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.1H chemical shift tensors are valuable in the structural and dynamical studies of a variety of materials, and are directly measurable with fast MAS spinning experiments. The use of these novel techniques to reveal the structural differences water can adopt in pharmaceutical hydrates is demonstrated.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138433/1/slct201701547_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138433/2/slct201701547-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138433/3/slct201701547.pd

Pharmaceutical solvate formation for the incorporation of the antimicrobial agent hydrogen peroxide

Antimicrobial functionality is introduced into a pharmaceutical formulation of miconazole while improving solubility. The work leverages hydrate formation propensity in order to produce hydrogen peroxide solvates. The ubiquity of hydrate formation suggests that hydrogen peroxide can be broadly deployed in pharmaceuticals, rendering a liquid excipient suitable for solid pharmaceutical formulations

Electrostatic Constraints Assessed by ¹H MAS NMR Illuminate Differences in Crystalline Polymorphs

Atomically resolved crystal structures not only suffer from the inherent uncertainty in accurately locating H atoms but also are incapable of fully revealing the underlying forces enabling the formation of final structures. Therefore, the development and application of novel techniques to illuminate intermolecular forces in crystalline solids are highly relevant to understand the role of hydrogen atoms in structure adoption. Novel developments in ¹H NMR MAS methodology can now achieve robust measurements of ¹H chemical shift anisotropy (CSA) tensors which are highly sensitive to electrostatics. Herein, we use ¹H CSA tensors, measured by MAS experiments and characterized using DFT calculations, to reveal the structure-driving factors between the two polymorphic forms of acetaminophen (aka Tylenol or paracetamol) including differences in hydrogen bonding and the role of aromatic interactions. We demonstrate how the ¹H CSAs can provide additional insights into the static picture provided by diffraction to elucidate rigid molecules