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.

Over the last two decades, the use of template surfaces to induce heterogeneous crystal nucleation has been explored primarily to address two different goals: first, as an alternative to the conventional seeding technique used for polymorph control and, second, as a technique to promote the nucleation rate in novel crystallisation processes and formulations. The former need conceivably arises due to the risk of crystallising a new polymorph despite pre-seeding the solution with the desired crystal form. In this context, we review ongoing efforts in the research area of template-induced crystallisation, covering both experimental and simulation studies directed towards deeper understanding of the underpinning mechanisms. In addition, we report on the use of template-induced crystal nucleation as a process intensification technology for formulating drug substances and as a technique for enabling nucleation and polymorphic control during continuous manufacturing of active pharmaceutical ingredients.

Protein crystallization has immense potential to be used for separation and formulation applications on an industrial scale. Crystallization under static conditions is often limited by the diffusion of molecules from the bulk solution to the growing crystal surface. This results in a lower overall yield of the product and longer crystallization periods. Hence, protein crystallization under flow conditions has attracted attention with the capability to improve the convective protein transport, reducing the crystallization time and improving yield. In this study, we investigate the effects of flow, specifically intermittent oscillatory flow on protein (insulin) crystallization. It was observed that the nucleation and crystal yield is very much influenced by the flow conditions and herein we present some key observations in insulin crystallization conducted under intermittent oscillatory flow. For oscillatory flow velocities ranging from 6 to 16 mm/min at a frequency of 1 cycle/min, a considerable increase in nucleation has been observed with an increase in flow rate resulting in the formation of large number of crystals in tubes with flow compared to the stationary tubes. Also 50% yield for flow crystallization was achieved in contrast to only 24% yield for the stationary growth over the 48 h period. The flow condition was thus found to affect the number and size of crystals. In addition, the intermittent flow pattern utilized in this study helps to separately understand the influence of flow on nucleation and crystal growth. The flow strategy proposed herein could potentially be utilized to optimize crystallization processes for proteins so as to be used in downstream separation and formulation of products.

Cooling crystallisation of carbamazepine solution in glass vials functionalised with different silane molecules resulted in preferential nucleation of metastable form II or stable form III polymorphs within a definite range of supersaturation. In contrast, the two crystal forms nucleated concomitantly on a control substrate under similar solution conditions.