A Tale of Two Stoichiometrically Diverse Cocrystals

Abstract

Liquid-assisted grinding of an equimolar amount of pyrazinamide and p-nitrobenzoic acid yields two stoichiometric cocrystals in a 1:1 and 2:1 ratio, respectively. The 2:1 cocrystal was found to be the thermodynamically stable cocrystal based on solid stoichiometric interconversion, solvent-mediated conversion, and solubility studies. M echanochemistry 1,2 is one of the go-to methods for the synthesis and screening of cocrystals. A technique that goes back to the early 19th Century 3 was pioneered in the context of engineering cocrystals by the late Margaret Etter. 4−6 She demonstrated through a series of studies that cocrystals can be formed by grinding two components together in the solid state. Since then, synthesis of cocrystals by mechanochemistry has become widely popular. Mechanochemistry is particularly attractive because it can produce cocrystals not readily accessible by solution or melt synthesis. Moreover, it has been shown to afford control over the polymorphic outcome and stoichiometric composition of cocrystals. 7,8 The technique produces microcrystalline materials, which are primarily characterized by powder X-ray diffraction (PXRD). A unique PXRD pattern that is different from the starting materials generally indicates the formation of a new product. However, unlike in the case of a single component system where variation in the PXRD pattern of the product can be attributed to polymorphism, in a two-component system stoichiometric variation is an additional possibility that has to be taken into consideration. Differentiating between polymorphs and stoichiometrically diverse cocrystals by PXRD alone is not an easy task, and misinterpreting PXRD data can easily confuse polymorphs and stoichiometric cocrystals. A case in point is presented herein with a pair of pyrazinamide (PZA)·p-nitrobenzoic acid (pNBA) cocrystals. The relative thermodynamic stability based on solvent-mediated conversion, solid state stoichiometric interconversion and solubility studies is also discussed.pNBA is a suitable coformer for PZA that was selected to complement our previous study 9 on the effect of electronwithdrawing/-donating substituents on cocrystal formation. Figure 1 depicts the molecular structure of PZA and pNBA and the supramolecular synthons 10 likely to sustain the resulting cocrystal.Equimolar amounts of PZA and pNBA were reacted by liquid-assisted grinding (LAG) in the presence of various solvents. The resulting microcrystalline product was analyzed by PXRD and differential scanning calorimetry (DSC). PXRD data revealed the formation of a new phase, as indicated by a unique PXRD pattern that is different from either of the starting materials. DSC data showed two endotherms at ca. 171 and 183°C suggesting that two phases existed. Influenced by Figure 1. Molecular structures of pyrazinamide (PZA) and pnitrobenzoic acid (pNBA) and the possible supramolecular synthons that could sustain the two in a cocrystal.Communication pubs.acs.org/crystal

The phase relationship between the pyrazinamide polymorphs α and γ

“…Besides the polymorphs, a lot of crystallographic work has been carried out on mixtures of PZA with excipients or other APIs. Cocrystals containing pyrazinamide with carboxylic acids (Abourahma et al, 2015;Adalder et al, 2012;Kulla et al, 2016;Luo and Sun, 2013), with haloperfluorinated compounds (Choquesillo-Lazarte et al, 2017), with hydrochlorothiazide (Wang et al, 2014), with pyrogallol (Thakuria et al, 2012) and with diflunisal (Évora et al, 2011) have been described. Several polymorphs of cocrystals of PZA with succinic acid (Cherukuvada and Nangia, 2012;Luo and Sun, 2013), malonic acid (Kulla et al, 2017) and theophylline (Eddleston et al, 2015) have been found and investigated.…”

First-line antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a salt

“…S1-S5 of the supporting information. 2013; Lou et al, 2015;Wang et al, 2014Wang et al, , 2015Abourahma et al, 2011;Luo & Sun, 2013;Eddleston et al, 2016;Aree & Chaichit, 2009;Adalder et al, 2012;Aakerö y et al, 2004;Grobelny et al, 2011;Thakuria et al, 2012;Abourahma et al, 2015;McMahon et al, 2005;Thorat et al, 2015). From the structural analysis of the reported cocrystals it was observed that acid-pyridine (synthon I), acid-acid, amideamide and acid-amide dimers (synthon II, III and IV, respectively) are more common for cocrystals of Pyz containing coformers with acid functionality.…”

Cocrystal Dissociation under Controlled Humidity: A Case Study of Caffeine–Glutaric Acid Cocrystal Polymorphs

“…Polymorphism in single-component and multicomponent systems is quite common. An additional complication for multicomponent solids is the possibility of producing diverse solid-state forms such as variable-stoichiometry cocrystals − as well as crystallization of individual components. − Before a pharmaceutical (potentially) polymorphic cocrystal is considered for drug formulation, the following questions therefore need to be addressed: Can these materials be prepared on a large scale? Are they stable toward hydration? Are they stable under mechanical stress such as grinding, compression, and compaction? Does particle size reduction influence the stability? Therefore, the selection of a polymorphic cocrystal system as a model is particularly relevant to investigate these issues.…”