Pharmaceutical cocrystallization techniques. Advances and challenges

Cocrystals are homogenous (single-phase) crystalline structures composed by two or more components in a definite stoichiometric ratio bonded together by noncovalent bonds. Pharmaceutical industry has been showing interest in cocrystals due to their ability to improve active pharmaceutical ingredients (API's) properties, such as solubility, dissolution, bioavailability, stability and processability. The necessity for high-throughput screening methods and methods capable of producing cocrystals in an industrial scale still hinders the use of cocrystals by the pharmaceutical industry. The aim of this review is to present an extensive overview of the cocrystallization methods, focusing in the specificities of each technique, its advantages and disadvantages. The review is divided into solvent-based and solvent-free methods. The most appropriate methods to the different stages of cocrystals manufacture, from the screening phase to industrial production are identified. The use of continuous and scalable methods in cocrystal production as well as the implementation of quality-by-design and process analytical technology concepts are also addressed.