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

Abstract

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.

Revealing Intermolecular Hydrogen Bonding Structure and Dynamics in a Deep Eutectic Pharmaceutical by Magic-Angle Spinning NMR Spectroscopy

“…The presence of water in API-DESs or -ILs can be expected to influence the properties. Similarly, the presence of water in crystalline hydrates is known to dramatically alter the physicochemical properties of pharmaceuticals compared to their anhydrous forms. , The environment of water molecules and the role of hydrogen bonding in solid pharmaceutical hydrates has been characterized by fast (>60 kHz) 1 H MAS solid-state NMR. , The environment of water in API-ILs or -DESs, such as Lid·Ibu, could be characterized by further MAS NMR studies.…”

“…33,34 The environment of water molecules and the role of hydrogen bonding in solid pharmaceutical hydrates has been characterized by fast (>60 kHz) 1 H MAS solid-state NMR. 35,36 The environment of water in API-ILs or -DESs, such as Lid• Ibu, could be characterized by further MAS NMR studies.…”

Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)

“…Solid-state NMR spectroscopy is very sensitive to local molecular disorder (including dynamic disorder) and structural defects. Thus, it is no surprise that this method is frequently used in different branches of science, in particular in the pharmaceutical sciences, to study structural features and to verify the quality and/or homogeneity of the studied material. − …”

Exploring Accuracy Limits of Predictions of the 1H NMR Chemical Shielding Anisotropy in the Solid State

“…mid-2017 period were summarized in Reference [4]. Later, the ultrafast MAS experiments on pharmaceutically active hydrates [5] and small peptides [6] also led to the 1 H CSA values. It should be noted that above-mentioned SC measurements directly characterize the full 1 H-NMR chemical shielding tensor, σ⃡, in terms of its three eigenvalues, σ11, σ22, σ33 (σ11≤ σ22≤σ33false), and the eigenvectors, trueξ1→, trueξ2→, trueξ3→, associated with them (the eigenvectors are then used to describe an orientation of σ⃡ in the reference frame of an investigated crystal).…”