Studies On The Polymorphism Of Gimeracil

Taiho Pharmaceutical Industry Co., Ltd. in Japan developed a kind of anti-cancer drug named TS-1, including Tegafur, Gimeracil and Potassium Oxonate three kinds of composition. TS-1 was approved in Japan for gastric cancer, head and neck cancer treatment. Gimeracil was one of the three components of TS-1, and its role was to inhibit the anticancer drug Tegafur toxic side effects, improve curative effect.The medicine's curative effect relies on their characters, purity, dosage, production procedures, the dosage form, the moment and so on. With the development of science and technology, it has been affirmed that polymorphism of drug substances is the other one major reason which affects drug dissolution, chemical stability, as well as drug bioavailability. Even a small amount of contamination of polymorphs and amorphous form may alter its physicochemical properties of the original drug substances. The process of medicine preparation often involves selection of the polymorphism, so it is very important to study them for clinical effete and safety in synthesis and formulation processes. The process of medicine preparation often involves selection of the polymorphism, so it is very important to study them for clinical effect and safety in synthesis and formulation processes.Reported in the literature so far, there are two kinds of Gimeracil's crystal form:and P-form. We prepared two kinds of Gimeracil's crystal form:A-form and B-form. Based on the measured data with IR spectra, DSC and powder XRD instruments, compare A-form we prepared with the reported crystal L-form.We make sure that A-form is a new crystal form which had been reported in any literature.; B-form we prepared was the same to P-form reported in the literature.We study the solubility of Gimeracil's A-form and B-form. Determination of the two kinds of crystal solubility in all sorts of solvent, experimental results showed that the solubility of B-form was more than that of A-form. Also,the effects of temperature and polymorphism on them were discussed.The crystallization processes of different polymorphs of Gimeracil were studied experimentally. Crystallization mechanisms of different forms of Gimeracil were analyzed. The effects of several parameters on the polymorphic transformation were investigated experimentally and theoretically. Through systemic study of the polymorphic crystallization and transformation, the operational conditions of the crystallization of the appointed form and the effect factors of polymorphic transformation were obtained. It supplied the evidences to realize the control of the polymorph of Gimeracil. By using the orthogonal experiment method, the effects of the crystallization conditions, such as the solvent ratio, the stirring speed and grain of crystallization on the qulity, crystal form and the yield of product were studied. The optimized operational conditions were finally determined:add B-form,. solvent ratio was 9,and stirring speed was 60r/min.The industrial experimenatal results showed that this new technology not only can improve the quality of the product and the stability of the producing process, but also cut down the operating costs.