Study On Co-crystallization Of Gefitinib And Rhein

Co crystallization of two drugs with synergistic effects can simultaneously improve the physicochemical properties of both drugs,in order to better achieve the therapeutic effect of combined medication.Controlling the conditions of co crystallization can increase the probability of generating co crystalline polymorphs,thus providing more options for the development of compound formulations.Gefitinib（GTB）is an oral targeted anti-tumor small molecule drug for the treatment of non-small cell lung cancer.Its poor water solubility leads to low bioavailability,which limits its clinical therapeutic efficacy.Rhein（RH）is an anthraquinone active anti-tumor component extracted from rhubarb,but it also has poor water solubility and cannot be absorbed by the gastrointestinal tract.Research has shown that when combined with RH,GTB can synergistically promote cell apoptosis,inhibit cell proliferation,reverse cell resistance,and enhance anti-tumor efficacy.This article attempts to co crystallize GTB and RH to improve their water solubility,promote the oral absorption and clinical efficacy of the compound formulation.By means of suspension,this work was able to successfully create five co-crystallization that contained GTB and RH,GTB-RH·MeOH,GTB-RH·0.5MeCN,GTB-RH·4.25H₂O,GTB-RH Ⅰ and GTB-RH Ⅱ;Partially dehydrate GTB-RH·4.25H₂O to obtain GTB-RH·1.25H₂O,and heat GTB-RH Ⅱ to obtain GTB-RH Ⅲ.Then,XRD,¹H NMR,TG,DSC,FT-IR,SEM,etc.were used to characterize these solvates,hydrates,and polycrystalline forms,the crystal structure of GTB-RH·4.25H₂O confirmed the proton transfer between GTB and RH,which formed salt rather than cocrystal,while three of the crystal water were channel water,which was removed and transformed into GTB-RH·1.25H₂O under heating or drying conditions.Finally,a systematic investigation was conducted on the stability,solubility,compressibility,and phase transition relationships under various conditions of GTB-RH·4.25H₂O,GTB-RH·1.25H₂O,GTB-RH Ⅰ,GTB-RH Ⅱ,and GTB-RH Ⅲ.Accelerated stability tests show that GTB-RH·1.25H₂O and GTB-RH Ⅰ converted to GTB-RH·4.25H₂O while GTB-RH·4.25H₂O,GTB-RH Ⅱ and GTB-RHⅢremained intact within three months.The powder dissolution experiment showed that the apparent solubility of GTB and RH was in the order of GTB-RHⅢ>GTB-RH Ⅱ>GTB-RH Ⅰ>GTB-RH·1.25H₂O>GTB-RH·4.25H₂O,and the solubility of GTB and RH in GTB-RHⅢwas significantly improved.The compressibility test showed that the order of maximum tensile strength was GTB-RH·1.25H₂O>GTB-RH·4.25H₂O>GTB-RHⅢ>GTB-RH Ⅱ>GTB-RH Ⅰ.The maximum tensile strength was greater than 2 MPa except for GTB-RH Ⅰ,which can be used for direct compression.The phase transition relationships of various crystal forms show that GTB-RH Ⅰ and GTB-RH Ⅱ are monotropically related while GTB-RH Ⅱ and GTB-RHⅢare enantiotropically related;GTB-RH·4.25H₂O is dried at 0%RH to remove three channels of water and convert to GTB-RH·1.25H₂O.GTB-RH·1.25H₂O undergoes hygroscopic transformation into GTB-RH·4.25H₂O at 90%RH;In aqueous solution,all crystal forms are converted to GTB-RH·4.25H₂O,and in acetone,ethyl acetate,all crystal forms are converted to GTB-RH Ⅱ.In summary,GTB-RHⅢimproves the solubility of GTB and RH at the same time,and exhibits good stability and tablet compression,to provide a research foundation for achieving better anti-tumor effects.