Synthesis And Preparation Research Of Picoplatin,A Platinum-based Antitumor Drug

Cancer is a serious threat to hunman health and life,chemotherapy plays an important role in the struggle history with it.Since the discovery of cisplatin,the research of platinum-based antitumor drugs has bacame the hot spot of the research of antitumor drugs.Picoplatin with wide anticancer spectrum has no or a little cross resistance with cisplatin,and its side effects are mainly hematology toxicity and there are not nephrotoxicity and neurotoxicity.It is undergoing a variety of phase?/?clinical trials currently.However,the clinical application of it is restricted by the low solubility and unstability in water.In this paper,firstly,synthesis of picoplatin was conducted.Secondly,a new HPLC analytical method for an easy and rapid determination of it was developed.Then,the aquation of picoplatin and its stability in acid,alkaline,oxidative and reductive conditions were investigated through the HPLC method.Finally,a kind of stable picoplatin injection with high concentration which is convenient for the preclinical studies and clinical use was prepared by the selection of suitable solvent and the optimization of formula.The main contents and conclusions are as follows:1.K[Pt?NH₃?Cl₃] was prepared by refluxing cisplatin and HCl with Pt metal catalyst,and the percent conversion of cisplatin was 74.4%.Synthesis of picoplatin starting from K[Pt?NH₃?Cl₃],the crude product yield was 89.7% and recovery rate of recrystallization was 73.2%.Characterization of product by EA,UV,IR,1H-NMR and MS.And its structure was consistent with the theoretical construct.2.Developing a HPLC analytical method for the determination of picoplatin and its injection,which is rapid,sensitive and specific.The content of picoplatin?API?is more than 99%.3.The aquation of picoplatin followed the law of the first-order reaction,and the Arrhenius equationis is lgk=-4210.1/T+12.836.The activation energy was 80.6 kJ/mol and the half-life period was 22.5 h at 293.15 K.The hydration reaction could be inhibited by Cl-.Picoplation is unstable in alkaline and oxidative conditions,also could be devastated when the pH value is too low,and the most stable pH value is between 3 and 5.4.Acquired a picoplatin injection formulation through orthogonal test,A:B?v:v?=4:1,A is PEG400,B is 0.9% NaCl/HCl solution,in which picoplatin has higher solubility.Finally,two formulations of 5 mg/ml and 10 mg/ml were developed.The injection should be cryogenically preserved and keep out light because of its thermo-optical instability.