Physicochemical properties of amphoteric .BETA.-lactam antibiotics. III. Stability, solubility, and dissolution behavior of cefatrizine and cefadroxil as a function of pH.

Tsuji, Akira; Nakashima, Emi; Nishide, Kazunori; Deguchi, Yoshiharu; Hamano, Shoichiro; Yamana, Tsukinaka

doi:10.1248/cpb.31.4057

Cited by 13 publications

(6 citation statements)

References 1 publication

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“…Both compounds contain a β-lactam ring fused to another ring, a thiazolidine in penicillins and a dihydrothiazine in cephalosporins . The antibacterial activity of these compounds is, to some degree, related to their chemical reactivity, and there have been many studies on the mechanisms of their reactions. − In aqueous solution, both classes undergo acid- and base-catalyzed hydrolysis. Despite the structural similarity of penicillins and cephalosporins, their pH log−rate profiles show clear differences.…”

Section: Introductionmentioning

confidence: 99%

Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain

et al. 1998

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The rate of degradation of 6-epi-ampicillin in acidic, neutral, and alkaline aqueous solutions was followed at 35°C and an ionic strength of 0.5 mol dm -3 (KCl) by high-performance liquid chromatography (HPLC) and spectrophotometric assays. Pseudo-first-order rate constants were determined in a variety of buffer solutions, and the overall pH-rate profile was obtained by extrapolation to zero buffer concentration. The hydrolysis of 6-epi-ampicillin is subject to acid and hydroxide-ion catalysis and, for a penicillin, an unusual pH-independent reaction. Intramolecular general base-catalyzed hydrolysis by the side chain amido group is proposed to explain the enhanced rate of neutral hydrolysis of 6-epi-ampicillin and cephalosporins. The -lactam of 6-epi-ampicillin also undergoes intramolecular aminolysis by nucleophilic attack of the 6-R side chain amino group to give a stable piperazine-2,5-dione derivative. The low effective molarity for intramolecular aminolysis of only 40 M is partly attributed to the unfavorable trans to cis isomerization about the 6-amide side chain required for ring closure. Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the R-face of the -lactam ring with an activation energy of 14.4 kcal/mol.

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Section: Introductionmentioning

confidence: 99%

Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain

et al. 1998

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“…The most easily understood drug instability is the loss of drug through hydrolysis or any other degradation pathways resulting in a reduction of potency. In cephalosporins, the cyclic amides or b-lactams undergo rapid ring opening due to hydrolysis and there have been many studies on this hydrolytic degradation (Yamana & Tsugi 1976;Tsugi et al 1981Tsugi et al , 1983Fabre et al 1984;Namiki et al 1987;Okamoto et al 1996a, b).…”

mentioning

confidence: 99%

Kinetic measurements of the hydrolytic degradation of cefixime: effect of Captisol complexation and water-soluble polymers

Mallick

Mondal

Sannigrahi

2008

Journal of Pharmacy and Pharmacology

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We have taken kinetic measurements of the hydrolytic degradation of cefixime, and have studied the effect of Captisol complexation and water-soluble polymers on that degradation. The phase solubility of cefixime in Captisol was determined. Kinetic measurements were carried out as a function of pH and temperature. High-performance liquid chromatography (HPLC) was performed to assay all the samples of phase-solubility analysis and kinetic measurements. Chromatographic separation of the degradation products was also performed by HPLC. FT-IR spectroscopy was used to investigate the presence of any interaction between cefixime and Captisol and soluble polymer. The phase-solubility study showed A L -type behaviour. The pH-rate profile of cefixime exhibited a U-shaped profile whilst the degradation of cefixime alone was markedly accelerated with elevated temperature. A strong stabilizing influence of the cefixime-Captisol complexation and hypromellose was observed against aqueous mediated degradation, as compared with povidone and macrogol. The unfavourable effect of povidone and macrogol may have been due to the steric hindrance, which prevented the guest molecule from entering the cyclodextrin cavity, whereas hypromellose did not produce any steric hindrance.

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“…A more pronounced reduction of fetal blood pH could be expected during the abortive process. The CFT ionization constants are reported to range between pK a,1 = 2.62 and pK a,3 = 9.42 [12] . It is expected, that after crossing the placenta, CFT will become more ionized.…”

Section: Discussionmentioning

confidence: 98%

“…Nevertheless, the value of such conclusions is limited by the experimental sampling intervals of the T max estimation. Since CFT behaves as a weak acid and its uptake involves an absorption window in the upper gastrointestinal tract [12,13] , we would expect an increased absorption rate due to pregnancy. Indeed, the reduction in gastric emptying or intestinal transit rate and the increased gastric pH induced during pregnancy is expected to alter the absorption characteristics of drugs like CFT [2] .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Oral Cefatrizine in Pregnant and Non-Pregnant Women with Reference to Fetal Distribution

Papantoniou

Ismailos²,

Karabinas³

et al. 2006

Fetal Diagn Ther

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Objective: To investigate the effect of gestation on the pharmacokinetics of orally administered β-lactams, choosing cefatrizine as the model antibiotic. Setting: A tertiary teaching hospital. Design: Prospective study. Methods: In 20 women with affected fetuses, 17 by β-thalassemia major and 3 with congenital malformations, termination of gestation between 19 and 24 weeks was induced by intra-amniotic administration of prostaglandin F₂_α. Pharmacokinetics of cefatrizine in maternal and fetal blood were studied after the administration of three 1 g doses of oral cefatrizine, every 12 h. Twenty female non-pregnant volunteers consisted the control group. Results: Gestation was found to decrease substantially both cefatrizine oral bioavailability and maximum serum plasma concentration (42.8 and 44.5%, respectively) but increased elimination half-life. This effect can be attributed to a substantial increase of the apparent volume of distribution of cefatrizine in relation to a moderate increase of clearance that occurs during pregnancy. Fetal serum cefatrizine levels were lower for the first few hours after administration and then exceeded the corresponding maternal ones. Conclusions: Our results indicate that gestation decreases the oral bioavailability of cefatrizine. A delay in the maternal drug elimination compared to non-pregnant controls was more pronounced in the fetus.

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Physicochemical properties of amphoteric .BETA.-lactam antibiotics. III. Stability, solubility, and dissolution behavior of cefatrizine and cefadroxil as a function of pH.

Cited by 13 publications

References 1 publication

Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain

Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain

Kinetic measurements of the hydrolytic degradation of cefixime: effect of Captisol complexation and water-soluble polymers

Pharmacokinetics of Oral Cefatrizine in Pregnant and Non-Pregnant Women with Reference to Fetal Distribution

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