Study On Cocrystals Of Two Tinib Anti-cancer Drugs

Good solubility is the prerequisite for the efficacy of oral solid formulations.Currently,40% marketed drugs and 75% of candidate drugs are insoluble drugs,which restricts the oral absorption and therapeutic effect of drugs.Thus,how to improve the solubility of insoluble drugs is a main problem faced by drug researchers.Pharmaceutical cocrystals can improve the physicochemical properties of active pharmaceutical ingredients(APIs)by introducing co-formers(CCFs)to modify the crystal structure of APIs,which is widely used in pharmaceutical field due to its advantages on adjustable structure and desirable properties.In this study,the solubility of insoluble drug axitinib was increased by cocrystal technology,and the solubility of two insoluble drugs was improved by preparing drug-drug multi-component cocrystals of gefitinib and active ingredients of traditional Chinese medicines.The main content is summarized as follows:1.Axitinib is an anticancer drug belonged to the class II of biopharmaceutics classification system(BCS)exhibited low solubility and poor oral bioavailability.To improve the solubility of axitinib,four molecular cocrystals of axitinib with suberic acid,trans-cinnamic acid,p-hydroxy-cinnamic acid and ferulic acid were obtained by liquid-assisted grinding and slurry method.The cocrystals were characterized by a series of solid-stated characterization techniques.The powder dissolution and intrinsic dissolution rate experiments indicate that the apparent solubility and dissolution rate of axitinib-suberic acid(1:1),axitinib-trans-cinnamic acid(1:1),axitinib-phydroxycinnamic acid hydrate(1:1:1)are better than commercial crystal form XLI.Accelerated stability experiments show that these three cocrystals have good physical stability and are worth of further development.2.Meanwhile,Axitinib-fumaric acid salt cocrystal and axitinib-glutaric acid cocrystal were obtained,and they were found to have the pseudo-polymorphic phenomenon,including axitinib-fumaric acid salt cocrystal(2:3),axitinib-fumaric acid ethanol solvate(1:1:1),axitinib glutaric acid cocrystal(1:1),axitinib glutaric acid hydrate(1:1:1).Comprehensive solid-state characterization,Hirshfeld surface analysis,BFDH crystal habit prediction,powder dissolution and accelerated stability experiments were carried out,the results indicate that cocrystals and these pseudopolymorphs are obviously different in intermolecular interactions and dissolution properties.For axitinib-fumaric acid cocrystal system,different stoichiometric ratios are the reason for the better solubility of axitinib-fumaric acid cocrystal than its ethanol solvate.For axitinib-glutaric acid cocrystal system,crystal habit is the reason for the better solubility of axitinib-glutaric acid cocrystal than its hydrate.Phase transformation study indicates that axitinib-fumaric acid ethanol solvate could be transformed to axitinib-fumaric acid II(1:1)at room conditions;axitinib-glutaric acid hydrate could be transformed to axitinib-glutaric acid II(1:1)at 0% RH conditions,axitinib-glutaric acid hydrate and axitinib-glutaric acid II could be transformed to axitinib-glutaric acid I by heating.Considering the solubility and stability,axitinib-fumaric acid salt cocrystal and axitinib-glutaric acid cocrystal I have further development value.3.Gefitinib is the first generation of oral tyrosinase inhibitor for lung cancer treatment,but patients will develop acquired drug resistance after oral administration for 9-12 months,which will reduce the efficacy of gefitinib.It has been reported that resveratrol,rhein and other insoluble active ingredients of traditional Chinese medicines with anticancer activity could be combined with gefitinib to reverse drug resistance and synergistic treatment.In this paper,gefitinib-resveratrol and gefitinibrhein were prepared by liquid-assisted grinding and slurry method,then a comprehensive characterization was carried out by a series of solid-state techniques,The powder dissolution tests show that the formation of cocrystals significantly improved the solubility of resveratrol and rhein,but the solubility of gefitinib was significantly reduced,it is disadvantage to the synergistic antitumor effect.4.Gefitinib-rhein drug-drug cocrystal was selected as a model,in order to simultaneously increase the solubility of gefitinib and rhein,gefitinib-succinic acidrhein multi-component crystals were prepared by liquid-assisted grinding and slurry method with water-soluble succinic acid as a "bridge",a comprehensive characterization was carried out.The results of powder dissolution test show that gefitinib-succinic acid-rhein and its ethanol solvate increased the apparent solubility of gefitinib by 2.3 times and 1.9 times,and increased the apparent solubility of rhein by3.6 times and 4.8 times.It has a good potential in developing the combination of gefitinib and anticancer ingredients of traditional Chinese medicines.This work provides an effective way to simultaneously improve the solubility of two insoluble drugs by introducing a water-soluble co-former,which provides an effective way to better realize their synergistic administration.