| The study on quality control and stability of drugs is an important content of drug pre-clinical studies. During the study on drug quality standards, it needs to do a thorough check of drug quality to guarantee the safety and reliability of drugs, and ensure the smooth progress of pre-clinical research, as well as the safety of post-marketing drugs. Drug storage conditions and validity of drugs are determined by the stability. Based on the study on drug quality standards and stability, the contents and methods of the quality standards and stability of Cimetinib and the draft quality standards of Cimetinib were established.In Chapter1, the structure of Cimetinib was confirmed. By UV, IR, NMR, mass spectrometry, DSC and X-ray for structural confirmation of Cimetinib, reliable raw material for the study on quality standards and stability was provided.In Chapter2, the quality standard of Cimetinib was investigated according to Chinese Pharmacopoeia and technical specifications of the drug quality standards. According to the structure and property of the Cimetinib, we selected the appropriate method for its quality control. The items of solubility, melting point, identification, examination of inorganic impurities, moisture, weight of moisture absorption, and residue on ignition et al were studied to determine the appropriate test methods and results.The methods of residual organic solvents inspection, the related substances inspection and assay were established for the first time. Verification methodology was conducted, and was used for the determination of relevant contents of Cimetinib.The results indicated that organic solvent residues of Cimetinib met Chinese Pharmacopoeia requirements. The results of related substances inspection were between0.1-0.8%and the main structure of the related substances was speculated. The Cimetinib content determined by nonaqueous titration and high performance liquid chromatography were greater than99%.In Chapter3, the stability of Cimetinib was conducted according to the guiding principles of drug stability test. Impact factors test, accelerated test and long-term test were carried out respectively. The sample characteristics, the main component content and related substances content of stability samples were analyzed. It is found that Cimetinib is sensitive to light, but it is insensitive to temperature and humidity. After the accelerated tests at40℃, humidity of75%, and long-term test at25℃, humidity of60%, the related substances content increased to0.847%and0.904%and main component content were decreased to98.73%and99.10%.Cimetinib should be stored under the condition of room temperature, dark and dry.In Chapter4, the draft quality standards of Cimetinib and drafting instructions were formulated and drafted according to the first two chapters of the research content. This chapter provides norms and basis for quality control of Cimetinib. In Chapter5, infrared-assisted extraction (IRAE) was developed and combined with HPLC for the determination of catechin, epicatechin, and procyanidin B2in grape seeds. Three factors, extraction solvent, solid/liquid ratio, and illumination time, were investigated to optimize the extraction method of catechin, epicatechin, and procyanidin B2from grape seeds. The chosen infrared-assisted extraction conditions were as follows:a50%methanol solution as extraction solvent, solid/liquid ratio of1:150g/mL and illumination time of30min. The extraction efficiency of IRAE was compared with conventional microwave-assisted extraction (MAE), ultrasonic extraction (UE). An initial HPLC method was established to identify and quantify catechin, epicatechin, and procyanidin B2from grape seeds, simultaneously. The HPLC method was validated for parameters including linearity, analytic limit, reproducibility, accuracy and recovery. The results indicated that IRAE has a great potential for offering an alternative technique for extraction of active components from plants.In summary, the main contributes of this dissertation is that we initially studied on quality control and stability of new drug-Cimetinib. The developed methods were successfully applied to comfirm the structure and the crystal form of Cimetinib. The methods of the determination of Cimietinib and the related substances inspection and assay were established for the first time. In addition, infrared-assisted extraction (IRAE) was developed and combined with HPLC for the determination of the active compounds in grape seeds. |
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