Study On Ploymorphism Of Telmisartan And Its Crystallization And Properties

Telmisartan is a drug treatment of hypertension emerged in 90’s last century. It has at least 3 polymorphs.Different polymorphic form has different physicochemical properties(such as melting point, solubility, stability), which would affect drug effect and efficiency. So the study of polymorphs not only is theoretical significance, but also is of practical value.In this work, the telmisartan was solected as model compound and was studied as follows.Developing a new crystallization process, technology and researching of the polymorphs are cannot do without thermodynamics stability data(such as solubility, dissolution heat, enthalpy of solution). In this paper, Using a laser monitoring technique,the solubilities of telmisartan(form A)in nine pure solvents were determined by the synthetic methord from 277.85 K to 338.35 K.Results were correlated by ?h and Apelblat equation and ?h epuation shows a better fit than Apelblat equation.To the mixed solvent, Results were correlated by CNBIS/Redlich-Kiser and Apelblat equation and CNBIS/Redlich-Kiser epuation shows a better fit than Apelblat equation.The metastable zone we determined by dilution crystallization.With the increase of trichlormethane mole fraction,the metastable zone width is increase. The effects of operation conditions such as agitation speed and adition rate of dilute agent, on the metastable zone width were examined. The results were stable after the first insersce. The enthalpy and entropy of dissolution were calculated in pure and mixed solutions. The results show that the dissolution enthalpy are all above zone,that means their solution is an endothermic process. The dissolution entropy is low zone when trichlormethane mole fraction is more than 0.32. It means telmisartan form A is easier crystal on the above condition. This can also provide basis for the selection of conditions of telmisartan form A crystallization process.The effects of operation conditions such as agitation speed,initial solution concentration, aging time, seed adition and rate of dilute agent, on the yield and particle size distribution were examined by dilution crystallization. The optimal conditions are: initial solution concentration was 0.033g/g, adding seeds 1% in metastable zone, Accelerated flow the dilute agent, agitation speed was 300 r/min,and aging time was 24 h.It provides experimental date for the production pharmaceuticals.The effects of operation conditions such as evaporation rate and agitation speed,on the particle size distribution were examined by evaporation crystallization. The products of the particle size distribution obtained in the above conditions are chaotic.So,the products of dilution crystallization is better than evaporation crystallization in particle size distribution.The thermal kinetics of telmisartan form C were investigated using DSC and TD-DTA.The modle-fitting and modle-free methods were used to analysis the thermal kinetics, the activation energy, per-exponentisl factor, kinetic mechanism function and thermodynamic parameters were calculated in dehydration and removal of acid stage. The activation energy and per-exponentisl factor were calculated by DSC date during the change of telmisartan from form B to form A stage.Using a laser monitoring technique,the solubilities of telmisartan(form A)in formic acid(11%-66% mass fraction)solvents were determined by the synthetic methord from 277.15 K to 347.15 K.You can get telmisartan form C by recrystallization The effect of milling time on crystal form A and C was studied.The results show that you can get amorphous of telmisartan after form A milling 120 min and form C milling 30 min.You can get telmisartan form A after form C milling 30 min,165 drying 12 h in ℃ Vacuum drying box. Three polymorphs of telmisartan were Characterized by PXRD、SEM and DSC.