Study On Crystal Form Of The Hypoglycemic Drug Empagliflozin

Drug molecules are going to get more and more complicated with the development of chemical drug preparation technique.Drug polymorphism has an increasing influence on physicochemical property of drug.Therefore the polymorphism research is strongly emphasized in the field of international drug R&D and management.Empagliflozin,chemical name:(2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxym ethy)oxane-3,4,5-triol,is a kind of SGLT2 inhibitors and useful in the treatment of Type2 diabetes,molecular formula:C23H27ClO7,molecular weight:450.89.According to the patent investigation results,it is known that there are six crystal forms that have been disclosed by far,one of which is a pseudo-polymorph type—empagliflozin hydrate.In this paper,the polymorphism of empagliflozin was studied.Firstly,a new preparation technology of the empagliflozin amorphous was explored,and its physicochemical properties and hydrothermal stability under normal conditions were studied.Secondly,a new crystalline single crystal of empagliflozin was discovered,the crystal structure was analyzed by single crystal X-ray diffractometer to obtain crystal structure information.Finally,the dissolution and dissolution rate of empagliflozin A crystal form and amorphous tablets were tested and compared,it is seen that the key factor that affecting the dissolution and dissolution rate of empagliflozin rests on the grain size.The contents are as follows:The amorphous of empagliflozin was prepared by rotary evaporation technology.The method reduces the cost and process difficulty,and is better than the patented method.Stability of the drug under different temperature and humidity conditions show that amorphous empagliflozin has better stability under low temperature and low humidity conditions,It slowly crystallizes to crystal form A at higher temperatures and humidity.HPLC testing found that saturation concentration in water of the amorphous is 0.043 mg/mL,which was significantly higher than the forms A is 0.022 mg/mL.A new single crystal form(Crystal form ?)of empagliflozin was prepared by high pressure nucleation and low temperature crystallization technology.The single crystal diffraction data of the crystal form ? was obtained by single crystal X-ray diffraction test as follows:a=5.64850(10)A,b=9.2361(2)(?),c=39.6396(9)(?)?=90°,?=90°,?=90°,V=2068.00(7)A3.The space group is P 21 21 21,the number of independent area in the unit cell is Z=4,and the total number of diffraction points in the unit cell F(000)=952.The single crystal has poor mechanical force stability.It was found that the single crystal be going to undergo crystal form transformation after grind at different time,the X-ray diffraction pattern is as same as the form A,which means a transformation to form A.It was found that the dissolution and dissolution rate of the crystal form A were larger than those of the amorphous by comparing the dissolution profiles of the two crystal forms.After analysis,the particle size of the drug is the main influence factor about its dissolution rate.In a word,the preparation process of empagliflozin amorphous was optimized and a new crystalline single crystal were cultivated and its crystal structure was resolved.In addition,the particle size was found to be a major factor for the dissolution rate of each crystal form of empagliflozin.