Quantification And Crystal Transformation Kinetics Of Gefitinib Metastable Polymorphs

Objective: Gefitinib is an essential drug for the treatment of non-small cell lung cancer. The crystal form of Gefitinib in original patented drug is stable polymorph, which has lower solubility. Beijing research institute of Yabao pharmaceutical group has succeeded in preparing a new metastable polymorph(form7) of gefitinib. In this paper, we first characterize the nature of this two polymorphs of gefitinib, then we establish a quantitative method for gefitinib polymorphs of form 1 and 7. After that, we research the influencing factors of the transformation of form 7 and the transformation kinetic equation of form 7. The aim of this paper is to make this polymorph of gefitinib to be a stable pharmaceutical raw material with higher solubility.Methods: 1. Used fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder x-ray diffraction to characterize the nature of the crystal form 1 and 7 of Gefitinib. And detecting the solubility of form 1 and form 7 at the same conditions. The most suitable analytical technology was choosed to establish the quantitative method for gefitinib polymorphs of form 1 and 7. 2. The effect of temperature, humidity, light and time on the transformation of form 7 were examined. After selected influence factor, investigated the influence of factors at different conditions on the transformation of the form 7. We fitted the transformation kinetic equation of form 7 based on the aforementioned data, and analyzed if polymorph of form 7 could be stable exist under ordinary conditions.Results: 1.The gefitinib polymorphs of form 1 and 7 showed different morphology when observed under the scanning electron microscope. Analyzed different spectrums of gefitinib polymorphs of form 1 and 7 captured by different analytical technologies, we found the powder X-ray diffractograms of form 1 and form 7 showed obviously different and it is suitable for quantitative determination of mixtures of gefitinib polymorphs. The equilibrium solubility of gefitinib form 7 and form 1 was 0.326mg/ml and 0.249mg/ml. Form 7 in the mass fraction of 6%-100% range showed excellent linear relationship. 2. The experiment of influencing factors showed that temperature is the key factor affecting the transformation of form 7. According to the rate of form 7 transformed for different times and at different temperatures, we fitted kinetic equations for the most common mechanism of solid-state reactions. The result showed that the most suitable transformation kinetic equation of form 7 is [1-(1-α)1/3]2 = kt.Conclusion: 1.The equilibrium solubility of form 7 was higher than the equilibrium solubility of form 1. Powder X-ray diffraction technique is feasible for the quantitative analysis of mixtures of gefitinib polymorphs. 2. According to the different transformation kinetic equations of form 7 at different temperatures, we knew that gefitinib form 7 can be stable at normal atmospheric temperature. It is certain possibility that gefitinib form 7 with higher solubility instead of gefitinib form 1 in drug as raw material.