Study On Quality And Stability Of Anastrozole

Objective:Anastrozole is an effective and highly selective third-generation aromatase inhibitor,mainly used in the treatment of postmenopausal women with breast cancer,and is widely used[1-3].The American pharmacopoeia(USP36-NF31toUSP40-NF35)?EP9.2 and the Chinese pharmacopoeia(2015 edition)[4]both received anastrozole API.Since anastrozole is synthetic,different impurities may be produced by different synthetic processes.Therefore,it is necessary to study detailedly on the synthetic processes.The quality for homemade anastrozole API is detailed researched,especially for related substances[5-7],to improve the level of the quality control of anastrozole API.Methods and results:the characteristics of anastrozole were investigated by means of appearance,wet test,solubility test and melting point.The identification of infrared spectra,uv spectral identification,liquid phase retention time and color reaction were investigated.Among them,the liquid phase retention time is specificity and the infrared spectrum proves to be consistent with the functional group in the molecular structure of the product,which is the effective identification method of the API.In this paper,according to the characteristics of the molecular structure of anastrozole and the characteristics of the synthesis process,using chromatography investigates its relevant materials such as raw materials,intermediates,degradation,isomer,polymers and side reaction products.First of all,to anastrozole chromatographic system referred to quality standards in the United States pharmacopoeia,adopts the starting material,intermediate,USP known impurities and degradation products of the chromatographic conditions mentioned with whole wavelength scanning test and chose the 210 nm/215 nm for suitable detection wavelength.Next,investigateing specificity of detection method and specificity results show that the chromatographic system can effective separation and detection of anastrozole API impurity.Finally,according to the above results,the methodology validation parameters including specificity of methods,the LOD and LOQ of solution,stability and the precision of the relevant material is verified,the verification results showed that the detection method in accordance with the measurement requirements.Secondly,the chromatographic system mentioned in the quality standard of the 2015 version of the pharmacopoeia was investigated and the optimization of the chromatographic system was obtained "method 3".According to the results of the optimization,methodology verification parameters including methods,the LOD and LOQ of solution,stability and the precision of the relevant material,the verification results showed that the detection method in accordance with the measurement requirements and impurities.Finally comparing test results of the mature process synthesis of three groups of anastrozole API with the original preparations under the condition of two kinds of chromatographic system,and according to the final tentative "method 3" as chromatographic system for the related substances test of production of anastrozole API homemaded.Later,referred to anastrozole chromatographic system in EP9.2,specificity/LOD/LOQ/stability and the precision of the known impurities is validated.Then,the known impurities in EP9.2 can't be checked out in the production of the three validation batche.Study of comparative test of chromatographic systems of Anastrozole is continue.If in the production of the three validation batches can't be checked out the known impurities mentioned in EP9.2 until it is out ofdate the chromatographic system to test anastrozole API related substances will be confirmed.Because of the use of acetonitrile,dichloromethane,toluene,isopropanol and n-hexane in the synthesis process of this product,the residual volume of the gas chromatographic method was used to check the residual amount.The results of analytical methodology show that the specificity,repeatability,sensitivity,linearity and accuracy of the method meet the determination requirements.On this basis,the residue of organic solvents in three batches of mature process samples were tested.At the same time,according to the synthetic process of this product,will examine such as inorganic impurities on ignition residue,heavy metals and arsenic salts,sulfate,chloride,bromide,cyanide and other checks were studied,respectively.According to the nature of this product with titration method and HPLC method respectively the contrast research method for the determination of anastrozole content,method of analysis is verified,including linear and range,precision,etc.The results proved the feasibility of two methods of content determination of all,although the titration precision high consumption sample amount is large.So choose the HPLC method for content determination method to control the amount of this product.The research about the quality of the anastrozole API provides the experimental data to control product quality and quality standards.Through determination,three batch samples AN091001,AN091101,AN091102 content was 99.95%,99.82%,99.83%.The relevant substances contained in the samples AN091001,AN091101 and AN091102 were mainly impurityI,and the content of the samples was 0.04%,0.10%and 0.01%respectively.Total impurities was 0.04%,0.10%,0.01%.The inorganic impurities of anastrozole are consistent with the regulations.Finally,based on the scientific quality standard,the stability of anastrozole was carried out according to the requirements of the appendix of the pharmacopoeia,including the influencing factor test,accelerated test and long-term stability test.The results showed that the sample of anastrozole was stable under high humidity and high temperature.The results of 6 months of accelerated test and 36 months of long-term stability also indicate that the sample is stable.Conclusion:Through the investigation of the characteristics and identification of anastrozole,the HPLC and IR spectra were confirmed as effective identification methods,and its physicochemical properties were confirmed.According of the researching of anastrozole API inorganic impurities,organic impurities and solvent residual,quality standards known in 2015 edition of "Chinese pharmacopoeia" referred to in the relevant material for chromatographic system optimization "method 3" can effectively control the anastrozole API related material,and on this basis,the content with chromatographic system can effectively control the content of anastrozole API.