Role of Anomalous Water Constraints in the Efficacy of Pharmaceuticals Probed by 1H Solid-State NMR.

Water plays a complex and central role in determining the structural and reactive properties in numerous chemical systems. In crystalline materials with structural water, the primary focus is often to relate hydrogen bonding motifs to functional properties such as solubility, which is highly relevant in pharmaceutical applications. Nevertheless, understanding the full electrostatic landscape is necessary for a complete structure-function picture. Herein, a combination of tools including 1H magic angle spinning NMR and X-ray crystallography are employed to evaluate the local landscape of water in crystalline hydrates. Two hydrates of an anti-leukemia drug mercaptopurine, which exhibit dramatically different dehydration temperatures (by 90°C) and a three-fold difference in the in vivo bioavailability, are compared. The results identify an electrosteric caging mechanism for a kinetically trapped water in the hemihydrate form, which is responsible for the dramatic differences in properties.