Research On Screening Of Co-amorphous Form Telmisartan And Solubility Properties

In recent years,the field of pharmaceutical has been of interest to a growing number of scientific researchers,partly because the field of pharmaceutical is more closely linked to our daily lives,but the main reason is that researchers have found that the phenomenon of polymorphism and cocrystal is widespread,and we know more and more on phamaceutical polymorphism and phamaceutical cocrystal.The different polymorph or cocrystal of the drug can lead to significant differences in the physicochemical properties of the drug,particularly in terms of solubility,stability,bioavailability,tableting,etc.The phenomena of polymorph and cocrystal in drugs have become the key factors in the areas of drug research,synthesis,production and clinical application.Generally,most of the drugs are poorly water-soluble,a directly resulting in extremely bioavailability,which requires us to change the crystalline form of the drug or synthesis the cocrystals of the drug in order to improve the properties of the drug fundamentally.In this paper,we study the antihypertensive drug,telmisartan.(i)we used the solution evaporation method,the slurry method and the liquid-assisted grinding method to obtain the cocrystals of telmisartan.The products were characterized by Powder X-Ray Diffraction,Differential Scanning Calorimetry and Infrared Spectroscopy.The formation of cocrystal was explained from the point of intermolecular interaction.(ii)The stability,hygroscopic stability of the co-amorphous form of telmisartan prepared by the liquid-assisted grinding was tested and the solubility test was carried out.The difference between the co-amorphous form of Telmisartan and the pure telmisartan was investigated.The main research work is as follows:(1)The six co-amorphous forms of telmisartan and pimelic acid,adipic acid and glutric acid were obtained for the first time using liquid-assited grinding.Powder X-Ray Diffraction,Differential Scanning Calorimetry and Infrared Spectroscopy were used to characterize the six co-amorphous forms of telmisartan.We believe that the carboxy group in the molecule structure of telmisartan is connected with the carboxyl groups of the three co-formers by hydrogen bonding.In addition,the transition process of crystalline telmisartan and co-formers turning into co-amorphous forms was characterized.From the results,it can be seen that the characteristic peaks of telmisartan and co-formers in the samples decrease gradually with the time laspe of the grinding with the characteristic peaks of C=O broadening and shifting.It suggests that the initial mixture of telmisartan and co-formers transform to co-amorphous forms during the process of liquid-assited grinding.(2)The stability of six co-amorphous forms of telmisartan was measured.We measured the stability of the co-amorphous forms of telmisartan with a constant temperature and humidity condition(65℃,60%R.H.)and then under normal conditions(25 ℃,20%R.H.).It is shown that the recrystallization of the co-amorphous occurred within two days under accelerated conditions,and no crystalline transformation was observed within 35 days under normal conditions(25 ℃,0-90%R.H.).It suggests that the six co-amorphous forms of telmisartan are more sensitive to the temperature than that to the relative humidity.(3)The solubility of six co-amorphous forms of telmisartan were measured.We used high performance liquid chromatography(HPLC)to get the solubility of six co-amorphous forms of telmisartan at pH 2.0 condition which simulated gastric juice in vitro.The results show that the six co-amorphous forms of telmisartan could reached their maximum solubility within 10 to 20 minutes,respectively.The maximum solubility of the co-amorphous forms of telmisartan were 9～19 times larger than that of crystalline telmisartan.When tthe six co-amorphous forms of telmisartan reached their maximum solubility,the solubility decreased slowly with time.This phenomenon occurs in many cocrystals of drugs and is called "spring and parachute effect".In the process of the solubility measurement,it was observed that the co-amorphous forms of telmisartan were dissolved in the solvent and then slowly precipitated.We believe that the amorphous forms are relatively unstable.Then the recrystallization of the co-amorphous forms leads to the decreased concentration of telmisartan,resulting in the precipitation of telmisartan.