Preparation And Characterization Of Gefitinib-Bumetanide Pharmaceutical Cocrystal

Gefitinib,also known as Iressa,is a highly specific targeted antitumor therapy developed by Astra Zeneca.Gefitinib is the first molecular-targeted drug for the treatment of non-small cell lung cancer(NSCLC)in locally advanced or metastatic NSCLC with prior chemotherapy.Although gefitinib has been proved to have a good therapeutic effect in the clinical treatment of NSCLC,it also has some limitations and disadvantages.Clinical studies have shown that some patients also cause a variety of toxic and side effects during the use of gefitinib.Gefitinib has the characteristics of low solubility,which limits its bioavailability.Pharmaceutical cocrystal can improve the physicochemical properties of drug APIs,including solubility and dissolution rate,without changing the covalent structure of drugs,which is important for improving the medicinal value of gefitinib.Based on the principle of supramolecular chemistry and crystal engineering,the cocrystal of gefitinib was prepared with bumetanide as the cocrystal conformer and ethanol as the solvent system.The differences between different proportions of gefitinib and bumetanide in the preparation of cocrystal samples by solution method were investigated to optimize the crystallization conditions and prepare single crystal samples of gefitinib-bumetanide cocrystal.X-ray powder diffraction,X-ray single crystal diffraction,Fourier transform infrared spectroscopy,thermogravimetric analysis,Differential scanning calorimetry,etc.,were used to characterize and analyze the structure and physical and chemical properties of the gefitinibbumetanide cocrystal.The results of X-ray single crystal diffraction show that gefitinib and bumetanide pharmaceutical molecule form cocrystal by intermolecular hydrogen interactions,gefitinib and bumetanide and water molecule interaction with each other mainly by N-H???O,O-H???O,OH???N hydrogen interactions,so that the two components can be separated from the ethanol solvent form stable gefitinib-bumetanide cocrystal.The stability experimental results show that the cocrystal has good stability under the conditions of 40? and 75% relative humidity.The solubility of gefitinib and bumetanide in the cocrystal was 258?g/ml and 16?g/ml,respectively.The solubility and dissolution rate results of the cocrystal show that the solubility and dissolution rate of gefitinib were slightly higher than that of the cocrystal,while the solubility and dissolution rate of bumetanide were slightly lower than that of the cocrystal.The results of this study would provide reference for the research and application of gefitinib and bumetanide pharmaceutical cocrystal.