Study Of The Cyclodextrin On The Clathration,Solubilization And Antitumor Activity

Objective Prepare the polymorphism of regorafenib and explore the crystal structure.Three cyclodextrin(β-cyclodextrin,γ-cyclodextrin and Hydroxypropyl-β-cyclodextrin)inclusions were prepared.The aim is to improve the solubility and the dissolution rate of poorly soluble drug regorafenib by cyclodextrin inclusion technolygy.Method and Result①The preparition of regorafenib two crystalline forms.Recrystallzation method was employed and optimized the condition of solvent,concentration,temperature,the stirring rate,the cooling rate during the process of production.The preparation method of form I was in the acetone solution when the ratio between the material and solvent ranged from 1(g):60(ml)～1(g):100(ml).The temperature to dissolve the bulk drug was to be 50～60℃ and the temperature to crystallize out was observed to be 20～30℃.The preparation method of monohydrate was in the methanol and water solution mixture when the ratio between the material and solvent ranged from 1(g):60(ml)～1(g):100(ml).The temperature to dissolve the bulk drug and the temperature to crystallize was as the above form I.②The characterization of regorafenib polymorphism.A series of characterization which consist of X-ray powder diffraction,single crystal X-ray diffraction,thermal analysis were carried out to distinguish the two crystalline forms.The two crystalline forms were proved by X-ray diffraction and consistent with the patent reports.The single X-ray diffraction indicated that the regorafenib form I and monohydrate were solved as orthorhombic system P21/c space group.Form I has the unit cell parameters:a=7.6972(4)(?),b=24.3703(12)(?),c=11.3580(7)(?),V=2126.5(2)(?),Z=4.While monohydrate form has the unit cell parameters:a=4.7783(2)(?),b=21.9538(9)(?),c=20.5581(8)(?),V=2154.78(15)(?),Z=4.③The preparation of cyclodextrin inclusion with regorafenib:coprecipitation method were employed and optimized the condition of solvent,concentration,the stirring rate,the cooling rate prepared regorafenib-β-cyclodextrin inclusion,the best process was regorafenib and β-cyclodextrin 1:1 in the 70%alcohol solution 40～100(ml).The temperature to dissolve the bulk drug was to be 70℃ and the temperature to precipitation was observed to be in room temperature.And regorafenib-γ-cyclodextrin inclusion,the best process was regorafenib andγ-cyclodextrin 1:1 in the 80%alcohol solution 40-100(ml).The temperature to dissolve the bulk drug was to be 60℃ and the temperature to precipitation was observed to be in room temperature.The regorafenib-Hydroxypropyl-β-cyclodextrin was prepared with solvent evaporation method,the best process was regorafenib and Hydroxypropyl-β-cyclodextrin 1:1 in the absolute alcohol solution 20-60(ml).Then make the solvent evaporation.④The characterization of three cyclodextrin inclusions:three cyclodextrin inclusions were characterized by X-ray powder diffraction,thermal analysis,Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy.They are indicated the formation of inclusion compound.It is distinguished with physical mixture.⑤The dissolution and drug efficacy of three cyclodextrin inclusions and re gorafenib.The ability of solubility and dissolution were measured in water,pH 1.2 acid solution and pH6.8 phosphate buffer solution.The regorafenib-β-cyclod extrin inclusion is proved to have the best stability while the regorafenib-Hydro xypropyl-β-cyclodextrin inclusionthen.The less enhanced was regorafenib-γ-cyclodextrin inclusion.The best dissolution of regorafenib-β-cyclodextrin inclusion c-omplex was to bring as the tumor suppression assay,the result shows that reg orafenib inclusion with β-cyclodextrin is better than regorafenib itself.Conclusion When the anti-cancer drug regorafenib inclusion with cyclodextrin will significantly improve the solubility,dissolution rate and the bioavailability.