| Bicalutamide is a newer non-steroidal anti-androgenic drug developed by AstraZeneca Pharmaceuticals.It is strong specificity,effective oral administration,good tolerance and few adverse reactions.And mainly used in combination therapy for advanced prostate cancer clinically.The company’s Bicalutamide APIs are mainly sold to the Japanese market,and customers require that the ethyl acetate residue in the product is less than or equal to 700ppm.In order to satisfy the needs of customers and at the same time reduce the probability of the company’s own production safety accidents,this dissertation study the risk assessment of Bicalutamide Sulfide Intermediate oxidation reaction and Crystallization Optimization of Bicalutamide API.Bicalutamide sulfide intermediate oxidation reaction risk assessment,based on the "Guidance Opinions on Strengthening the Safety Risk Assessment of Fine Chemical Reactions" issued by the State Emergency Management Department(formerly State Administration of Work Safety)in 2017 Assessment,is determined in five aspects:degree,possibility,risk matrix and process hazard level.The testing equipment mainly includes reaction calorimeter(RCle),differential scanning calorimeter(DSC)and adiabatic calorimeter(Phi-tec).By testing the mixing process of acetone and hydrogen peroxide,the heat and temperature rise of the oxidation reaction under catalyst-containing and catalyst-free conditions.During the mixing process of acetone and hydrogen peroxide,the adiabatic temperature rise is 23.49℃,the unit exotherm is 1.14kJ/kg,the reaction severity level is level 1,and the reaction will form triacetone peroxide(TATP).The target reaction with sodium tungstate as a catalyst,the adiabatic temperature rise is 29.02℃,the unit exotherm is 1.46kJ/kg,the reaction severity level is 1,the process hazard level is 2,that is,Tp(5℃)<MTSR(34.01℃)<TD24(51.2℃)<MTT(55℃).Studies have shown that the exotherm of the oxidation reaction process is dominated by the mixing of acetone and hydrogen peroxide.Under the existing technical conditions,in order to reduce the risk of accidents,a temperature chain control system and a remote control system should be added to prevent loss of control due to dripping or misoperation by personnel causes the temperature of the system to rise sharply,which leads to production safety accidents.The solubility of bicalutamide in methanol,ethanol,ethyl acetate,n-heptane/ethyl acetate(volume ratio 9:1)and n-heptane/ethyl acetate(volume ratio 4:1)is determined using the isothermal method.The solubility increases with increasing temperature,the solubility in ethyl acetate is the largest,and there is no significant increase in methanol and ethanol with temperature changes.Solubility order x ethyl acetate>Xn-heptane/ethyl acetate(volume ratio 4:1)>Xn-heptane/ethyl acetate(volume ratio 9:1)＞X methanol>X ethanol.The van’t Hoff equation was used to obtain the enthalpy of dissolution and the entropy of dissolution of bicalutamide with a mixed solvent system of methanol,ethanol,ethyl acetate,ethyl acetate and n-heptane,and the measured data had a good regression.According to calculations,the enthalpy of dissolution is between 10.93 and 44.32 kJ·mol-1,which is an endothermic process.By investigating the effects of seed crystal,vacuum degree and solution stirring rate on the distribution of bicalutamide product particles and solvent residue,the optimal crystallization scheme was determined.Atmospheric evaporative crystallization,stirring rate is 200 rpm,the amount of seed crystal added is 0.2%.We repeat three times in the laboratory,the results of M.S.values are 74.51 μm,74.12 μm and 74.23 μm;C.V.values are 61.23,60.58 and 61.23;and the solvent residues are 412 ppm,388 ppm and 390 ppm,respectively.After a batch of 50kg pilot production,workshop pilot production 50kg,final product 44.45kg,yield 88.9%,ethyl acetate residue 365ppm,purity 99.3%.The product meets customer quality specification. |
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