了解非布司他共晶的形成和性质中结构、微环境 pH 值和形态的作用。
Role of Structure, Microenvironmental pH, and Speciation To Understand the Formation and Properties of Febuxostat Eutectics.
机构信息
Division of Pharmaceutical Sciences Arnold and Marie Schwartz College of Pharmacy and Health Sciences , Long Island University , 75 Dekalb Avenue , HS Building 612, Brooklyn , New York 11201 , United States.
Department of Pharmaceutics , National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67 , S.A.S. Nagar , Punjab 160062 , India.
出版信息
Mol Pharm. 2019 Nov 4;16(11):4610-4620. doi: 10.1021/acs.molpharmaceut.9b00716. Epub 2019 Oct 11.
Cocrystallization studies were undertaken to improve the solubility of a highly water-insoluble drug, febuxostat (FXT), used in the treatment of gout and hyperuricemia. A liquid-assisted grinding (LAG) method was successfully employed, starting with the screening of various coformers for obtaining cocrystals. However, in this process, three eutectic systems with coformers (probenecid, adipic acid, and α-ketoglutaric acid) were formed. Affinities of the different functional groups to form a hydrogen bond and Δp differences, leading to the eutectic formation, were discussed. The eutectic systems thus formed were further characterized and analyzed using a differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD). Binary thermal phase diagrams were plotted using different ratios of the systems to confirm the formation of eutectics, and pH-dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all three eutectic systems. The solubility of FXT reduced from 46.53 μg/mL (pH 5.63) to 46.03 μg/mL, 28.53 μg/mL, and 18.88 μg/mL; 770.58 μg/mL (pH 8.21) to 307.574 μg/mL, 116.63 μg/mL, 113.40 μg/mL; and from 13165.97 μg/mL (pH 10.13) to 1409.737 μg/mL, 854.51 μg/mL, and 1218.99 μg/mL for FXT-probenecid, FXT-adipic acid, and FXT-α-ketoglutaric acid eutectic systems, respectively. Furthermore, the microenvironmental pH studies were carried out to understand the effect of the microenvironment on the solubility of these eutectic systems. The contribution to solubility from lattice and nonlattice forces considering the microenvironment was also discussed.
为提高用于治疗痛风和高尿酸血症的高度水不溶性药物非布司他（FXT）的溶解度，进行了共结晶研究。成功采用了液辅助研磨（LAG）方法，从筛选获得共晶的各种共晶形成剂开始。然而，在这个过程中，与共晶形成剂（丙磺舒、己二酸和α-酮戊二酸）形成了三个共晶体系。讨论了不同官能团形成氢键的亲和力和导致共晶形成的Δp 差异。使用差示扫描量热法（DSC）和粉末 X 射线衍射（PXRD）对形成的共晶体系进行了进一步的特征和分析。使用不同比例的体系绘制二元热相图以确认共晶的形成，并进行 pH 依赖性溶解度研究，与所有三个共晶体系相比，药物的溶解度均显著降低。FXT 的溶解度从 46.53μg/mL（pH 5.63）降低到 46.03μg/mL、28.53μg/mL 和 18.88μg/mL；从 770.58μg/mL（pH 8.21）降低到 307.574μg/mL、116.63μg/mL 和 113.40μg/mL；从 13165.97μg/mL（pH 10.13）降低到 1409.737μg/mL、854.51μg/mL 和 1218.99μg/mL，对于 FXT-丙磺舒、FXT-己二酸和 FXT-α-酮戊二酸共晶体系分别为 307.574μg/mL、116.63μg/mL 和 113.40μg/mL；从 13165.97μg/mL（pH 10.13）降低到 1409.737μg/mL、854.51μg/mL 和 1218.99μg/mL，对于 FXT-丙磺舒、FXT-己二酸和 FXT-α-酮戊二酸共晶体系分别为 854.51μg/mL、113.40μg/mL 和 1218.99μg/mL。此外，还进行了微环境 pH 研究，以了解微环境对这些共晶体系溶解度的影响。还讨论了考虑微环境时晶格和非晶格力对溶解度的贡献。
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