Synthesis and Characterization of Xylazine Hydrochloride Polymorphs, Hydrates, and Cocrystals: A 35Cl Solid-State NMR and DFT Study

Xylazine HCl (X) is a veterinary analgesic with many known solid forms, making it an ideal system for studying the noncovalent interactions, such as hydrogen bonding, that provide stability to polymorphs, solvates/hydrates, and cocrystal of pharmaceuticals. Herein, we report methods for the reliable preparation and interconversion of polymorphs of X (including mechanochemical pathways), the discovery of a novel polymorph, and the synthesis of three cocrystals with coformers containing amide and carboxylic acid moieties. An understanding of ball milling protocols is essential for optimizing these reactions and ensuring clean and reproducible syntheses of the products in high yields. All materials were characterized using thermal analysis, powder and single-crystal X-ray diffraction (PXRD and SCXRD), and multinuclear solid-state NMR (SSNMR) spectroscopy. 35Cl SSNMR is highlighted for its versatility for fingerprinting polymorphs, and the detection of that are not always evident from PXRD and offering an avenue for optimizing synthetic protocols) and providing molecular-level structural information. The 35Cl electric field gradient (EFG) tensor is extremely sensitive to the unique hydrogen-bonding network in each solid form of X, resulting in distinct powder patterns. Dispersion-corrected plane-wave density functional theory (DFT) structural refinements yield better models of the hydrogen-bonding environments of the chloride ions than is possible through XRD methods alone. Calculations employing the refined structures yield 35Cl EFG tensors that agree well with experiment. PXRD and 35Cl SSNMR, in tandem with reliable calculations of EFG tensors, are essential for the development of NMR crystallographic and crystal structure prediction protocols and crucial for future studies involving HCl salts and their concomitant solid forms.