Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2

Abstract

The propensity of molecular organic compounds to form stoichiometric or nonstoichiometric crystalline hydrates remains a challenging aspect of crystal engineering and is of practical relevance to fields such as pharmaceutical science. In this work, we address the propensity for hydrate formation of a library of eight compounds comprised of 5-and 6-membered Nheterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted Schiff bases, and tripodal molecules. Each molecular compound studied possesses strong hydrogen bond acceptors and is devoid of strong hydrogen bond donors. Four methods were used to screen for hydrate propensity using the anhydrate forms of the molecular compounds in our library: water slurry under ambient conditions, exposure to humidity, aqueous solvent drop grinding (SDG), and dynamic water vapor sorption (DVS). In addition, crystallization from mixed solvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate screening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps, full interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a compound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds (herein numbered 4−11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one anhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P2 1 /a, while 7 and 10 crystallized in the monoclinic space group P2 1 /c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not find any direct correlation between the number of H−bond acceptors and either hydrate propensity or the stoichiometry of the resulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not facilitate intermolecular interactions.

Structural and Energetic Aspects of Entacapone-Theophylline-Water Cocrystal

“…However, cocrystal screening for a case as the ENT-THP-water cocrystal meets the limitations of these methods for hydrates. Moreover, computational cocrystal knowledge-based screening tools can lead to inconclusive results because of the strong homodimeric hydrogen bond motifs appearing in hydrate components [69,105]. Further investigation is needed for more accurate prediction tools of cocrystals cases where only hydrate cocrystal components could meet screening criteria when lattice water actively participates.…”

Dehydration of a crystal hydrate at subglacial temperatures

“…Above T on , the rate of dehydration is influenced by environmental factors, sample conditioning and further intensive parameters such as activation energy E a , the frequency factor and reaction order 12 . T on is typically determined by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC) in an atmosphere consisting of nitrogen purge gas at 0% RH and a pressure of 1 atm 5 . Values of T on for the dehydration of channel hydrates have been reported over the wide temperature range of 20–200 °C (Supplementary Table 1 ), with T on greater than 60 °C in most cases.…”

Study on Hydration and Dehydration of Ezetimibe by Terahertz Spectroscopy with Humidity-Controlled Measurements and Theoretical Analysis

“…Approximately one-third of pharmaceutical molecules are thought to be capable of forming crystalline hydrates . Hydrates usually have lower dissolution rates than anhydrates, and pharmaceutical excipients affect hydration and dehydration reactions in formulations that contains API and some excipients .…”

“…3 Approximately one-third of pharmaceutical molecules are thought to be capable of forming crystalline hydrates. 4 Hydrates usually have lower dissolution rates than anhydrates, 5 and pharmaceutical excipients affect hydration and dehydration reactions in formulations that contains API and some excipients. 6 However, very few spectroscopic studies on the crystalline form in pharmaceutical formulations have been reported because of the difficulties of understanding the complex spectra resulting from multiple compounds.…”