Quality Study Of Letrozole API And Analysis Of Organic Impurities

Letrozole is a third-generation non-steroidal aromatase inhibitor and is the first-line drug in the clinical treatment of patients with advanced breast cancer.As the production process of letrozole continues to improve,the types of impurities and their production mechanisms change,requiring targeted analysis,control and monitoring according to the concept of quality by design to ensure stable and controllable quality of letrozole bulk drug.In domestic and international pharmacopoeias,the quality analysis of letrozole bulk drug is only for individual impurities and there are too few indicator components.This research starts from the analysis of organic impurity spectrum of letrozole bulk drug,establishes the process impurity and principal component analysis methods,and studies the polycrystalline form of letrozole bulk drug,which has practical application value and significance to the quality control and quality standard research of letrozole batch production.Specifically,the following four areas are covered:1.The organic impurity profiles were analyzed in conjunction with the synthesis process of letrozole bulk drug.Starting from the classification of the main impurity sources of letrozole bulk drug,the potential impurities that may appear in the final product,such as intermediates,by-products,degradation products and reaction materials,were analyzed,and the mechanisms of each type of impurities were deduced.2.A high performance liquid chromatographic（HPLC）method was developed for the analysis of various organic impurities in letrozole bulk drug,and the method was validated by methodological validation.The method was performed on an ODS-BP C₁₈（4.6 mm×150 mm,5μm）column with the mobile phase of acetonitrile-water,the detection wavelength of 230 nm/200nm,the column temperature of 25℃and the flow rate of 1.0 m L/min for gradient elution.The results of the method validation showed that the method was sensitive and linear,and the nine organic impurities and the main components could be effectively separated from each other,which was suitable for the qualitative and quantitative determination of the organic impurities in letrozole API.3.An HPLC method was developed for the determination of letrozole bulk drug and the method specificity,linearity,limit of quantification,limit of detection,solution stability and precision were systematically investigated.The reversed-phase HPLC analysis was carried out on an ODS-BP C₁₈（4.6 mm×150 mm,5μm）column with a mobile phase of acetonitrile:water（4:6）,UV detection at 230 nm,a column temperature of 25℃,a flow rate of 1.0 m L/min and an isocratic elution for 16 min.The results of the method validation showed that the good linearity（r=0.9994）over the concentration range of 5.55-22.20μg/m L for letrozole.The method has good accuracy and durability and is suitable for the rapid determination of letrozole bulk drug content.4.Crystallographic preparation and crystallographic studies were carried out on letrozole bulk drug.The crystals were prepared by recrystallization of letrozole using five different solvents and characterized by infrared spectroscopy,X-ray powder diffraction and differential scanning calorimetry analysis,and the crystalline sample C was preliminarily confirmed to have the characteristics of a novel crystalline diffraction peak.The paper has 61 figures,34 tables,and 114 references.