febuxostat; cocrystal; solid-state NMR; solubility; active pharmaceutical ingredient

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An, J.-H.; Lim, C.; Ryu, H.C.; Kim, J.S.; Kim, H.M.; Kiyonga, A.N.; Park, M.; Suh, Y.-G.; Park, G.H.; Jung, K. Structural Characterization of Febuxostat/l-Pyroglutamic Acid Cocrystal Using Solid-State 13C-NMR and Investigational Study of Its Water Solubility. Crystals 2017, 7, 365.

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