| 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 ensure 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 SM934 and the draft quality standards of SM934 were established. The work was divided into the following five parts:1. The structure confirmation of SM934By elemental analysis, UV, IR, NMR (13C,1H) and mass spectrometry for structural confirmation of SM934, reliable raw material for the study on quality standards and stability was provided.2. The quality control of SM934The quality standard of SM934 was investigated according to Chinese Pharmacopoeia and technical specifications of the drug quality standards. According to the structure and property of the SM934, we selected the appropriate method for its quality control. The items of solubility, melting point, rotation, identification, examination of inorganic impurities, moisture, weight of moisture absorption, 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 SM934.The results indicated that organic solvent residues of SM934 met Chinese Pharmacopoeia requirements. The results of related substances inspection were between 0.2-0.5% and the main structure of the related substances was speculated. The SM934 content determined by nonaqueous titration and high performance liquid chromatography were greater than 99%.3. The stability study of SM934Stability of SM934 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 SM934 is sensitive to light, temperature and humidity and should be stored under the condition of low temperature, dark and dry. After the accelerated tests at 40℃, humidity of 75%, sample characteristics of SM934 changed, related substances content increased, and main component content decreased significantly. After the accelerated test at 30℃, humidity of 65% and long-term test at 25℃, humidity of 60%, the related substances content increased to 0.8% and 0.4% and main component content were decreased to 98.5% and 99.0%. For statistical analysis on the validity, if main component content of SM934 becomes 98.5%, the retention time is 22.5 months. So the SM934 is valid for 22.5 months.SM934 should be stored under the condition of room temperature, dark and dry.4. The draft quality standards of SM934 and drafting instructionsThe draft quality standards of SM934 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 SM934.5. The initial study of SM934 in vivoA method of pre-column derivatization-HPLC determination of SM934 concentrations in plasma was initially established and used to determine its concentration-time curve in rats. Through the optimization of derivation conditions, the best reaction conditions pH8.0, FMOC-C1 concentration 8mM, reaction time 15min were selected. Under these conditions, SM934 concentration in the range of 0.025～0.8μg/ml had good linear relationship (r= 0.9989). Detection limit (S/N=3) was 0.01μg/ml. This method was used to determine the concentration-time curve in rats after oral administration of SM934. |
