The triterpene Oleanolic Acid (C₃₀H₄₈O₃) OA-H which has poor aqueous solubility crystallizes from various organic solvents, particularly alcohols, to give solvate co-crystals. Chapter 2 describes the preparation of a number of these solvates and their characterization by pXRD and SXRD. The control of the formation of solvated versus anhydrous phases are also discussed and appears to be controlled by the initial temperature of crystallization, with lower temperatures favoring solvates. A predicted unit cell from powder diffraction data is discussed for the oleanolic acid anhydrous phase, for which a single-crystal is difficult to obtain.

In Chapter 3, the ability of oleanolic acid to form salts with various amines and its potential as a chiral resolving agent via the formation of d...[ Read more ]

The triterpene Oleanolic Acid (C₃₀H₄₈O₃) OA-H which has poor aqueous solubility crystallizes from various organic solvents, particularly alcohols, to give solvate co-crystals. Chapter 2 describes the preparation of a number of these solvates and their characterization by pXRD and SXRD. The control of the formation of solvated versus anhydrous phases are also discussed and appears to be controlled by the initial temperature of crystallization, with lower temperatures favoring solvates. A predicted unit cell from powder diffraction data is discussed for the oleanolic acid anhydrous phase, for which a single-crystal is difficult to obtain.

In Chapter 3, the ability of oleanolic acid to form salts with various amines and its potential as a chiral resolving agent via the formation of diastereomeric salts is explored. Oleanolic acid is a chiral acid and thus it may be able to resolve racemic organic bases, hence it can be a potential resolving agent for cations. Various racemic amines were used to study the effectiveness of oleanolic acid as a resolving agent for cations.

In our investigation, we discovered that oleanolic acid forms a hydrated salt when recrystallized with S-2-methylpiperidine. However, there occurs some H/Me disorder of the amine and both R- and S-isomers are incorporated in the same crystal. Thus, the S-isomer is resolved with only 50% enantiomeric excess. Whilst the 2-methylpiperidine is not well resolved, its stereoisomer – 3-methylpiperidine was also recrystallized with oleanolic acid to resolve the S-isomer, with almost 100% enantiomeric excess. Furthermore, the amine s-butylamine was also successfully resolved using oleanolic acid as a chiral resolving agent. Therefore, our studies demonstrate the great potential for oleanolic acid as a low-cost, efficient chiral resolving agent via the formation of diastereomeric salts.

The use of oleanolic acid as a resolving agent is not limited to diastereomeric salt formation. Chapter 4 investigates the potential for oleanolic acid as a chiral resolving agent via the formation of co-crystals with neutral molecules. In particular, we investigate the ability of oleanolic acid to resolve chiral alcohols via cocrystallization of solvated phases, owing to oleanolic acid’s ability to form solvated phases as demonstrated in Chapter 2. Oleanolic acid was found to partially resolve (2R, 3R) 2,3-butanediol by forming a co-crystal phase whilst oleanolic acid sodium salts were able to partially resolve s-butanol.

Given the potential of oleanolic acid for various applications and the importance of molecular perturbation on structural chemistry, the studies conducted in chapters 2, 3 and 4 are then expanded to oleanolic acid synthetic derivatives and similar triterpenes, ursolic acid and glycyrrhetinic acid, in Chapter 5 to study the differences in structure and crystallization that may occur when slight changes are made to the oleanolic acid structure.

It was discovered that oleanolic acid derivatives appear to crystallize in different crystal systems in the anhydrous phase and the conditions for forming solvates were also different for these oleanolic acid derivatives, most likely owing to their difference in solubilities. Two solvated crystal structures were obtained for the oleanolic acid isomer ursolic acid, which are compared with the oleanolic acid solvated phases and to ursolic acids own reported solvated structures. It appears that these similar solvated triterpenes favour orthorhombic P2₁2₁2 and P2₁2₁2₁ crystal systems and tend to crystallize in these two crystal systems when possible. The potential for ursolic acid and Glycyrrhetinic acid as chiral resolving agents for 2-methylpiperidine have also been discussed.

Chapter 6 discusses the summary and highlights of the previous chapter, the impact of this research as well as some suggestions for future research.