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.

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 °C, 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.

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures.