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Polymorphism in Ionic Cocrystals Comprising Lithium Salts and l-Proline.

ABSTRACT: The occurrence of polymorphism in ionic cocrystals formed by two lithium salts, lithium salicylate (LIS) and lithium 4-methoxybenzoate (L4M), and l-proline (PRO) has been investigated. The previously reported monoclinic form of the 1:1 cocrystal of LIS and PRO, LISPRO(α), and a new thermodynamically stable orthorhombic polymorph, LISPRO(β), were prepared and characterized. The two polymorphs form square grid, sql, topology coordination networks and differ mainly in the conformation of the salicylate ions and positioning of the sql nets. LISPRO(α) was observed to transform to LISPRO(β) under slurry conditions. The 1:1 ionic cocrystal of L4M and PRO (L4MPRO) was found to form three polymorphs. Apart from the previously reported orthorhombic crystal form, L4MPRO(α), two new monoclinic crystal forms, L4MPRO(β) and L4MPRO(γ), were obtained by modifying crystallization conditions. The new polymorphs were found to be metastable, undergoing transformations to L4MPRO(α) upon exposure to humidity. Experimental conditions that induce transformations between the polymorphs of LISPRO and L4MPRO are detailed, and the structural differences between the polymorphs are discussed in the broader context of polymorphism.

SUBMITTER: Sanii R

PROVIDER: S-EPMC9490868 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Polymorphism in Ionic Cocrystals Comprising Lithium Salts and l-Proline.

Sanii Rana R Andaloussi Yassin H YH Patyk-Kaźmierczak Ewa E Zaworotko Michael J MJ

Crystal growth & design 20220503 6

The occurrence of polymorphism in ionic cocrystals formed by two lithium salts, lithium salicylate (LIS) and lithium 4-methoxybenzoate (L4M), and l-proline (PRO) has been investigated. The previously reported monoclinic form of the 1:1 cocrystal of LIS and PRO, LISPRO(α), and a new thermodynamically stable orthorhombic polymorph, LISPRO(β), were prepared and characterized. The two polymorphs form square grid, sql, topology coordination networks and differ mainly in the conformation of the salicy ...[more]

PMID: 36160301

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Project description:Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B-A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B-C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31-46 kJ mol-1. The azolium-triazole ICC (A+B-C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.

Dataset Information

Polymorphism in Ionic Cocrystals Comprising Lithium Salts and l-Proline.

Publications

Polymorphism in Ionic Cocrystals Comprising Lithium Salts and l-Proline.

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