Solid-State Forms of β-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be?

Abstract

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found.

Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate

“…The distinct steps and hysteresis between the sorption and desorption isotherms are characteristic of a stoichiometric hydrate. 14,77,78 …”

Synthon preference in a hydrated β-resorcylic acid structure and its cocrystal with thymine

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The chemistry of resorcinol carboxylation and its possible application to the CO2 removal from exhaust gases

“…2. For a detailed assignment of the peaks, dedicated paper are available [10,11]. Presumably, the short time of reaction and the low temperatures, hindered the formation of the g-isomer, and the IR spectra show only the b-resorcylic acid signals.…”