Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Lesinurad (systematic name: 2‐{[5‐bromo‐4‐(4‐cyclopropylnaphthalen‐1‐yl)‐4H‐1,2,4‐triazol‐3‐yl]sulfanyl}acetic acid, C₁₇H₁₄BrN₃O₂S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High‐throughput solid‐form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH₃OH) and ethanol (C₂H₅OH). Binary systems with caffeine (systematic name: 3,7‐dihydro‐1,3,7‐trimethyl‐1H‐purine‐2,6‐dione, C₈H₁₀N₄O₂) and nicotinamide (C₆H₆N₂O), polymorphs with urea (CH₄N₂O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT–IR. The crystal structures were solved by single‐crystal and powder X‐ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid–triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid–triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid–triazole heterosynthon is replaced by an acid–amide synthon. Among the urea cocrystal polymorphs, Form I (P, 1:1) consists of an acid–amide (urea) heterodimer, whereas in Form II (P2₁/c, 2:2), both acid–amide heterosynthons and urea–urea dimers co‐exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad–urea Form I (43‐fold) > lesinurad–caffeine (20‐fold) > lesinurad–allopurinol (12‐fold) ? lesinurad–nicotinamide (11‐fold) > lesinurad, and this order is correlated with the crystal structures.     

含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂的合成及其构效关系

分别以1-溴萘和酮或1-萘甲醛及有机金属试剂为原料,经12步反应合成了8个含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂(1h~1o),其结构经¹H NMR, ¹³C NMR和MS（ESI）表征。体外活性测试结果显示：对URAT1的抑制活性最强的是1k,是阳性对照药lesinurad的133倍［IC₅₀=0.054 μmol·L^-1(1k), 7.18 μmol·L^-1(lesinurad)］。