SCXRD, CSP-NMRX and microED in the quest for three elusive polymorphs of meloxicam.

Abstract

Crystal structure determination is a crucial aspect of almost every branch of the chemical sciences, bringing us closer to understanding crystallization, polymorphism, phase transitions, and the relationship between a structure and its physicochemical and functional properties. Unfortunately, many molecules notoriously crystallize as microcrystalline powders, providing a significant challenge in establishing their structures. In this work, we describe the crystal structure determination of three elusive polymorphs of the anti-inflammatory drug meloxicam (MLX) using three approaches, of which only one was successful for each crystal phase. Single-crystal X-ray diffraction allowed us to solve the structure of MLX-III, MLX-II was solved by a combination of NMR crystallography and crystal structure prediction (CSP) calculations, and MLX-V (Z' = 4 polymorph) was only solvable using electron diffraction. By considering the factors influencing the choice of crystal structure determination method, we showcase their strengths and weaknesses as an indication of their applicability. Additionally, we discuss the issues encountered in the CSP search for MLX-II and MLX-III (both Z' = 2 polymorphs) which turned out to be computationally elusive, in addition to being so in crystallization experiments. This indicates a complex crystal energy landscape for MLX and hints at more general challenges in CSP.