Importance of Nuclear Quantum Effects for Molecular Cocrystals with Short Hydrogen Bonds

Abstract

Many efforts have been recently devoted to the design and investigation of multicomponent pharmaceutical solids, such as salts and cocrystals. The experimental distinction between these solid forms is often challenging. Here, we show that the transformation of a salt into a cocrystal with a short hydrogen bond does not occur as a sharp phase transition but rather a smooth shift of the positional probability of the hydrogen atoms. A combination of solid-state NMR spectroscopy, X-ray diffraction, and diffuse reflectance measurements with density functional theory calculations that include nuclear quantum effects (NQEs) provides evidence of temperature-induced hydrogen atom shift in cocrystals with short hydrogen bonds. We demonstrate that for the predictions of the salt/cocrystal solid forms with short H-bonds, the computations have to include NQEs (particularly hydrogen nuclei delocalization) and temperature effects.

Highly Luminescent and Semiconducting Supramolecular Organic Charge Transfer Complex Generated via H‐Bonding Interaction Pathway

“…The amine protons get deshielded by 0.145 ppm whereas the aromatic protons get deshielded by 0.0949 and 0.1238 ppm respectively which is expected due to the generation of charge separated state from the cocrystal state. [ 32 ] The Raman spectra of the cocrystal 1’ shows clearly distinguishable peaks whereas the Raman spectra for the charge separated state 1 shows a broad band due to the delocalization of charge and generation of band structure in CT complex (Figures S10 and S11, Supporting Information). The solid‐state UV–vis spectra in the supporting information (Figure S12, Supporting Information) also shows the generation of a band structure in charge separated state 1 with the appearance of a broadband from 350 to 650 nm as compared to the cocrystal state 1’ .…”

“…Salt to cocrystal transition for a particular multicomponent system is rare and has been recently observed through different techniques. [32][33][34][35][36][37][38][39][40] Herein we report an orthophenylene diamine (D) and pyromellitic acid (A) based novel CT complex 1 where the conduction path is established solely via H-bonding interaction. Formation of the CT complex 1 is achieved in two steps.…”

New Insights into the Solubilization of Multicomponent Crystals: A Case Study of Pipemidic Acid

“…The hot stage microscope images (Figure S20c) and cyclic DSC curve (Figure S20d) demonstrates that there is an endothermic peak at 101.65 °C during the heating process and an exothermic peak at 98.63 °C during the cooling back to room temperature, which further demonstrates that there is a polymorph transformation during the heating and cooling processes. The temperature-variable single crystal structure analysis revealed that the PPA-GA cocrystal is the most stable form at high temperature, whereas the salt form is the most stable form at low temperature …”

“…The temperature-variable single crystal structure analysis revealed that the PPA-GA cocrystal is the most stable form at high temperature, whereas the salt form is the most stable form at low temperature. 50 3.7. Solubility Studies.…”

Discovering the Solid-State Secrets of Lorlatinib by NMR Crystallography: To Hydrogen Bond or not to Hydrogen Bond

“…It is evident from Figure 7 that the GIPAW calculated 1 H chemical shifts for the high-ppm NH2 resonances, namely 30a I , 30b I , and 30a II at 8.8, 9.5 and 10.3 ppm are significantly higher than the experimental value of 7.0 ppm. Such a discrepancy is well established for hydrogen-bonded 1 H resonances and can be explained by the known experimental temperature-dependence of such hydrogen-bonded 1 H chemical shifts [99][100][101][102][103][104][105][106][107] , whereas GIPAW calculation is effectively performed at 0 K. 108 In other words, if variable-temperature 1 H MAS NMR spectra were recorded, these 1 H resonances would move to higher ppm as the temperature is lowered.…”