Polymorphism in Xaliproden (SR57746A): An X-ray Diffraction, Calorimetric, and Solid-State NMR Investigation

Abstract

Three polymorphic phases of Xaliproden are evidenced through thermal analysis: Form II has an orthorhombic symmetry while Forms I and III have monoclinic unit cells. Structural characterizations of Xaliproden are carried out by means of single-crystal and synchrotron powder X-ray diffraction (XRD), as well as high-resolution solid-state 13 C cross-polarization at magic angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy. Diffraction crystallography indicates that the structures of two of the polymorphs are highly similar despite different thermal events observed by thermal analysis. Further X-13 C (X = 1 H or 19 F) CPMAS NMR spectra, recorded under either 1 H or double-resonance 1 H/ 19 F decoupling, provide evidence for the occurrence of 19 F self-decoupling in Form III, indicating that the structural disorder observed in the X-ray diagram is dynamic, with rotation of the CF 3 group around the C-C single bond. The results show that polymorphism between Xaliproden Forms I and III mostly deals with the degree of freedom of the CF 3 group, higher in Forms III than in Form I and clarifies the status of Form III that can therefore be assigned to a well-defined polymorph of Xaliproden.

A theoretical and experimental study of the NMR spectra of 4,5,6,7-tetrafluorobenzazoles with special stress on PCM calculations of chemical shifts

“…Similar, but less clear examples, of a CF 3 group that appears static in crystallography and dynamic in solid-state NMR have been reported. [50][51][52] Conclusion -The present work confirms that DFT/GIAO/6-311++G(d,p) calculations afford reliable chemical shifts when combined with robust regression equations relating σ and δ values. Other authors have compared different basis sets agreeing that the 6-311++G(d, p) is a convenient one for 19 F NMR chemical shifts.…”

“…For the isolated molecule, we calculated a barrier of 1.6 kJ mol −1 that reduces to 1.1 kJ mol −1 value when zero‐point energy is included. Similar, but less clear examples, of a CF 3 group that appears static in crystallography and dynamic in solid‐state NMR have been reported …”

Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction

“…A study conducted by Actins et al [ 7 ] investigated the crystal structures of the pseudo-polymorphs of the hemihydrate and anhydrate of Droperidol using SXD analysis. In their study, Chandrappa et al [ 8 ], by means of SXD analysis, determined the conformation and intermolecular interaction of the form-I and form-II polymorph structures of a clinical candidate compound, namely Xaliproden (SR57746A). Moreover, being unable to obtain single crystals of form-III, researchers have endeavored to establish the crystal structure using solid-state C-NMR analysis.…”

Combining Nuclear Magnetic Resonance Spectroscopy and Density Functional Theory Calculations to Characterize Carvedilol Polymorphs

“…13 The identification and structural characterization of polymorphs can be performed using a combination of infrared/ Raman spectroscopy, thermal methods, and X-ray diffraction techniques. 14 SSNMR, in particular cross-polarization (CP), at magic angle spinning (CP MAS) is also a powerful technique to study and characterize amorphous and crystalline pharmaceutical solids. [15][16][17] It is a valuable source of structural information, mainly because of the sensitivity chemical shifts to the structure of molecular crystals.…”

“…[15][16][17] It is a valuable source of structural information, mainly because of the sensitivity chemical shifts to the structure of molecular crystals. 14,18 This is especially important for solid-state forms that can not be crystallized and studied by single-crystal X-ray techniques. In the case of organic molecules that present nitrogen in its structure, CP MAS uses the magnetization of a highly sensitive nucleus that is transferred by CP to the 13 C/ 15 N nuclei, allowing acquisition of 13 C/ 15 N NMR spectra usually in a couple of hours.…”