Solvent-free Methods for Co-crystal Synthesis: A Review

Background: Pharmaceutical co-crystals are the homogeneous crystalline substances composed of two or more substances bound together in the same crystal lattice via noncovalent interactions like hydrogenbonding, electrostatic interaction and Vander Waals interactions. Currently, co-crystals provide excellent opportunities to the formulation scientists in developing new pharmaceutical products by improving the pharmaceutically significant properties like solubility, dissolution rate, bioavailability, stability, and some other derived properties. Due to their ability to improve pharmacokinetic performance and their important intellectual property status, co-crystals are likely to have a very significant role in future drug development. Thus, formulation scientists have their focus on the development aspects of a co-crystallization process that include a rational selection of co-former, the discovery of novel synthetic procedures and new characterization techniques, and large scale production of these novel materials. Objective: The objective of this article is to present an extensive review of solvent-free methods for co-crystal synthesis, mainly focusing on the principle mechanisms, advantages, and drawbacks of each method. Conclusion: From the review of the topic, it is clear that the solvent-free methods can offer numerous advantages over solvent-based methods in the design and the production of co-crystals of pharmaceutical use and these methodologies can also pave the path to advancing the field of co-crystal synthesis. Some of the advantages accompanied with solvent-free methods are the use of no or very less amount of solvent(s), exceptional purity and quality of produced co-crystal, large scale production and the short reaction times in few cases.