Controlled hydrolysis of ceftiofur sodium, a broad-spectrum cephalosporin; isolation and identification of hydrolysis products.

Ceftiofur sodium is the salt of (6R,7R)-7-{[(2-amino-4-thiazolyl)-Z-(methoxyimino)acetyl]amino}-3-{[(2-+ ++furanylcarbonyl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid. This compound is very susceptible to acid, alkaline-, and enzyme-catalyzed hydrolysis, producing a number of unstable degradation products. In this report, we describe the preparation and identification of the hydrolysis products that are formed under controlled alkaline conditions. The primary hydrolysis product was desfuroyl ceftiofur, which is the most abundant metabolite in bovine blood. Desfuroyl ceftiofur was carefully oxidized with H2O2 to prepare the disulfide dimer, a urinary metabolite of ceftiofur sodium in the rat and cattle. Under acidic conditions, desfuroyl ceftiofur was converted to the corresponding thiolactone. The preparation of desacetyl cefotaxime, which is the oxygen analog of desfuroyl ceftiofur, is also described. Furoic acid was readily formed by hydrolytic cleavage of the thioester bond. Thiofuroic acid, formed by the less common cleavage on the alkyl side of the thioester bond, was also isolated.

Stability of aqueous solutions of mibolerone.

The kinetics and mechanism of degradation of mibolerone were studied in aqueous buffered solutions in the pH range of 1-8 at 67.5 degrees. Mibolerone showed maximum stability between pH 5.5 and 6.4. At pH 1-2, the major degradative pathway was dehydration followed by migration of the 18-methyl group to form 7alpha,17,17-trimethylgona-4,13-dien-3-one. While there was only one degradation product at pH 1-2, the degradation at pH 7-8 was complex. As many as 12 degradation products were detected by GLC. Mass spectral data indicated that the majority of these products were either oxidation products or isomers. At pH 7.6, the apparent first-order rate constants exhibited marked dependency on buffer concentration. Incorporation of a sequestering agent into the solutions eliminated this dependency, suggesting that trace metal impurities from the buffer reagents were catalyzing the degradation. This was confirmed by degradation studies of solutions in water for injection containing 5 ppm of trace metal ions. Sn+2, Cu"2, and Fe+2 accelerated the degradation, with Fe+2 having the most catalytic effect. The temperature dependence of the rate of degradation was studied in 0.05 M phosphate buffer at pH 6.4. The activation energy was 19.6 +/- 1.63 kcal/mole.

Structure-gas chromatographic electron capture sensitivity relationships of some substituted 17alpha-acetoxyprogesterones.

Structure-electron capture sensitivity relationships were established for underivatized 17alpha-acetoxyprogesterones. While progesterone was very insensitive, 17alpha-acetoxyprogesterone had a response of 4.8 X 10(2) C/mole. Methyl groups in the A or B ring of 17alpha-acetoxyprogesterone had no effect. A keto group at C-6 was 25 times more sensitive (1.2 X 10(4) C/mole). A double bond at C-6,7 enhanced the sensitivity sevenfold (3.5 X 10(3) C/mole), but double bonds at C-1,2 or C-9,11 had only slight effect. Substitution at C-16 was important. A methyl group at C-16 had two and three times the sensitivity in the 3-keto delta4 and 3-keto delta4,6 series (1.1 X 10(3) and 1.1 X 10(4) C/mole), respectively. A methylene group at C-16, in contrast showed a six-and twofold greater sensitivity over the C-16 methyl in the two series (7 X 10(3) and 2.2 X 10(4) C/mole), respectively. The most sensitive compound was 6-dehydro-6methyl-16-methylene-17alpha-acetoxyprogesterone (melengestrol acetate). Its sensitivity was 2.2 X 10(4) C/MOL, Comparable to the most sensitive halo esters of steroid alcohols reported in the literature. Its electron capture coefficient was 3-7.6X 10(10) 1/mole. The coef-icient was independent of the detector temperature, indicating low activation energy for electron absorpiton.