Crystal structures of two furazidin polymorphs revealed by a joint effort of crystal structure prediction and NMR crystallography

Abstract

This work presents the crystal structure determination of two elusive polymorphs of furazidin, an antibacterial agent, employing a combination of crystal structure prediction (CSP) calculations and an NMR crystallography approach. Two previously uncharacterized neat crystal forms, one of which has two symmetry-independent molecules (form I), whereas the other one is a Z 0 = 1 polymorph (form II), crystallize in P2 1 /c and P1 space groups, respectively, and both are built by different conformers, displaying different intermolecular interactions. It is demonstrated that the usage of either CSP or NMR crystallography alone is insufficient to successfully elucidate the abovementioned crystal structures, especially in the case of the Z 0 = 2 polymorph. In addition, cases of serendipitous agreement in terms of 1 H or 13 C NMR data obtained for the CSP-generated crystal structures different from the ones observed in the laboratory (false-positive matches) are analyzed and described. While for the majority of analyzed crystal structures the obtained agreement with the NMR experiment is indicative of some structural features in common with the experimental structure, the mentioned serendipity observed in exceptional cases points to the necessity of caution when using an NMR crystallography approach in crystal structure determination. research papers Acta Cryst. (2020). B76, 322-335 Marta K. Dudek et al. Two furazidin polymorphs 323 research papers Acta Cryst. (2020). B76, 322-335 Marta K. Dudek et al. Two furazidin polymorphs 331 Figure 10Hydrogen-bonding pattern in the experimental crystal structure of form I (a) and in the third-lowest-energy crystal structure (b), built by the same conformers as the experimental structure; hydrogen bonds are marked with dotted green lines.

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

“…CSP is usually used when there is no structural information on the investigated molecule available. Its results direct the future experimental approach or support the previous assumptions on the existence and/or structure of the hydrate, as has happened in the case of orotic acid crystal forms [ 75 ]. Application of CSP enabled to characterize the structural disorder, and showed stacking faults as well as small variability in packing indices of the anhydrous orotic acid.…”

Solid‐State NMR‐Driven Crystal Structure Prediction of Molecular Crystals: The Case of Mebendazole

“…The first generation of crystal structures was created using the random-sampling operator, while subsequent generations were obtained applying the genetic algorithm embedded in USPEX, employing different variation operators, i. e. rot-mutation, topological random generator [71] and lattice mutation. All the structures were sampled within a set of the most common observed space groups for organic molecules (i. e. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The energy-density diagrams of all predicted structures for phases A-C are reported in the Supporting Information (Figures S11-S22).…”

“…The recent development of crystal structure prediction (CSP) methods [1,2] has led to the employment of such powerful tools in crystal engineering. In particular, CSP is used not only for the screening of the polymorph landscape, [3][4][5] but also for the crystal structure characterization of pharmaceutical compounds. [6] In spite of the fact that CCDC blind tests highlighted how challenging it is to select the correct crystal structure relying only on the computed lattice energy, the CSP approach has constantly been attracting researchers and pharmaceutical industries.…”

Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions

“…The experimental studies have been additionally supplemented with ab initio calculations giving an insight into new solvates as well as 13 C and 15 N NMR shielding constants. Noteworthy is the ability of such a multitechnique approach to describe the molecular and crystal structures, particularly in the case of problematic crystals in scXRD experiments [16,17]. The ssNMR technique provides information about the near vicinity of the studied atoms in a complementary way to the data obtained from diffraction techniques.…”