Date of Award


Publication Type


Degree Name



Chemistry and Biochemistry


Crystalline solids, Amorphous solids, Drug, Dosage forms


R. Schurko


S. Loeb




Xylazine HCl (X), a common veterinary analgesic, has four reported polymorphs that are stable under ambient conditions, Form A (Xa), Form X (Xx), Form Z (Xz), and Form M (Xm), and one monohydrate (Xh). A commercial sample of X was found to contain mixtures of polymorphs and previous synthetic approaches proved unreliable and/or unsuccessful for the production of pure phases in high yields. Herein, we report methods for the reliable preparation and interconversion of polymorphs of X (including mechanochemical synthetic pathways), the discovery of a novel polymorph (Xy), and synthesis of three novel cocrystals with coformers containing amide and carboxylic acid functional groups. An understanding of ball milling protocols is essential so that these reactions can be optimized to ensure reproducible synthesis of the products in high yields.

All materials in the current work were characterized using a combination of thermal analysis (TGA and DSC), powder and single-crystal X-ray diffraction (pXRD and scXRD), and multinuclear solid-state NMR (SSNMR) spectroscopy. 35Cl SSNMR is highlighted in this study for its versatility as a method for fingerprinting of polymorphs, hydrates, and cocrystals, and providing molecular-level structural information. Dispersion corrected plane-wave density functional theory (DFT-D2*) calculations are used to accurately position hydrogen atoms in the crystal structures obtained by pXRD or scXRD, yielding better ground-truth models of the hydrogen bonding environments of the chloride ions. Calculations on the refined structures yielded 35Cl EFG and magnetic shielding tensors that agree well with experimental values. PXRD and 35Cl SSNMR, in tandem with reliable calculations of EFG tensors, are essential for the development of crystal structure prediction protocols, and crucial for future studies involving HCl salts and their concomitant solid forms.