Natural product pharmaceuticals (NPP) are small molecules that can be isolated from plants, animals, and fungi. These may be used to treat diseases from simple inflammation to cancer treatment. Flavonoids such as wogonin and triterpenes such as oleanolic acid are natural products that were found to exhibit important bioactivities. In such cases, several issues arise where crystal engineering can play a role, whether in the formulation, separation, or for chiral compounds application as natural product resolving agents.

Chapter 1 outlines the background to natural product systems studied in the thesis and the methodologies applied to investigating their structures in the solid-state as pure crystalline materials, as well as hydrates, solvates, salts, cocrystals, and inclusion complexes....[ Read more ]

Natural product pharmaceuticals (NPP) are small molecules that can be isolated from plants, animals, and fungi. These may be used to treat diseases from simple inflammation to cancer treatment. Flavonoids such as wogonin and triterpenes such as oleanolic acid are natural products that were found to exhibit important bioactivities. In such cases, several issues arise where crystal engineering can play a role, whether in the formulation, separation, or for chiral compounds application as natural product resolving agents.

Chapter 1 outlines the background to natural product systems studied in the thesis and the methodologies applied to investigating their structures in the solid-state as pure crystalline materials, as well as hydrates, solvates, salts, cocrystals, and inclusion complexes.

Chapter 2 focuses on the study of wogonin. This is a flavonoid natural product that is typically found in mixtures of related compounds of similar solubility that are inefficiently separated and so commercially expensive. Synthetic approaches to the chemical synthesis of wogonin are explored and an improved method of preparation from the parent molecule chrysin is reported. Given sufficient authentic material, we show the wogonin typically crystallizes as two distinct but related hydrated forms, a monohydrate, and sesquihydrate that are difficult to distinguish by P-XRD. Wogonin may also form a variety of 4:1 solvate phases, namely with EtOAc and iso-propanol. We show that desolvation of the EtOAc phase is facile and smooth and may occur through a single crystal-single crystal transformation. This offers a route to a fully desolvated wogonin form that is stable to water uptake.

Chapter 3 explore the issue of separation of wogonin from its regioisomers Oroxylin A and Negletein, whose X-ray structures are determined for comparison. A separation approach through selective cocrystal formation for the flavonoids is explored. Wogonin was found to form cocrystals with various simple aromatic coformers such as 4,4 -bipyridine, nicotinamide, and imidazole, and some phenolics like catechol and resorcinol. Most of these are related phase types with cavities formed by wogonin rings. By contrast oroxylin A does not form cocrystals with these coformers and we are extending these studies to negletein, chrysin, and 8-Br-chrysin. By judicious choice of coformer and solvent, we aim to demonstrate the effective separation of wogonin from these molecular relatives through selective cocrystal precipitation.

Chapter 4 explores some crystal engineering issues related to oleanolic acid (OA) and other triterpene acids. Similar to OA, Ursolic acid (UA), Glycyrrhetinic acid (GA), and Cholic acid (CA), typically form solvate phases using different alcohols via Liquid Assisted Grinding (LAG). In general, the alcohols are found in 1D hydrophilic channels for OA and UA helping drive a needle-like crystal morphology which may have benefits for bronchial delivery. We have previously applied OA to some challenging resolutions of racemic amines via diastereomeric salt formation. Ursolic acid and Cholic also showed good potential in resolving chiral molecules such as sec-butylamine and 2-methyl piperidine, as well as neutral solvent sec-butanol. The enantioselectivity of OA and UA was found to be quite distinct from each other and none of the salt or solvent phases were isostructural despite the high similarity of OA and UA molecules that just involve a methyl group displacement.

Chapter 5 introduces a new approach to determining the structure of natural products and pharmaceutical molecules. The structure of a decoquinate derivative with potent anti-TB activity is reported to show the value of SC-XRD for structure identification, absolute structure, regiochemistry, and conformation. The crystalline sponge method of Fujita and the wealth of structural studies on inclusion complexes led us to combine the two areas to devise a new ‘crystalline host’ approach to natural product identification. β-cyclodextrin was used as a prototypical open host which is readily crystallized from aqueous methanol, with numerous solvent guest molecules. This was then applied to the inclusion of p-nitroaniline and later the flavonoid baicalein This is proof of the concept that it is possible to use β-CD as a crystalline host as an alternative to Fujita’s crystalline sponge MOF. This has ease of guest incorporation and it appears the method can be scaled down to 1mg or less of the guest molecule

Chapter 6 looks at how to further develop and apply the results in Chapters 2-5, as well as an approach to new polymorphic forms of APIs that we have started to explore via the heteroseeding of molecular analogs.