Crystal Engineering of Ionic Cocrystals Sustained by the Phenol–Phenolate Supramolecular Heterosynthon

Abstract

Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol–phenolate supramolecular heterosynthon (PhOH···PhO – ). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO – supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO – interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO – interaction to be around 3 times stronger than the phenol–phenol hydrogen bond. The PhOH···PhO – supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.

Conformational Trimorphism in an Ionic Cocrystal of Hesperetin

“…The symmetric or close-to-symmetric nature of the [PhO···H···PhO – ] anions is supported by the short O6···O6′ distance of 2.4256(19) Å and location of the proton from difference Fourier map inspection. In our recent work, a CSD survey revealed that the average O···O – distance for PhOH···PhO – H-bonds is 2.528 ± 0.08 Å; the PhOH···PhO – H-bond in HESTEA -γ is shorter than the vast majority of previously reported structures. The classification of this PhOH···PhO – H-bond as symmetric or close-to-symmetric cannot be asserted using SCXRD, and further studies will be required in this context.…”

“…supramolecular heterosynthon is robust and can be relied upon to form cocrystals. 37 We report herein on the synthesis and characterization of three polymorphs (α, β, γ) of the A + B − B type ICC formed between HES and its tetraethylammonium (TEA + ) salt, HESTEA.…”

“…Whereas cocrystals have long been known, their amenability to design through crystal engineering approaches was not well recognized until the early 2000s when four papers detailed the design of pharmaceutical cocrystals. − Successful crystal engineering approaches to cocrystal design are generally based on a knowledge of possible H-bonded supramolecular synthons . In this context, H-bonded supramolecular heterosynthons between coformers are key to understanding and designing cocrystals since their hierarchies − can be used to project whether a cocrystal is amenable to being readily isolated . Pharmaceutical cocrystals can significantly diversify the number of crystal forms available for a given API, thereby improving the likelihood that a crystalline form suitable for use in a drug product will be identified.…”

“…Phenols are classified as medium strength H-bond donors and have been established as being able to form supramolecular heterosynthons with H-bond acceptors such as chloride anions, carboxylate moieties, and aromatic nitrogen bases . Recently, we reported a crystal engineering study on ICCs of phenol and substituted phenol derivatives with their conjugate bases, which indicated that the phenol···phenolate (PhOH···PhO – ) supramolecular heterosynthon is robust and can be relied upon to form cocrystals . We report herein on the synthesis and characterization of three polymorphs (α, β, γ) of the A + B – B type ICC formed between HES and its tetraethylammonium (TEA + ) salt, HESTEA.…”

Technical and Formulation Aspects of Pharmaceutical Co‐Crystallization: A Systematic Review

“…Crystal engineering must have developed to the point by the discovery of the first urea-sodium chloride cocrystals in 1783. [13] Cocrystals are a subclass of multicomponent molecular crystals that have been demonstrated to enhance or alter the physicochemical characteristics of active pharmacological molecules including their solubility, bioavailability, and stability. [14] According to the latest United Food and Drug Administration (USFDA) guidelines, cocrystals are crystal structures that contain two or more molecules in the same crystal structure.…”