| Imatinib is one of 2-anilino pyrimidine derivation. As a targeting therapeutic agent of leukemia, it can occupy the ATP binding site for Bcr-Abl tyrosine kinase(BTK) in SH1 area, thus competitively inhibit the binding of ATP and its substrates to the catalytic center of the tyrosine kinase to block the phosphoslation of BTK and its substrates, thus cut down the abnormal signal pathway. Therefore, the antitumor effect is exhibited. The special mechanism enable the drug can be targeting to the malignant cells but show no or very little affect to normal cells. This drug has exhibited specificity, high efficacy and low toxicity since its clinical application.Carrying on the quality control of the drug is the basis and prerequisite to ensure safety and efficacy of drugs. For effective control, drug quality control should be multiple perspectives and multiple levels. This study established the quality standard of imatinib mesylate and its tablets,meanwhile conducted the validation studies to the analysical methods. It has vital significance to ensure the stability and safety of the product.The main study consists of the following 2 parts: Part I the study on quality standard of imatinib mesylateObjective: To provide basis for the establishment of quality standards for imatinib mesylate by studies on character, identification, examination and assay.Methods:Characteristics: the appearance, polymorphic forms, solubility, hygroscopicity, melting point, particle size et al were determined.Identification: The chemical method, infrared spectrophotometric method and high performance liquid chromatographic(HPLC) method were used in identification of the drug.Examination: The p H, chloride, water, residue on ignition, heavy metals et al were detected according to Appendix of Chinese Pharmacopoeia Volume II, 2010 Edition; The HPLC method, LC-MS and GC-HS-MS method were used in determination of related substance, raw materials N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyridine(T4) and by products methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate, the content of mesylate was investigated by Ion Chromatography method; the residues of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, N, N- dimethylformamide(DMF) and other organic solvent used in process were detected.Assay: The content was determined by HPLC method.Results:Characteristics : Imatinib mesylate was a white to light yellow crystalline powder, odorless, tasteless, and almost no hygroscopicity; it was soluble in water, slightly soluble in methanol and ethanol, almost insoluble ethyl acetate and acetone; the melting point of 218-222 °C.Identification: The test substance showed a positive result in mesylate identifying reaction. The Infrared absorption spectrum for the test substance was consistent with that of the reference substance; the peak retention time for test solution was consistent with that of the reference substance under the item of Assay.Examination: p H value for test solution(10 mg/m L in water) should be 5.0-6.0; the chloride in test substance should be no more than 0.01%, water should be no more than 0.5%; Ignition residue: Ignite at 500-600 °C, the residue should be less than 0.1%; Heavy metal: the residue under the item of Ignition Residue is used in heavy metal determination. The result should be less than 10 ppm; Related substance: was consistent with Assay and is determined by HPLC Gradient elution, the resolution between each impurity peak and main peak and the purity of main peak conform to requirement, demonstrating that the method is of good specificity and high sensitivity; The LC-MS method and GC-HS-MS method, which are both of high sensitivity and accuracy, were used in the determination of raw material T4 and by products methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate, respectively. The test result conform to the requirement; Residual solvent: the residuals of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide(DMF) were complied with the requirement.Assay: The content was determined by HPLC gradient elution method. The purity of main peak conform to requirement, demonstrating that the method was of good specificity. The test solution showed good linearity in range of 0.06-2.16 mg/m L and was of good stability, which is stable in 18 h under room temperature. The contents of imatinib mesylate were all at 98.0%-102.0% when calculated at the anhydrous base.Conclusion: Through the comprehensive studies on the methodology for the characteristics, identification, examination and assay of Imatinib mesylate, the analytical methods with good accuracy and sensitivity were established, thus provide references for the establishment of quality standards. Part II the study on quality standard of imatinib mesylate tabletsObjective: The study is to provide basis for the establishment of quality standards by studies on character, identification, examination and assay of imatinib mesylate tablets.Methods:Characteristics: The characteristics were determined visually.Identification: Chemical methods and HPLC identification were used.Examination: Weight variation and microbial limit for the drug product were tested according to the Appendix for General guidance for tablets of Chinese Pharmacopoeia Volume II, 2010 Edition; the related substances were determined by HPLC method; in dissolution experiment, the 0.1 mol/L HCl(1000 m L) was used as the dissolution medium, the rotate speed was set at 50 r/min. At 15 min, solution was taken out to determine by ultraviolet-visible(UV-Vis) spectroscopy, the detecting wavelength is 268 nm.Assay: The same to imatinib mesylate and determined by HPLC.Results:Characteristics: Imatinib mesylate tablet was dark yellow to brown-yellow film-coated, double convex tablets, and was white to light yellow after removal of the coat.Identification: The test product showed a positive result in mesylate identifying reaction. The retention time of the main peak for test solution is consistent with that of the reference substance under the item of Assay.Examination: The weight variation and microbial limit for the drug product were all met the requirement according to the pharmacopeia method. Dissolution was determined by UV spectrophotometer, and the corresponding wavelength was 268 nm. The expicients showed no interference to the determination. Imatinib mesylate showed good linearity in range of 2.0-12.0 mg/m L. The average recovery rate in the range 80%-120% of was 99.3% and the corresponding RSD was 0.5%. The analysical methods for related substances and assay were constent with those for the imatinib mesylate. Expicients showed no interference to the determination and the methods were of High impurity detection capability and high specificity.The test solution showed good linearity in range of 0.06-2.16 mg/m L. The linear Equation was y=31752x+665.3 and the correlation coefficient was 0.9995. The average recovery rate in the range of 80%-120% was 99.8% and the corresponding RSD was 0.6%. The imatinib mesylate contents of 3 batches of the test product were 95.0%-105.0% of the labeled amount.Conclusion: Through the comprehensive studies on the methodology for the characteristics, identification, examination and assay of Imatinib mesylate tablets, the analytical methods with good accuracy and sensitivity were established, thus provide references for the establishment of quality standards. |
PDF Full Text Request