Design of food grade particles with tailored properties using a crystal engineering approach

Crystalline materials are ubiquitous in the pharmaceutical, food, chemical and agrochemical industries, to name a few. The development of products and formulations containing crystalline solids requires the in-depth understanding and exploration of the various existing solid forms of these substances. At the same time, crystal engineering aims to design molecular crystals with directed properties, based on the knowledge of hydrogen bonding and intermolecular interactions within the crystal lattice. Such knowledge can enable delivering particles with optimized physiochemical properties, such as stability, morphology and surface chemistry, which can ultimately lead to a faster product development and more efficient formulations for specific applications. Therefore, there is a profound need of understanding how these properties related to the crystallographic characteristics of solids. In this doctoral project, different solid forms of an important food grade flavonoid substance, quercetin, including quercetin anhydrous (QA), quercetin monohydrate (QMH), quercetin dihydrate (QDH), quercetin DMSO-solvate (QDMSO), quercetin ethanol-solvate (QE) and their respective de-solvated forms, were studied in order to understand how the crystallographic structure affects the macroscopic properties of quercetin particles. The strength and nature of the intermolecular pairwise interactions (synthons) in the different structures were calculated and the lattice was comprehensively examined. The modelling work was integrated and validated with experimental solid-state characterization. It was found that crystallization of quercetin from an aqueous solvent favors the formation of hydrates, with QDH being the structure of highest stability at ambient conditions. This is because the water molecules in the lattice satisfy the hydrogen bonding interactions available in the quercetin molecules, allowing a more planar conformation of this molecule that enable the formation of stronger π-π interactions. It was, further, demonstrated that the stronger hydrogen bonding network between the quercetin and the DMSO molecules in QDMSO can lead to a higher relative thermal stability for the that structure compared to QDH, for which the hydrogen bonds between the quercetin and the water molecules were weaker. The attachment energy morphological predictions and surface chemistry analysis of quercetin forms, verified by experimental studies on the structures, demonstrated surface anisotropy and heterogeneous surface energies for the quercetin forms. The facet-specific surface chemistry was explained based on the study of the extrinsic synthons. It was shown that overall QDH has more non-polar surfaces compared to QDMSO, whose dominant surface was found to grow by polar hydrogen bonding interactions. The solid-form landscape of quercetin was also further explored, and four new structures were discovered: two new solvates (QDMSO and QE) and their de-solvated forms. The transformation conditions between the different solid forms were also established. The approach presented in this work can be extremely useful when designing products and processes involving different solid forms, specifically solvates, and for understanding and controlling the morphology and surface chemistry of crystalline solids. The interlink established between the crystal lattice and the physiochemical properties of quercetin not only elucidates the underlying chemistry behind many crystallization phenomena, such as the formation of solvates and their anisotropic nature, but also assists in enabling the prediction and design of tailor-made crystals with optimal characteristics.