Basic Research Of Chemical Resolution Of Ibuprofen

Ibuprofen is a nonsteroidal anti-inflammatory drug widely used as analgesic and antipyretic although it is also used for relief of symptoms of rheumatoid arthritis and osteoarthritis. Clinical studies have shown that S-ibuprofen is the pharmacologically active component of ibuprofen. The S-ibuprofen is reported to be about 160 times more potent than the R-ibuprofen in pharmacologically activity. The R-ibuprofen has low pharmacologically activity and side-effects. Also the R-ibuprofen can be potentially toxic, so the study of separate the ibuprofen enantiomer is important.Crystal technology is decided by crystallization thermodynamics. In this thesis, the equilibrium of solid and liquid of ibuprofen and S-ibuprofen n-octyl-d-glucamine salt in different pure solvents were determined by the light extinction measurement, and the equilibrium of solid and liquid of S-ibuprofen n-octyl-d-glucamine salt in ethanol+water solvents was also determined. The experimental data were regressed used Apelblat empirical equation, and got good fitting result. The crystallization metastable zone of S-ibuprofen n-octyl-d-glucamine salt in ethanol was determined. These data provide the theory basis for the crystallization technology of resolution of ibuprofen and has the instruction significance with operating control and optimization.The thermodynamics functions of solution and mixing of S-ibuprofen n-octyl-d-glucamine salt, such as Gibbs energy, enthalpy, and entropy, were obtioned from these solubility data using Gibbs equation and van't Hoff equation. The graph of enthalpy-entropy chmpensation of S-ibuprofen n-octyl-d-glucamine salt at the mean temperature permit the observation of similar mechanisms for the solution process according to the tendencies obtained. In order to obtain the insight into the molecular mechanisms involved in the solution process, this thesis determined preferential salvation parameter using the quasi-lattice quasi-chemical (QLQC) method and the inverse Kirkwood-Buff integrals (IKBI) method. This thesis analyzed the solubility behavior of S-ibuprofen n-octyl-d-glucamine salt in ethanol+water solvents in the aspect of thermodynamics.These five different structures of S-ibuprofen n-octyl-d-glucamine salt and R-ibuprofen n-octyl-d-glucamine salt were optimized using density functional theory at the B2LYP/6-31G level. The results showed that the structures of S-ibuprofen n-octyl-d-glucamine salt and R-ibuprofen n-octyl-d-glucamine salt produced by the reaction of ibuprofen and n-octyl-d-glucamine were S-1 and R-1.On the basis of research of crystallization threomdymics, the n-octyl-d-glucamine was adopted as the resolution agent to separate the ibuprofen enantiomer, and resolution technology of ibuprofen was studied and optimized from the aspects of mole ratio of ibuprofen to n-octyl-d-glucamine, mole ratio of ethanol to n-octyl-d-glucamine, cooling temperature, and the time of crystal formation. The yield of S-ibuprofen is 36.02% and is higher than 32% which was reported by reference.