Study On Crystal Form Of Pinaverium Bromide API

In this study,we investigated the polymorphic phenomenon of pinaverium bromide,an antagonist for the intestinal tract,as an API.Firstly,we screened the poly crystalline forms of pinaverium bromide,characterized and analyzed the properties of the obtained new polycrystalline forms,and investigated the physical properties and stability of the polycrystalline forms;secondly,we cultured a single crystal of pinaverium bromide dihydrate,analyzed the crystal structure by single crystal X-ray diffractometer,and obtained the crystal structure data of the single crystal;finally,we prepared pinaverium bromide tablets and compared the solubility of pinaverium bromide.The dissolution degree and dissolution rate of different crystalline forms of pinaverium bromide at pH 6.8 were compared,and the effects of different crystalline forms on the dissolution properties of pinaverium bromide were investigated as follows:(1)The forms of pinaverium bromide were screened by setting different experimental conditions,and finally four forms of pinaverium bromide were obtained by the solvent-mediated multi-crystalline transformation experimental method.Subsequently,the new forms of pinaverium bromide were characterized by X-ray powder diffractometry;they were characterized by scanning electron microscopy,Fourier infrared spectroscopy,differential scanning calorimetry and thermogravimetric analyzer.The stability properties were determined under hygrothermal conditions,pressure conditions and grinding conditions.It was shown that the four forms of pinaverium bromide had different X-ray characteristic peaks,among which form Ⅰ,form Ⅱ and form Ⅲ were crystal-free,while form Ⅳ was a dihydrate solvent compound;the stability experiments showed that both form Ⅰ and form Ⅳ had good stability performance.(2)Single crystals of pinaverium bromide dihydrate were successfully prepared by slow volatilization experiments,and the obtained single crystals were characterized by X-ray single crystal diffractometer and their crystal structures were obtained;the thermodynamic properties of the single crystals were compared with those of poly crystalline powder samples;the obtained single crystal structures were analyzed by Hirshfeld surface analysis and the effect of the interaction between different elements on Hirshfeld surface analysis was performed on the obtained single crystal structures and the effect of the interaction between different elements on the molecular stacking was determined.The results show that pinaverium bromide dihydrate is a trigonal crystal system with space group P(?),cell parameters a=7.3128(4)?,b=13.5547(7)?,c=15.4049(8)?,a=81.568(2)°,p=82.425(2)°,γ=85.881(2)°,V=1495.14(14)?3,Z=2.The results of Hirshfeld surface analysis indicate that H…H interaction is the main force in the crystal stacking of pinaverium bromide dihydrate,accounting for 69.7%of the total interaction force.(3)As an intestinal drug,it is necessary to simulate the dissolution properties of the drug in the stomach and intestine,so the dissolution properties of the new forms of pinaverium bromide were determined in buffers of pH 1.2 and pH 6.8.Tablets of different forms of pinaverium bromide were prepared,tested by UV spectrophotometer and the dissolution curves of pinaverium bromide tablets were plotted.The dissolution curves of the four forms were obtained at more than 50%at 5 min,and the highest dissolution was achieved at 30 min,with 90.96%and 94.31%for form Ⅰ and Ⅳ,respectively,and 85.52%and 88.65%for form Ⅱ and Ⅲ at 30 min,and then leveled off.The equilibrium solubility of form Ⅳ was the lowest at pH 1.2 with only 1.47 mg/mL and the highest at pH 6.8 with 13.83 mg/mL.Compared with the traditional form Ⅰ,form Ⅳ has less loss under strong acid conditions and better solubility performance under neutral conditions,and is more suitable for enteral administration.This study identified several new forms of pinaverium bromide,which enriched the polycrystalline products of pinaverium bromide;meanwhile,the physicochemical and dissolution properties of each form were investigated,and the dihydrate form,which is more suitable for gastrointestinal use,was screened,and the results of this study are of great significance for the development of new active pharmaceutical ingredients of pinaverium bromide.