Exploring the salt-cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering.

Lalit Rajput,Manas Banik,Manoj Kumar Pandey,Sumy Joseph,Jayasubba Reddy Yarava,Yusuke Nishiyama,Gautam R Desiraju

doi:10.1107/s205225251700687x

Lalit Rajput, Manas Banik + Show 5 more

Open Access

https://doi.org/10.1107/s205225251700687x

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Abstract

There has been significant recent interest in differentiating multicomponent solid forms, such as salts and cocrystals, and, where appropriate, in determining the position of the proton in the X-H⋯A-YX-⋯H-A+-Y continuum in these systems, owing to the direct relationship of this property to the clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In the present study, solid forms of simple cocrystals/salts were investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples with naturally abundant 15N nuclei. Four model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting {PyN⋯H-O-}/{PyN+-H⋯O-} hydrogen bonds (Py is pyridine) were selected and prepared. The crystal structures were determined at both low and room temperature using X-ray diffraction. The H-atom positions were determined by measuring the 15N-1H distances through 15N-1H dipolar interactions using two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) 1H→15N→1H experiments at ultrafast (νR ≥ 60-70 kHz) magic angle spinning (MAS) frequency. It is observed that this method is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises. This work, while carried out on simple systems, has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of APIs is considered seriously.

Highlights

Detection of the H-atom position in an X—HÁ Á ÁA—Y hydrogen bond is a matter of fundamental and practical importance (Jeffrey, 1997; Desiraju & Steiner, 1999)
In order to confirm the solid form, i.e. the salt/ cocrystal/continuum, singlecrystal X-ray diffraction (SCXRD) data were collected at room temperature and at 110 K
The signal overlaps can be avoided in salt/cocrystal/continuum systems which typically include only one N—H hydrogen-bonding pair

Summary

Introduction

Detection of the H-atom position in an X—HÁ Á ÁA—Y hydrogen bond is a matter of fundamental and practical importance (Jeffrey, 1997; Desiraju & Steiner, 1999). Besides the chemical shift tensor, ssNMR is able to measure internuclear N—H distances through 15N-1H dipolar interactions, as the magnitude of the dipolar interaction is inversely proportional to the cube of the internuclear distance This potentially gives a straightforward solution to the ‘salt/ cocrystal/continuum’ problem, while diffraction-based methods provide internuclear distances from the atomic positions themselves. The use of high-field magnets, which are commonly available to researchers, improves the sensitivity further These combinations allow the observation of 1H-X dipolar interactions in natural-abundance samples with a limited sample volume. This article describes a method where high-field ssNMR is used to determine accurate 15N—1H distances in a series of prototypical salt/cocrystal/continuum systems of the type {PyNÁ Á ÁH—O—}/{PyN+—HÁ Á ÁOÀ} at natural abundance without any isotopic dilution/enrichment. The distances obtained from ssNMR data were compared with the distances obtained from singlecrystal X-ray diffraction (SCXRD) data

General procedures

Crystallization method

Single-crystal X-ray diffraction

Results and discussion

Conclusions