With an increasing interest in cocrystals due to various advantages, demand for large-scale cocrystallization techniques is rising. Solution cocrystallization is a solvent-based approach that utilizes several single-component crystallization concepts as well as equipment for generating cocrystals. Solution-based techniques can produce cocrystals with reasonable control on purity, size distribution, morphology, and polymorphic form. Many of them also offer a scalable solution for the industrial production of cocrystals. However, the complexity of the thermodynamic landscape and the kinetics of cocrystallization offers fresh challenges which are not encountered in single component crystallization. This review focuses on the recent developments in different solution cocrystallization techniques for the production of pharmaceutically relevant cocrystals. The review consists of two sections. The first section describes the various solution cocrystallization methods, highlighting their benefits and limitations. The second section emphasizes the challenges in developing these techniques to an industrial scale and identifies the major thrust areas where further research is required.

Continuous tubular crystallizers that can provide high yield and better control of crystal size would be of great interest to the industrial crystallization process. However, most continuous crystallizer designs face challenges either due to surface fouling or crystal breakage. In this paper, we explore the ability of slug-flow cooling crystallizers to continuously generate acetaminophen crystals using silicone oil as the continuous phase. Each slug acts as a crystallizer, and the crystals formed inside the dispersed phase avoid encrustation. Three crystallizer configurations were studied at a wide range of supersaturation and flow rates. It was found that a narrow crystal size distribution can be achieved at high flow rates and high supersaturation. Additionally, the average crystal size and the crystallization yield increased with supersaturation and residence time. The configuration of the tubular crystallizer was found to influence the crystallization yield by affecting the internal mixing in the slugs. With further studies, slug-flow cooling crystallizer can be developed for continuous crystallization of crystals with a narrow size distribution, polymorphic purity, and good yield.

Continuous production of the 1 : 1 acetazolamide (ACZ) : p -aminobenzoic acid (PABA) cocrystal was achieved via cooling cocrystallization in a tubular slug flow crystallizer, under conditions mimicking batch cooling crystallization.