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Cocrystals have gained much interest in recent years owing to their potential to improve the physicochemical properties of the parent compounds. It was once thought that cocrystals could be a means to prevent polymorphism but many recent examples of cocrystal polymorphism have been discovered and reported. Similar to single component crystals, polymorphs of cocrystals can display significantly different properties. In this contribution, we present a survey of polymorphic cocrystals. The different types of polymorphs, namely synthon, conformational, packing, and tautomeric, are identified and discussed with representative examples. In addition, polymorphs of cocrystals that showed distinct physicochemical properties are highlighted.

The first example of a trimorphic cocrystal involving two active pharmaceutical ingredients, ethenzamide and gentisic acid, is reported; metastable polymorphs convert to the stable form upon solid-state grinding; pharmaceutical cocrystals involving two or more APIs have potential relevance to combination drugs.

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A 1:1 cocrystal involving an analgesic drug, ethenzamide (EA), and 3,5-dinitrobenzoic acid exists in two polymorphs and forms a series of solvates. All the crystalline materials have been characterized by various analytical techniques, such as single-crystal and powder X-ray diffraction, 1 H NMR, and DSC/TGA. It was found that one of the polymorphs (form II) and the solvates, except mesitylene solvate, contain a common hydrogen-bonded tetrameric motif in their crystal structures. Desolvation of all the solvates resulted in form I and the process features the switch over of supramolecular synthon from amide-amide homosynthon to an acid-amide heterosynthon. This observation was rationalized on the basis of facile transformation of form II into form I at ambient conditions and the structural similarity of form II with that of the structures of solvates. The ability of EA cocrystals to form polymorphs and solvates is compared with statistics extracted from the Cambridge Structural Database on the prevalence of polymorphs and solvates/hydrates in the cocrystals. It was found that the number of polymorphic cocrystals being added to the database is increasing, and the tendency of solvate/hydrate formation is significantly higher for cocrystals when compared to the crystalline solvates/hydrates of a single solid component.

The inadvertent errors in the lattice energy calculations of the cocrystal polymorphs reported in our previous article were rectified.

Novel cocrystals of an anti-tuberculosis drug, Isoniazid (INH), with pharmaceutically acceptable coformers such as nicotinamide (NA), 4-hydroxybenzoic acid (HBA), fumaric acid (FA), and succinic acid (SA) are reported. Cocrystallization experiments involving INH and HBA produced two polymorphs of a novel hydrate of the INH?HBA cocrystal. Similarly, cocrystallization of INH and FA produced a novel polymorph of the reported INH?FA cocrystal. We have successfully explored the idea of designing ternary cocrystals involving INH with NA and FA or SA. All the novel solids were thoroughly characterized and their crystal structures determined. All the crystal structures feature an acid-pyridine heterosynthon involving INH and the carboxylic acid. Stability of the novel cocrystals was evaluated by slurry experiments and dynamic vapor sorption studies. In addition, stability of the cocrystals at accelerated test conditions (40 uC, 75% RH) was also tested. Anhydrous INH?HBA cocrystal and Form I of INH?HBA cocrystal hydrate were found to convert to Form II of the INH?HBA hydrate, and Form II of INH?FA cocrystal converted to Form I of the INH?FA cocrystal. Ternary cocrystals remain stable at all test conditions. Solubility and dissolution experiments revealed a greater solubility of the INH?NA?SA cocrystal and its dissolution rate is comparable to the dissolution rate of the native INH. All other cocrystals showed lower solubility and dissolution rate compared to INH.

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4'-bipyridine-N,N'-dioxide (BPNO), and solid-state stability were studied. Apart from a known X-ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3-hydroxypyridine-N-oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N--HN(imidazole) and N--HN(tetrazine) interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZBPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen-bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N-H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C==O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen-bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen-bond reorganization.