2016/02/29 by Daniel O’ Nolan, Miranda L. Perry, Michael J. Zaworotko · 1 citation
Chemistry · Materials Science · Medicine · #Crystallography and molecular interactions #Crystallization and Solubility Studies #Crystal structures of chemical compounds #Cocrystal #Chloral hydrate #Hydrate #Chemistry #Materials science #Organic chemistry #Anesthesia #Medicine #Molecule #Hydrogen bond
paper · doi:10.1021/acs.cgd.6b00032
openalex publication_date 2016/02/29 · openalex created_date 2025/10/10 · openalex updated_date 2026/06/22
Chloral hydrate has the distinction of perhaps being the first reported example of a pharmaceutical compound to exhibit polymorphism (1877) and the first use of a pharmaceutical cocrystal in a drug product (Beta-Chlor, 1960s). Nevertheless, chloral hydrate represents a microcosm of contemporary issues in solid-state chemistry and its importance to pharmaceutical science. Ironically, the single crystal structures of the β-form of chloral hydrate and its pharmaceutical cocrystal with betaine have not yet been reported. In this contribution, the single crystal structures and physical properties of these crystal forms are reported for the first time. The previously termed “high temperature” β-form of chloral hydrate was obtained by melting the α-form of chloral hydrate and crystallizing from the melt. The α-form of chloral hydrate is comprised of diol–diol homodimers that further assemble into a sheet of six-membered rings. The β-form is sustained by head-to-tail OH···O hydrogen bonds that form a sheet built from two types of three- and five-membered rings. The diol–diol interactions that sustain these polymorphs are placed in context through a Cambridge Structural Database analysis. The chloral hydrate–betaine cocrystal (CHOBTN) was obtained by slow cooling from water, exhibits higher thermal stability than the chloral hydrate polymorphs, and is sustained by a previously known 2-point diol-carboxylate supramolecular heterosynthon that could be of general utility.