Structural characterization of febuxostat/L-pyroglutamic acid cocrystal using solid-state 13C-NMR and investigational study of its water solubility

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Abstract

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 ScanningCalorimetry (DSC), and ThermogravimetricAnalysis (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-Ain deionizedwater and two-fold and five-fold greater than FB form-Aat 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.

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An, J. H., Lim, C., Ryu, H. C., Kim, J. S., Kim, H. M., Kiyonga, A. N., … Jung, K. (2017). Structural characterization of febuxostat/L-pyroglutamic acid cocrystal using solid-state 13C-NMR and investigational study of its water solubility. Crystals, 7(12). https://doi.org/10.3390/cryst7120365

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