Matching ROY crystal structures to high-throughput PXRD

Abstract

The ability of a compound to form different crystalline structures, possessing distinct chemical and physical properties, is known as polymorphism. To identify the isolable polymorphs of a compound, extensive screening of experimental crystallization conditions is often carried out in a high-throughput fashion, where only powder X-ray diffraction (PXRD) patterns are obtainable. The room-temperature diffractograms must then be compared to low-temperature, single-crystal X-ray structures, such as from the Cambridge structural database (CSD), to identify if a particular solid form is a new or pre-existing polymorph. This comparison is problematic because the PXRD peak positions shift substantially with temperature. The variable-cell experimental powder difference (VC-xPWDF) method was recently developed to allow reliable comparison of experimental PXRD patterns to simulated diffractograms of known crystal structures. This work demonstrates the utility of VC-xPWDF to solve crystal structures from PXRD data generated during high-throughput polymorph screening for the test case of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, also known as ROY, which is a prolific polymorph former. The method is shown to be successful for the comparison of PXRD patterns to both experimental crystal structures from the CSD and computationally generated structures obtained from a previous crystal structure prediction study. The experimental diffractogram quality was shown not to affect the results in most cases, although some errors do occur due to preferential orientation and low intensity/high baseline noise, which could potentially be reduced by additional grinding of the samples prior to making the PXRD measurements or slightly longer X-ray exposure during data collection.