Study on the Organic Impurities of Ceftriaxone Sodium
|School||Shenyang Pharmaceutical University|
|Keywords||Impurity Ceftriaxone Sodium Margin of safety Degradation products|
The purpose of this study is to establish a set of international registration requirements impurities qualitative and quantitative methods, the foundation for the the ceftriaxone sodium products in the European registration and exports. The same time, the the impurity analysis method can improve production conditions, control product quality, improve the safety of the drug in patients, to provide a basis. The object of this study is ceftriaxone sodium in the organic impurities, including process impurities (containing unreacted synthesis completely the reactants and reagents, intermediates, and byproducts, etc.), degradation products and other impurities from the reactants and reagents mixed, The qualitative and quantitative analysis of these impurities. Ceftriaxone sodium for the third-generation cephalosporins, with strong activity against Enterobacteriaceae. The presence of impurities will affect the purity of the drug itself although no therapeutic effect, but will produce adverse reactions, and damage the health of the human body. The drug most likely to produce the impurities in the process of synthesis, purification and storage and potential impurities, and a rational, scientific assessment. 1. Apparent actually exist in the drug substance is greater than or equal to 0.05% of impurities (maximum daily dose of more than 2 g): The starting material (impurity C) a triazine ring, with the intermediate 7-ACT (impurity E) , a quantitative and qualitative analysis. (1) First, the prepared samples of impurities MS, NMR and IR structure confirmation impurity C, included in its structure and European Pharmacopoeia under consistent impurity E; (2) with the method of the European Pharmacopoeia method (HPLC) to confirm triazine ring with 7-ACT of its purity. Chromatographic conditions: octadecyl-bonded silica gel (ODS) column (150mm x 4.6mm, 5μm); mobile phase was a 4-heptyl and the four decyl bromide, ammonium ion of the solution - 0.067 mol / L phosphate buffer the liquid-pH5.0 citrate buffer - acetonitrile (440:55:5:500, V / V) solution; flow 1.5mL/min; detection wavelength was 254 nm. The results showed that the triazine ring with 7-ACT purity of 99.72% and 98.61%, respectively, suitable as an impurity reference product use content area normalization method. And measuring their degree of separation with ceftriaxone main peak were 15.7 and 9.2, in line with the requirements of the separation must be greater than 2.0; draw their relative retention time of the main peak with ceftriaxone were 0.59 and 0.81. (3)) with an impurity reference goods relative retention time to confirm the peak position of the triazine ring contained in the product and 7-ACT comparison method, based on the peak area values ??to determine the content of the impurities triazine ring with 7-ACT more than 0.05% of impurities, thereby completing the qualitative and quantitative analysis. 2. According to ICH (drug registration technology requirements of the recommendations of the International Conference on Harmonization), ceftriaxone sodium potential impurities: isomer, 7-ACA starting material and reaction byproducts deacetylase cefotaxime lactone (impurity B ), a qualitative and quantitative analysis. (1) isomers (impurity A) is purchased by the United States Pharmacopoeia standards, the International Registration institutions ICH recognized its structure, without qualitative and purity test, can be directly used as the reference product use; still uses the impurities with ceftriaxone separation test The result of the European Pharmacopoeia HPLC method, calculated as follows: the degree of separation with ceftriaxone 15.7, the relative retention time of 1.36. (2) internally of 7-ACA reference substance and desacetyl cefotaxime lactone (impurity B structure, according to the production process of the ceftriaxone sodium synthetic) recognized the same using the MS, NMR and IR methods, and its structure was identified, and 7 impurities B consistent under-ACA standards and European Pharmacopoeia listed. (3) with a the Chinese pharmacopoeia method (HPLC) method to confirm the purity of 7-ACA desacetyl cefotaxime lactone (impurity B). Chromatographic conditions: column octadecylsilane bonded silica (ODS) as a filler (150mm × 4.6mm, 5μm); mobile phase was 0.02mol / L octylamine solution acetonitrile (73:27, v / v) solution, and the pH was adjusted to 6.5 with phosphoric acid; flow rate of 1.5mL/min; detection wavelength is 254 nm. Area normalization method, results showed that the 7-ACA and the deacetylase cefotaxime lactone purity were 99.2% and 90.8%, suitable as an impurity reference product use; separation with ceftriaxone main peak was 13.1 and 38, respectively meet the requirements of the degree of separation; with ceftriaxone main peak of the relative retention time of 0.51 and 0.44, respectively. (4) the relative retention times of the reference standard with an impurity than the method, to confirm the isomers contained in the product ,7-ACA and deacetylation yl cefotaxime lactone peak position them in the product is determined according to the peak area content. 3. This study by establishing qualitative and quantitative methods set to meet international requirements for registration impurities, more than 0.05% of the impurity in the European Pharmacopoeia Ceftriaxone listed under 5 specific impurities (A, B, C, D, E), Qualitative and quantitative analysis; and other impurities that may exist in the qualitative and quantitative analysis of the results showed that the batch of product impurities contained within safe limits (specific impurity is not greater than 1.0%, not more than 0.05% of other impurities).