Cocrystal polymorphs through experiment and theory

Pharmaceutical cocrystals are promising materials composed of two or more different molecules with at least one drug molecule in the structure. Cocrystals are of increasing interest as they enable to modify important properties of the materials, i.e. solubility, stability or manufacturability which can in turn improve drug absorption in the human body. These modifications are attractive from both academic and industrial perspective in designing novel solid state forms of drug substances with optimized properties including biopharmaceutical features, without affecting their pharmacologicalherapeutic profile. Up to date several experimental methods have been developed to synthesise cocrystals with little consistency in the application of the proposed experimental protocols. The published research describes experimental pathways of finding new cocrystals with very little attention on understanding the different ways of arranging molecules (building blocks) in the solids (cocrystal polymorphs). These on the other hand significantly affect the targeted properties of the final material. Furthermore, the trial and error approach is used in the majority of the studies as there is a substantial knowledge gap in our ability to predict if two selected molecules will form a cocrystal and specially to predict the properties of a final product. The proposed project aims at developing predictable ways for cocrystal formation along with an understanding of different packing arrangements of molecules in the formulated solid and the relative stability of the obtained forms. In order to achieve this, a set of eight model drug molecules and eight coformers of different structure and properties were selected to evaluate their propensity to form cocrystals. By applying a vast diversity of experimental and theoretical methods we will search for new cocrystals and their modifications in order to develop a guideline for predictable screening of cocrystals and cocrystals polymorphs. The obtained materials will be thoroughly characterised with advanced analytical techniques in order to understand the correlation between structural features and pharmaceutical applicability (dissolution, water sorption and compressibility). The proposed project combines the expertise and research infrastructure of the Preformulation and Polymorphism group in Innsbruck (PI Braun) and the Drug Forms Technology Department in Wroclaw (PI Nartowski), enabling a successful advancement for a broad range of single- and multicomponent solid forms. The unique position of both collaborators facilitates in a single project to investigate all aspects of cocrystal formation from theory through a variety of experimental synthetic methods to the determination of cocrystal properties. The outcome of this project will improve the general understanding of cocrystal formation and will be transferrable to other materials (agrochemicals, fine chemicals, dyes, cosmetics, energy storage materials, etc.).

Pharmaceutical cocrystals are innovative molecular compounds composed of two or more substances, with at least one being an active pharmaceutical ingredient. The formation of such cocrystals allows for the modification of important drug properties without compromising therapeutic efficacy. These properties include solubility, stability, processability, and the drug's absorption in the human body. To date, various experimental approaches have been employed to discover and produce cocrystals, often relying on trial and error. The primary goal of many studies has been to identify cocrystals of specific substances, with little emphasis placed on the different organizational possibilities of their components (polymorphic forms - having the same chemical composition but differing spatial arrangements of molecules) or solvates (containing additional solvent molecules). However, these various solid forms can significantly impact the properties and efficacy of a drug molecule. Despite intensive efforts in solid-state chemistry, neither the existence nor the properties of cocrystals and their polymorphic forms are predictable. The main objective of this research project was to enhance the predictability of cocrystal formation, cocrystal polymorphism, and stability of these multi-component compounds. Four pharmaceuticals (dapsone, sulfanilamide, sulfaguanidine, griseofulvin) and coformers with different molecular and structural properties were selected as model systems. Their tendency to form cocrystals was investigated using classical experimental methods as well as innovative experimental and theoretical approaches. The results indicated that the easily accessible virtual pre-screening tools are not always reliable. In contrast, more time- and resource-intensive methods such as crystal structure prediction yielded excellent results. Importantly, combining these pre-screening tools can reduce the number of experiments required. Experimental investigations revealed that cocrystals frequently form various solid forms similar to single-component systems, thereby opening new avenues for optimizing the physicochemical properties of pharmaceuticals. This work on model pharmaceuticals demonstrated that methods need to be tailored to each specific system, with simple stirring experiments and melt extrusion proving effective for the phase-pure upscaling of cocrystals. Furthermore, this project contributed to the development and enhancement of methods for measuring stability differences among cocrystal polymorphs, various cocrystal stoichiometries, and single-component solid-state forms. Such information is crucial for understanding cocrystal formation and particularly for optimizing computer-based prediction tools for multi-component systems. The knowledge gained on pharmaceutical cocrystals can be directly applied to other important materials such as agrochemicals, fine chemicals, dyes, cosmetics, and explosives, highlighting the broader significance of this research.