| Tazobactam(sodium) following clavulanic acid and sulbactam becomes the new β-lactamase inhibitor in penicillium alkyl sulfone, and it is stronger than sulbactam in inhibitory activity, and better than clavulanic acid in stability. This product is very weak in antibacterial activity when used alone. The first compound preparation consisting of it is piperacillin-tazobactam, already on the market in several countries in the 1990 s. This compound preparation significantly increases the stability of piperacillin for enzyme, and enhances its antibacterial activity and clinical efficacy. In recent years, due to the increase of drug-resistant strains and the occurrence of ESBL(extended-spectrum β-lactamases), the efficacy of third generation cephalosporins is decreased, and that’s why the current research in compounds of third generation cephalosporins and tazobactam is active. Tazobactam sodium is the pharmaceutical form for tazobactam.Suzhou Erye Ltd. used a self-designed synthetic route to get tazobactam in crystalline forms, and tazobactam was conformed by using a series of spectral techniques which inclouding DSC, TG, UV, IR, NMR, MS, XRD.This article focused on systematical quality research for related substances, sodium ion contents, residual solvents, polymers and tazobactam contents, and provided the basis for the scientific development of quality standards.To control the residue of starting materials, intermediates, degradation products, byproducts and other impurities in this product, a measurement for related substances was necessary. The measurement for related substances used octadecyl silane bonded silica as a packed column [Agilent HC-C18(2)], a mixture of 0.03mol/L acetonitrile, 10% potassium dihydrogen phosphate solution and tetrabutyl ammonium hydroxide solution(190:795:15)(adjusted to pH 4.0 by phosphoric acid) as the mobile phase with a flow rate of 1.0ml/min, the column temperature of 30℃, the injection volume of 20μl, and detection wavelength of 230 nm. The measurement conditions can completely separate starting materials, intermediates, and degradation impurities destroyed by light, oxidation, acid, alkali and heat. As a known impurity, the relative correction factor of tazobactam impurity A is 0.75.The salt-forming agent used for this product was sodium bicarbonate. The sodium content was determined by cation exchange column(Waters Spherisorb SCX), using a mixture of 0.05mol/L ammonium acetate(adjusted to pH 4.8 by glacial acetic acid)and methanol(95:5,v/v)as mobile phase with the flow rate of 1.0ml/min,the column temperature of 25℃ and the injection volume of 20μl,and detected by evaporative light scattering detector with the nebulizing temperature of 50℃,the carrier gas(nitrogen)pressure of 25 psi and the power level of 100%. The method has good specificity, can completely separate anions from cations with different valences.This product used ethanol, methylene chloride, ethyl acetate, methyl isobutyl ketone, toluene as the solvent, and methanol from tazobactam degradation impurities.According to the appendix of Chinese Pharmacopoeia 2010(Ⅱ), headspace gas chromatography was used to research the above residual solvent. A mixture of 6% cyanopropyl-phenyl and 94% dimethyl polysiloxane(or similar polarity) was capillary column(Agilent DB-624) for stationary liquid; the starting column temperature was 80℃ for 7min, then up to 120℃ at 10℃/min heating rate and lasted for 4min; inlet temperature was 200℃; detector(FID) temperature was 250℃; head-space vial equilibrium temperature was 70℃ for 30 min. These conditions can completely separate all residual solvents.The high polymers existed in drugs are allergenas for a variety of immediate hypersensitivity. Polymers were measured by sephadex G-10 column with mobile phase A of 0.02mol/L phosphate buffer at pH7.0 [a mixture of 0.02mol/L disodium hydrogen phosphate solution and 0.02mol/L sodium dihydrogen phosphate solution(61:39)] and mobile phase B of water, having 1.0ml/min flow rate, 30℃ column temperature, 20μl injection volume and 220 nm detection wavelength. These conditions can effectively separate polymers from tazobactam.It’s necessary to build a method for determining the content of tazobactam, the active ingredient in tazobactam sodium. The measurement used octadecyl silane bonded silica as a packed column [Agilent HC-C18(2)], a mixture of 0.03mol/L acetonitrile, 10% potassium dihydrogen phosphate solution and tetrabutyl ammonium hydroxide solution(190:795:15)(adjusted to pH 4.0 by phosphoric acid) as the mobile phase with a flow rate of 1.0ml/min, the column temperature of 30℃, the injection volume of 20μl, and detection wavelength of 230 nm. The method has good specificity, simple operation and fast analysis.These qualitative and quantitative methods have good specificity, high sensitivity, good accuracy, repeatability and durability, as well as effective control of product quality, to provide accurate and effective data for follow-up study and the basis for the scientific development of quality standards. |
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