Stability Research Of8-Hydroxypiperidinemethyl-baicalein Mesylate

Scutellaria baicalensis is a commonly used traditional Chinese medicine in China and many other eastern countries with baicalin as its main effective components (content9-21%), and baicalein (BA), its hydrolysis product, has stronger activity. BA is a natural flavonoids CDKl selective inhibitor, but possesses poor solubility, low bioavailability and low blood drug concentration. So direct use of B A could not reach the requirements of clinical treatment of cancer and AIDS. Therefore, structure modification of BA has aroused wide attention, among which the most effective are Mannich bases derivatives. In our previous work, B A was taken as lead compound, and a new structure of CDK1Mannich bases derivatives inhibitor8-Hydroxypiperidinemethyl-baicalein (BA-j) was obtained. Compared with lead compound, BA-j has better broad-spectrum antitumor activity and more potent inhibition of cancer cell proliferation.In order to control drug quality and further pharmaceutical researches, in this paper, stability research of BA-j was conducted.8kinds of BA-j decomposition were separated and identified, among which7were identified for the first time and the other one was BA. BA-j as water solution was firstly oxidized in the light into soluble8-hydroxymethyl oxized Baicalein (M298) which is not stable, and further condenses into insoluble8,8’-methelene di-Baicalein (M552). M552was then isolated and characterized. Oxidative decomposition was mainly8-hydroxymethyl oxidized Baicalein (M298), followed by BA and8,8’-methylene di-Baicalein (M552). HPLC-UV was adopted to establish and verify the analysis method of oxidative decomposition M298and M552. Regression equation of BA-j, M298and M552, within the scope of1.25-20p.g/ml, was separately y=233619x+19454(R2=0.9997, n=6), y=133164x+2026.2(R2=0.9998, n=5) and y=241023x-23460(R2=0.9998, n=5), with good linear relationships; Relative BA-j correction factor of M298and M552was separately1.75and0.97; RSD%was separately2.32%(n=6) and4.32%(n=6), conforming to the rules (<5.0%). LOQ were0.24μg/ml and0.34μg/ml. Selectivity of this method is good, and accuracy, repeatability, durability have reached the requirements of limits determination.Stability factor tests, accelerated tests and long-term stability tests of BA-j were performed. The indicators were in line with standards, which confirm that BA-j is of good stability. By the method of HPLC-UV, BA-j stability test under the clinical condition was conducted. Crude drug of BA-j showed good stability while decomposition precipitation appeared under light in solution, indicating that the product can be used as a powder injection rather than injection storage solution; Within4h after dissolved in sodium chloride and glucose injection diluted stability was good, but decomposition appeared when dissolved in compound sodium chloride injection after4h, indicating that powder injection of BA-j can be diluted with glucose sodium chloride injection for intravenous drip. In artificial gastric juice and intestinal juice within4h showed good stability, indicating that BA-j can be made into oral solid agent. These results provide basis for further pharmaceutical researches.