New Salt and Cocrystal of Mequitazine: Impact of Coformer Flexibility and Hydrogen Bond Donors on Polymorphism

Abstract

New multicomponent crystals of mequitazine (MQZ) with succinic acid (SUC), fumaric acid (FUM), glycolic acid (GLC), and glycolamide (GLA) were obtained after liquidassisted grinding. The hydrate/anhydrate availability in the crystals differed owing to slight differences in the coformer structure. Therefore, the causes of these differences in the crystal structure were investigated. The structures of crystals, for which single crystals were difficult to obtain, were obtained using powder diffraction crystal structure analyses. The crystal structures, including the disordered structure and the structure in which the H atom position could not be identified, were validated via dispersion-corrected density functional theory calculations using the Quantum ESPRESSO code. MQZ-SUC and MQZ-FUM formed isostructural anhydrates, but only MQZ-SUC formed a hydrate by twisting the alkyl straight chain; hence, the difference between the dihedral angles that the coformer can form led to a small change in polymorphism. MQZ-GLC hydrate and MQZ-GLA anhydrate had no isomorphic crystals, MQZ-GLC formed a hydrate, and MQZ-GLA formed an anhydrate. Differences in the number of hydrogen bond donors in the coformer led to major changes in polymorphism. The results of this study might be useful for coformer selection and controlling multicomponent crystal polymorphism.

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

“…The RMSD values of the powder crystal structures were found to be somewhat higher than those of the single-crystal structures. Similar results had been previously obtained by Okura et al 81 A slight bias of crystal structures determined from X-ray powder diffraction toward higher 4). The third N1−H1•••O4 hydrogen bond between the imidazole nitrogen and the oxygen of the tosylate ion assembled the dimeric units into a chain (C( 8)) expanded along the c axis (Figure 4).…”

“…81 Moreover, since the positions of the hydrogen atoms cannot be correctly identified on the basis of powder diffraction, the periodic DFT calculations on powder crystal structures can be used as a valuable tool for refining the hydrogen sites, 82 providing the ultimate grounds for discrimination between cocrystals and salts. 81,83 According to van de Streek and Neumann, 84 structures are considered to be correct if the root-mean-square deviation (RMSD) in nonhydrogen atoms between experimental and optimized structures is less than 0.25 Å for a single-crystal structure and 0.35 Å for a powder structure. The geometry optimization of the [FNB+TSA+H 2 O] (1:1:1), [FNB+TSA] (1:1), and [FNB+MSA] (1:1) structures with the fixed cell constants resulted in RMSD values that were below the corresponding thresholds (Table S4).…”

“…As the next step, the correctness or accuracy of the structural models obtained for the single-crystal and powder XRD methods was further validated by the DFT-D method in the Quantum ESPRESSO program. , This procedure is recognized as an essential step in structure refinement, especially for the structures solved on the basis of powder diffraction data. ,− The geometry optimization by DFT-D is expected to reconcile the bond lengths and conformation of the molecules/ions with their supramolecular surroundings, to improve the metrics of the intermolecular contacts or to resolve the disorder . Moreover, since the positions of the hydrogen atoms cannot be correctly identified on the basis of powder diffraction, the periodic DFT calculations on powder crystal structures can be used as a valuable tool for refining the hydrogen sites, providing the ultimate grounds for discrimination between cocrystals and salts. , According to van de Streek and Neumann, structures are considered to be correct if the root-mean-square deviation (RMSD) in non-hydrogen atoms between experimental and optimized structures is less than 0.25 Å for a single-crystal structure and 0.35 Å for a powder structure.…”

“…As the next step, the correctness or accuracy of the structural models obtained for the single-crystal and powder XRD methods was further validated by the DFT-D method in the Quantum ESPRESSO program. , This procedure is recognized as an essential step in structure refinement, especially for the structures solved on the basis of powder diffraction data. ,− The geometry optimization by DFT-D is expected to reconcile the bond lengths and conformation of the molecules/ions with their supramolecular surroundings, to improve the metrics of the intermolecular contacts or to resolve the disorder . Moreover, since the positions of the hydrogen atoms cannot be correctly identified on the basis of powder diffraction, the periodic DFT calculations on powder crystal structures can be used as a valuable tool for refining the hydrogen sites, providing the ultimate grounds for discrimination between cocrystals and salts. , According to van de Streek and Neumann, structures are considered to be correct if the root-mean-square deviation (RMSD) in non-hydrogen atoms between experimental and optimized structures is less than 0.25 Å for a single-crystal structure and 0.35 Å for a powder structure. The geometry optimization of the [ FNB+TSA+H 2 O ] (1:1:1), [ FNB+TSA ] (1:1), and [ FNB+MSA ] (1:1) structures with the fixed cell constants resulted in RMSD values that were below the corresponding thresholds (Table S4).…”

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study

“…15 The less reports on cocrystal polymorphism may be due to the different solubilities of two or more components in various solvents, which make them difficult to cocrystallize from the solvents and thereby increase the difficulty of obtaining cocrystal polymorphs or pseudopolymorphs with a pure crystalline phase. 16–19 Thus, it is necessary to carry out more research on cocrystal polymorphism including synthesis strategies, solid-state characterization, performance evaluation and phase transition processes, which is of great significance for better application of cocrystallization technology in the pharmaceutical field. 20–25…”