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

Abstract

Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C 17 H 14 BrN 3 O 2 S) 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 (CH 3 OH) and ethanol (C 2 H 5 OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7trimethyl-1H-purine-2,6-dione, C 8 H 10 N 4 O 2 ) and nicotinamide (C 6 H 6 N 2 O), polymorphs with urea (CH 4 N 2 O) 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 acidamide synthon. Among the urea cocrystal polymorphs, Form I (P1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P2 1 /c, 2:2), both acidamide 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.

Spectroscopic Methodology and Molecular Docking Studies on Changes in Binding Interaction of Felodipine with Bovine Serum Albumin Induced by Cocrystallization with β-Resorcylic Acid

“…The crystal structure of FEL-βRA cocrystal was simulated obtained using density functional theory (DFT) method, which is widely used to construct and optimize the geometries of cocrystals. 33,34) The simulation results showed that the hydrogen bonds presented between FEL and βRA in the optimized configuration, which is consistent with the results derived from the IR spectrum.…”

Isostructural cocrystals of metaxalone with improved dissolution characteristics

“…The crystal structure was solved in the space group P 1̄ with the use of simulated annealing technique and refined (Rietveld refinement) with the program MRIA following the known procedure described by us earlier. 13 All non-H atoms were isotropically refined. H atoms were placed in calculated positions and refined accordingly.…”

Preparation and Characterization of Novel Anti-cancer drug (s) loaded Co-crystals

“…For recording the diffraction, the powder was put in a thin glass capillary and the sample was exposed to the X-rays. The diffraction patterns of the X-rays from the powder were recorded at 1.54 A 0 (Cu Kα 1 anode current 30 mA, accelerating voltage 40 kV) [20].…”