An industrial perspective on co-crystals: Screening, identification and development of the less utilised solid form in drug discovery and development.

Active pharmaceutical ingredients are commonly marketed as a solid form due to ease of transport, storage and administration. In the design of a drug formulation, the selection of the solid form is incredibly important and is traditionally based on what polymorphs, hydrates or salts are available for that compound. Co-crystals, another potential solid form available, are currently not as readily considered as a viable solid form for the development process. Even though co-crystals are gaining an ever-increasing level of interest within the pharmaceutical community, their acceptance and application is still not as standard as other solid forms such as the ubiquitous pharmaceutical salt and stabilised amorphous formulations. Presented in this chapter is information that would allow for a co-crystal screen to be planned and conducted as well as scaled up using solution and mechanochemistry based methods commonly employed in both the literature and industry. Also presented are methods for identifying the formation of a co-crystal using a variety of analytical techniques as well as the importance of confirming the formation of co-crystals from a legal perspective and demonstrating the legal precedent by looking at co-crystalline products already on the market. The benefits of co-crystals have been well established, and presented in this chapter are a selection of examples which best exemplify their potential. The goal of this chapter is to increase the understanding of co-crystals and how they may be successfully exploited in early stage development.

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction.

Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and maximizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment, such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea: barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD analysis uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information regarding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials.