| Clevidipine butyrate is the third generation of new type of short-acting two dihydropyridine calcium channel antagonist. It can reduce cell transmembrane inward calcium flux, which inhibits both myocardial and vascular smooth muscle contraction. Confirmed by plenty of clinical trials and drug researches, clevidipine butyrate applies to severe hypertension which is not suitable for oral treatments and acute blood pressure elevation after surgical operation. Clevidipine butyrate is synthesized by the Shanghai Institute of Pharmaceutical Industry and its stability research, related compounds and content determination have been studied.The study on stability research, related compounds and content determination of drugs is an important content of drug quality standards and drug pre-clinical studies. During the study on drug quality standards, a thorough analysis of drug quality should be done to guarantee the safety and reliability of drugs, and to guarantee the smooth progress of pre-clinical and clinical research, as well as the safety of post-marketing drugs. In this study, under the guidance of "Chinese Pharmacopoeia" and the technical requirements of the national drug quality research, the stability research, related compounds and content determination of clevidipine butyrate were systematically studied. We used techniques such as HPLC and QTof-MS to analyze the samples, whilst the stress degradation of samples was further studied. The dissertation was divided into the following three parts:3.1 Determinate related compounds of clevidipine butyrate by HPLCThe method of related compounds inspection was established to detect seven related compounds of clevidipine butyrate. Different mobile phase system and column were proved to influence the resolution. The method was finally performed on Ultimate AQ-C18 reversed-phase column with the gradient elution using a mobile phase system of acetonitrile-methanol-phosphate buffer. All the related compounds were successfully separated and the samples could be tested through this method.3.2 HPLC method for content determination of clevidipine butyrateHPLC method was established to perform the assay of the drug. The assay was performed in Ultimate AQ-C18 reversed-phase column (250mm×4.6mm,5μm) with isocratic elution using acetonitrile-methanol-phosphate buffer, pH≈3, and the flowing rate was 1.5mL/min, the UV detection wavelength was 220nm, the column temperature was 25～ and the sample volume was 20μL. The method was proved to be accurate and specified. We compared this method with cerimetry and use this method to test samples.3.3 The stability study of clevidipine butyrateStability of clevidipine butyrate was conducted according to the guiding principles of drug stability test. The impact factors test, accelerated test and long-term test had already been finished. In this research, the sample characteristics, the main component content and related substances of stability samples were analyzed. According to the results, clevidipine butyrate was very stable in 6 months under accelerated test condition,18 months under long term test condition and 10 days under high temperature, high light and high humidity. But clevidipine butyrate is not suitable for be stored under high humidity condition because of its little moisture absorbance property.In this dissertation, the method of LC-QTof-MS was used to study the stress degradation of clevidipine butyrate according to ICH guidelines, providing information about degradation behaviors of the drug under different stress conditions, including acidic, alkaline, oxidative, photolytic and thermal condition. The drug was found to undergo extensive degradation under acidic and alkaline condition, a mild extent under thermal condition and be extremely stable under oxidative and photolytic condition. Then confirm the presence of known products under acidic and alkaline conditions based on m/z values and retention time. |
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