Co-crystallization and small molecule crystal form diversity: from pharmaceutical to materials applications

Abstract

Co-crystallization is the supramolecular phenomenon of aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions. It encompasses the study of the manifestation of multi-component crystalline solids as well as their design. The chemistry community and the literature suggest cocrystals with reference to co-crystallization products and multi-component crystalline solids. Over the last decade cocrystals have become very popular as a potential new/alternate solid form of pharmaceuticals. However, there is no consensus on what exactly a cocrystal means and what it constitutes across academia, industry and regulatory bodies. On the other hand, cocrystals have been endorsed to the extent that the following facts have been obscured: (1) cocrystals are only one of the putative outcomes of co-crystallization, if at all, and (2) their application goes way beyond pharmaceuticals. Solvates, solid solutions, eutectics, salts, ionic liquids, solid dispersions, supramolecular gelators etc. are among the multifarious products of co-crystallization. The manifestation of these supramolecular/non-covalent crystalline adducts is controlled by the inherent nature of the system (the components involved) besides the surroundings (temperature, solvent, pH etc.); in effect it is a thermodynamic outcome. Each of these adducts, including cocrystals, are unique, exhibit varied physicochemical properties and are amenable to design and therefore have, and potentially find, manifold applications in diverse fields such as organic synthesis & separation, green chemistry, energy storage, solar cells, electronics, luminescent and smart materials, apart from pharmaceuticals. This article highlights the diversity of crystal forms and the utility of small molecule supramolecular combinations.

Two salts and the salt cocrystal of ciprofloxacin with thiobarbituric and barbituric acids: The structure and properties

“…Evidently, a further search for other CfH salts with improved properties is of great practical interest in pharmacology . Along with the salts, it is possible to use the so‐called salt cocrystals (or ionic cocrystals). The term “salt cocrystal” indicates that a salt, be it inorganic and organic, can cocrystallize with an organic molecule .…”

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

“…Therefore, a large number of neutral coformers including US-FDA approved GRAS (generally regarded as safe) (Burdock & Carabin, 2004), EAFUS (everything added to food in the United States) molecules, nutraceuticals and flavonoids can be used to prepare cocrystals Sinha, Rao Khandavilli et al, 2015;Bethune et al, 2011;Schultheiss et al, 2010Bevill et al, 2014;Brittain, 2012;Madusanka et al, 2014). This is the reason why pharmaceutical cocrystals have been widely explored in the recent past for a large number of neutral drug molecules (Childs & Zaworotko, 2009;Cherukuvada et al, 2016;Trask, 2007 Pyrazinamide (Pyz) is one of the essential drugs listed by the World Health Organization (Bansal & Purohit, 2013;Lindenberg et al, 2004;Bekker et al, 2016) for the treatment of tuberculosis (Zhang & Mitchison, 2003). It is used during monotherapy as well as fixed dose combination with other tuberculosis drugs, namely ethambutol, isoniazid and rifampicin (McNeill et al, 2003;McIlleron et al, 2006;Blomberg et al, 2001).…”

Cocrystals of Gallic Acid with Urea and Propionamide: Supramolecular Structures, Hirshfeld Surface Analysis, and DFT Studies

“…Further, two GA molecules in the ASU interact with two different GA molecules of the adjacent ASU resulting in the formation of acid–acid R 2 2 (8) supramolecular homosynthon through O2–H2…O6 (2.632 Å) and O7–H7…O1 (2.631 Å) hydrogen bonds. In the GA‐PR monohydrate cocrystal, the frequency of occurrence of acid‐dimer synthon (33%) is dominating the acid‐amide synthon (47%) due to its 2:1 stoichiometry . These homodimers are further connected through R 1 1 (6) ring motif and forms a staircase network when viewed down the a ‐axis.…”