Disclosing the Rich Crystal Chemistry of Lesinurad by ab Initio Laboratory X-ray Powder Diffraction Methods

Abstract

Lesinurad, a uric acid reabsorption inhibitor that received Food and Drug Administration approval in 2015, is known to crystallize in three unsolvated crystal forms and in a few solvated phases. The structures of the former have been determined by state-of-the-art powder diffraction methods, highlighting significant conformational as well as supramolecular differences, resulting in hydrogen bonded centrosymmetric dimers (Form 1) or helical chains (Form 2). In the complex crystal packing in Form 3, additional one-dimensional (1D) ribbons held together by unexpected CO···Br interactions of the halogen-bond type are found. Thermal analyses and variable-temperature powder diffraction measurements (including high-temperature synchrotron X-ray diffraction experiments) provided evidence for the reversible formation of a new phase, Form 2hT, obtained upon heating above 100 °C powders of Form 2. Structure solution and refinement of the high-temperature phase made it possible to attribute the structural change to a 60° rotation of the cyclopropyl residue, leaving unaffected the conformation of the (longer) polar branch and the supramolecular 1D helical chain arrangement found in the RT phase.

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

“…The crystal structure indicates one equivalent of lesinurad and methanol as the solvent in the asymmetric unit. The conformation of lesinurad is similar to that of reported Form 1 (Terruzzi et al, 2018), except for the triazole ring. The dihedral angle between the planes containing the naphthalene moiety and the triazole ring is 83.9 (3) .…”

“…Lesinurad exists as three anhydrous polymorphs (Forms 1, 2 and 3) and one high-temperature form (Form 2-HT), and all these forms were structurally confirmed by the ab initio synchroton powder X-ray diffraction method (Terruzzi et al, 2018). Obtaining a single crystal of lesinurad was highly challenging irrespective of the crystallization methods because the experiments resulted in polycrystalline materials.…”

“…Computer programs and processing: DataCollector (PANalytical, 2010), CrystalClear-SM Expert 2.0 (Rigaku, 2009), CrysAlis PRO (Rigaku OD, 2015), MRIA (Zlokazov & Chernyshev, 1992), SHELXT (Sheldrick, 2015a), SHELXL2016 (Sheldrick, 2015b), SHELXL2014 (Sheldrick, 2015b), olex2.refine (Bourhis et al, 2015), Mercury (Macrae et al, 2008), OLEX2 (Dolomanov et al, 2009) and SHELXL97 (Sheldrick, 2008a); the crystal structures were solved using the simulated annealing technique (Zhukov et al, 2001). land, 2008;Ueto et al, 2012;Terruzzi et al, 2018). High-resolution PXRD data for the three compounds were collected at room temperature on a Panalytical EMPYREAN diffractometer with a linear Xcelerator detector using nonmonochromated Cu K radiation ( = 1.5418 Å ), voltage 40 kV, current 30 mA; scan range 5-80 2.…”

“…In the literature, lesinurad is reported as three anhydrous crystalline forms (Terruzzi et al, 2018) and three solvates with dichloromethane, chloroform and 2-methyltetrahydrofuran [no three-dimensional (3D) coordinates] in a patent application (Chen et al, 2015). The imbalance of one donor (OH) and three acceptors (C O and two triazole N atoms) in lesinurad renders the possibility of balancing solvate/hydrate formation in the crystalline solid form (Boothroyd et al, 2018).…”

Solvatomorphism of Moxidectin

“…In order to answer the question whether the observed solvatomorphs discussed in this work show possible additional phases or transitions, we investigated them using variable-temperature powder X-ray diffraction (VT-PXRD) analysis. This analytical tool is very useful for pharmaceutical compounds [15,16,21] or coordination polymers [22,23]. While classical thermal analyses can detect solid-state phenomena without giving detailed information about the crystallinity of the species under investigations, VT-PXRD has the power to detect all irreversible and reversible phenomena which occur at specific temperatures, giving vital information on the crystal chemistry of the investigated samples.…”