Radiosensitivity study of cefazolin sodium.

The extent of physico-chemical changes induced by irradiation of cefazolin sodium was investigated. The methods used were potency determination, impurity profile, colour measurements and pH measurements. The potency of irradiated samples at 25 kGy was 4+/-2% lower than that of the non irradiated ones. The total amount of related substances increased from 0.72+/-0.01% in the non irradiated samples to 4.9+/-0.7% in the samples irradiated at 25 kGy. Most of the peaks showed trace amounts (<0.01%), the largest one represented 1.2+/-0.5% of the total related substances. Only two peaks were identified by chromatography: the methyl-1,2,3-thiazol-2 thiol-5 and the 7-aminocephalosporanic acid. The latter related substance is only produced by the irradiation of cefazolin sodium. The pH values of the samples were within the specifications of the European Pharmacopoeia. The colour of the cefazolin sodium powder changed from white to yellow upon irradiation. The yellow colour persisted after the dissolution of the powder. Most of the tests carried out met the Pharmacopoeia's specifications, except the one concerning the colour of the solution.

Method to identify products induced by radiosterilization. A study of cefotaxime sodium.

Before the use of radiations to sterilize cefotaxime sodium powder, four new products radioinduced must be identified and qualified. They have an apparent level of or above 0.1%, at the sterilization dose of 25 kGy and are potentially toxic. Their identification is difficult because these products are formed at very low concentrations and generally have a structure similar as that of the main compound. The method proposed is to irradiate the drug in aqueous solution in order to increase the yields in radiolysis products, to compare the retention time of the new products, measured by high performance liquid chromatography, with those obtained after the irradiation of the solid drug and to identify from the aqueous solution the products which are common. One common product was found after the irradiation of cefotaxime in solid state and in aqueous solution. It was easily identified from the irradiated aqueous solution as anticefotaxime. This new product induced by the radiosterilization treatment, is not toxic but less active.

Attack of cefotaxime by different radicals: comparison of the effects.

Free radicals are physiological products and can react to administrated drugs. Metabolic transformations by radical mechanisms are, therefore, possible. A fundamental study of radio-induced degradation of aqueous solutions of sodium cefotaxime, a third generation cephalosporin, was realized to describe these possible radical mechanisms. Different radicals produced by the radiolysis method (.OH, N3., Br2.-, Tbut., eaq- + .OH, and exq- + Tbut.) were successively used to induce the radical mechanisms and their effects were compared. All these radicals induce the formation of a same main radiolysis product identified as anticefotaxime. Radical mechanisms induced by N3., Tbut., and eaq- include chain reactions to explain the formation of anticefotaxime contrary to those induced by .OH and Br2.-.

Radical mechanisms of cephalosporins: a pulse radiolysis study.

Radiosterilization induces radicals, and it is very important to describe radical mechanisms before the possible use of cephalosporins gamma sterilization. Moreover, physiological or radiotherapeutically induced free radicals also initiate radical mechanisms. For this study, pulse radiolysis was used. This method permits to avoid in vivo direct study difficulties of bioradical processes and gives quantitative data. Reactions of solvated electron (eaq-), hydroxyl radical (.OH), azide radical (N3.), dibromine radical anions (Br2.-), oxygen, and superoxide radical (O2.-) with three cephalosporins have been studied. Absorption spectra and rate constants have been determined. It has been found that both eaq- and .OH quickly react (k congruent to 10(10) mol-1 L s-1) with the molecules to give radicals with similar absorption spectra. N3. gives an absorption spectra that has been attributed to an electron transfer, whereas a part of .OH and Br2.- could add themselves to an unsaturated bond.

Electron spin resonance study of radiosterilization of antibiotics: ceftazidime.

Fundamental information on radiosterilization of ceftazidime was obtained by electron spin resonance (ESR) measurement of free radicals produced in gamma-ray-irradiated ceftazidime at 4.2-295 K. Three types of free radicals are produced by gamma-irradiation. The first one shows septet lines in an ESR spectrum and decays at 230 K: it is assigned as a .C(CH3)2COOH radical. The second one shows triplet lines and decays at 293 K: it is assigned as iminoxyl radicals (> C = N-O.). The third one shows a broad singlet line and survives even at 295 K. The plausible assignment of this spectrum is discussed. It is concluded that an O-C bond of the gamma-irradiated ceftazidime is ruptured, producing the iminoxyl radicals and .C(CH3)2COOH radicals. The yields of free radicals increase linearly with the increasing dose of gamma-irradiation up to 10 kGy at 295 K as well as 77 K. Half of the radicals that show a broad singlet line survive at 295 K upon storage of the irradiated ceftazidime for 159 days. It is concluded that the ESR measurement of free radicals gives a good method for discrimination of irradiated antibiotics from non-irradiated ones and an estimation of an irradiation dose.