Solvothermal crystallization of organic compounds and natural products
by Wong Wan Yee
xxi, 165 leaves : ill. (some col.) ; 30 cm
This thesis continues the exploration of our group's research into the application of solvothermal crystallization methods to organic compounds, with specific reference to natural products. The background to these studies is presented in Chapter 1....[ Read more ]
This thesis continues the exploration of our group's research into the application of solvothermal crystallization methods to organic compounds, with specific reference to natural products. The background to these studies is presented in Chapter 1.
In this work we have taken Tetrahydropalmatine as an example of a natural product, available in two free base forms as both a racemic mixture ((d1)THP) and enantiopure isomer ((1)THP) and investigated their hydrothermal stability, hydrolytic breakdown products and the use of solvothermal conditions as a facile approach to producing stable salt and neutral co-crystal derivatives of these parent forms.
Chapter 2 describes the hydrothermal crystallization and subsequent single crystal X-ray structural determinations of eight salts of tetrahydropalmatine, including compounds with organic or inorganic counter-anions, hydrated or anhydrous formulations and either as racemic crystals or involving only enantiopure 1-(-)-tetrahydropalmatinium cations. The hydrochloride salt of this was used to establish the absolute structural configuration of this species and another chiral salt obtained from reaction with D-tartaric acid and 1-THP indicates a plausible way to resolve the racemic mixture of d1-THP .
Chapter 3 describes further crystallization of racemic d1-THP with other organic acids to examine the effect of the pKa of the organic acid. In this case a series of benzoic acids were used with varying substituents which affect the electronic properties and the acidity of the carboxylic acid functionality. It was found in a study of eight benzoic acid adducts that three species with pKa below 4.0 formed 1:1 salts with proton transfer to the THP moiety and +NH---O- hydrogen bonds involving the THP nitrogen atom. Conversely benzoic acids with pKa of 4.00 and higher formed 1:1 neutral molecular adducts with no proton transfer. These crystals usually possessed N:---HO hydrogen bonds involving the THP nitrogen. The cross-over in product type is marked and the 4-chloro and 4-bromo compounds. One conclusion from these studies is that many salts prepared for pharmaceutical formulations might in fact be neutral co-crystals and that care should be taken in considering the pKa of ionizable groups.
Chapter 4 discusses the use of ethanol solvent in place of water in many of these reactions between THP and organic acids. The resulting compounds were typically found to involve the hydrolysis product palmatine which is an oxidized form of THP and involves loss of hydrogen from rings B and C to form conjugated aromatic rings. Five organic salts of palmatine (which is cationic) were isolated and structurally characterized. The process of decomposition may involve an intermediate dihydropalmatine which has partial dehydrogenation of THP, with loss of hydrogen atom from the chiral center C13. This compound can be formed in good yield and purity after hydrothermal reaction of THP at 120°C for 6 days, or at 140°C for shorter time periods.
Finally in Chapter 5 two new polymorphs of organic compounds produced by hydrothermal crystallization are explored and their stability with respect to the original polymorphs examined by Differential Scanning calorimetry and variable temperature powder X-ray diffraction. Interestingly when alcohols were used to study the formation of these polymorphs in a different solvent system, the ester products were formed instead in good yield.
Understanding of these various issues such as salt and neutral co-crystal formation, hydrolytic breakdown products and high temperature polymorph formation and energetics, as well as the possibility of facile formation of derivatives, e.g. esters, are of importance to application of solvothermal crystallization methodology to pharmaceutical engineering. Perhaps the most important message however is that with the sparing aqueous solubility of many organic compounds such as drugs and natural products, a hydrothermal crystallization approach can offer a novel but facile method of producing single crystals of sufficient size (>100microns) to routinely allow X-ray structure determination and thus aiding product identification.