Aqueous Acidic Degradation of the Carbacephalosporin Loracarbef

Skibic, Michael J.; Taylor, Kmg; Occolowitz, John L.; Collins, Monte W.; Paschal, Jonathan W.; Lorenz, Leslie J.; Spangle, Larry A.; Dorman, Douglas E.; Baertschi, Steven W.

doi:10.1002/jps.2600821002

Cited by 126 publications

(13 citation statements)

References 16 publications

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“…Degradation pathways can now be compared with that of loracarbef, the 1-carba analog of cefaclor. 26,27 Evaluation of these aqueous and solid-state degradation pathways reveals the prominent role of the sulfur atom in the degradation of cefaclor.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

Baertschi

Dorman

Occolowitz

et al. 1997

Journal of Pharmaceutical Sciences

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The aqueous acidic degradation of the oral cephalosporin cefaclor was investigated. A number of degradation products were isolated and characterized. The degradation products can be loosely classified into three categories: thiazole derivatives, pyrazine derivatives, and simple hydrolysis or rearrangement products. Degradation pathways are proposed that involve (1) hydrolysis of the beta-lactam carbonyl with subsequent rearrangement, (2) ring contraction of the six-membered cephem nucleus to five-membered thiazole derivatives through an episulfonium ion intermediate, and (3) attack of the primary amine of the phenylglycyl side chain on the "masked aldehyde" at carbon-6 to form fluorescent substituted pyrazines.

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Section: Discussionmentioning

confidence: 99%

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

Baertschi

Dorman

Occolowitz

et al. 1997

Journal of Pharmaceutical Sciences

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“…This role becomes even more apparent when the degradation of cefaclor is compared with the degradation of the 1-carba analog of cefaclor, loracarbef. 13 The tremendous disparity between the degradation pathways and stability of these two closely related analogs is remarkable. It is hoped that an understanding of the chemistry of the degradation pathways of cefaclor will lead to new insights in understanding the chemical reactivity of other cephalosporin antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor in the Solid State

Dorman

Lorenz

Occolowitz

et al. 1997

Journal of Pharmaceutical Sciences

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Cefaclor is a beta-lactam antibiotic that degrades slowly under normal storage conditions to several minor products. To obtain samples large enough to permit structure elucidation, cefaclor was allowed to degrade at 40 degrees C (75% relative humidity) and at 85 degrees C. The profile of degradation products formed under these conditions is qualitatively similar to the profile of degradation products observed in samples of cefaclor aged for 14 years at room temperature, although some products found in the sample degraded at 85 degrees C are not formed at the lower temperatures. Using preparative reversed-phase high-performance liquid chromatography (rp-HPLC) and a combination of spectroscopic methods, we have isolated and characterized 17 of these degradation products. Some of these products were also isolated from studies of aqueous degradations. The major products appear to have arisen from five distinct pathways: (1) isomerization of the double bond in the dihydrothiazine ring; (2) decarboxylation; (3) ring contraction of the cephem nucleus to thiazole structures; (4) oxidative attack at carbon 4 of the dihydrothiazine ring; and (5) intramolecular attack of the primary amine of the side chain on either the beta-lactam carbonyl to form 3-phenyl-2,5-diketopiperazines or the "masked aldehyde" at carbon 6 to form 2-hydroxy-3-phenylpyrazine derivatives. The pathway involving oxidation at carbon 4 is particularly important at ambient temperatures and is unique to the solid-state degradation.

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“…Hydrolysis induced ring-opening is one of the main degradation pathways for antibiotics containing a b-lactam moiety (Skibic et al, 1993). LC-MS analysis of such ring-opened degradates of antibiotics is often quite difficult.…”

Section: Hydrolysismentioning

confidence: 99%

“…few years. Dimers as bulk drug impurities (Mistry et al, 1997) and as degradates (Burinsky et al, 1996;Skibic et al, 1993) in pre-formulation studies have been characterized by on-line LC-MS techniques. For some drugs, dimerization has become one of the major concerns of formulation stability.…”

Section: Dimerizationmentioning

confidence: 99%

The use of liquid chromatography-mass spectrometry for the identification of drug degradation products in pharmaceutical formulations

2000

Biomed. Chromatogr.

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Recent applications of LC-MS in the analysis of drug degradation products in pharmaceutical formulations are reviewed. Drug degradation products are categorized according to their formation mechanism: oxidation, hydrolysis, dimerization and adduct formation with excipients and packaging materials. The oxidative ring opening and dimerization of an indole derivative are discussed in detail. The examples used in this review clearly demonstrate that LC-MS is a very powerful technique for the analysis of low-level degradates in formulations without the time-consuming isolation process. At the same time, limitations and precaution of using LC-MS techniques for unknown identification are also addressed. In some cases, the LC-MS data could become misleading if the ionization process and gas-phase behavior of the analytes are not well understood.

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Aqueous Acidic Degradation of the Carbacephalosporin Loracarbef

Cited by 126 publications

References 16 publications

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor in the Solid State

The use of liquid chromatography-mass spectrometry for the identification of drug degradation products in pharmaceutical formulations

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