Stress-testing (forced degradation) studies have been conducted on pemetrexed disodium heptahydrate (1) (LY231514·2Na·7H2O) drug substance in order to identify its likely degradation products and establish its degradation pathways. Solid samples of the drug substance were stressed under various conditions of heat, humidity, and light, and solutions of the drug substance were stressed under various conditions of heat, light, oxidation, and over a wide pH range (1-13). The stressed samples were analyzed using a gradient elution reversed-phase HPLC method. The 7 major degradation products detected in the stress-testing studies were isolated, and the structures were elucidated via spectroscopic characterization. The structures of the degradation products and their proposed mechanisms of formation indicate that 1 degrades via 2 main pathways: oxidation and hydrolysis. Of the 7 identified degradation products, 6 are proposed to result from oxidation and 1 from hydrolysis.

Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.

A study of the degradation kinetics of gemcitabine hydrochloride (2'-deoxy-2',2'-difluorocytidine) in aqueous solution at pH 3.2 was conducted. The degradation of gemcitabine followed pseudo first-order kinetics, and rate constants were determined at four different temperatures. These rates were used to construct an Arrhenius plot from which degradation rates at lower temperatures were extrapolated and activation energy calculated. Four major degradation products were identified. Only one of these degradation products, the uridine analogue of gemcitabine, was a known degradation product of gemcitabine and was identified by comparison with synthesized material. The other three degradation products were isolated and characterized by spectroscopic techniques. Two of these products were determined to be the diastereomeric 6-hydroxy-5, 6-dihydro-2'-deoxy-2',2'-difluorouridines, and the other product was determined to be O(6),5'-cyclo-5,6-dihydro-2'-deoxy-2', 2'-difluorouridine. The mechanisms of formation of these degradation products are discussed.

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.

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.

The metabolism and disposition of LY231514 was studied in mice and dogs. LY231514 is a novel pyrrotopyrimidine-based multi-target antifolate (MTA) showing broad in vivo antitumor activity in mouse models and is currently in phase II human clinical trials. Doses (iv) of the compound showed high plasma levels, resulting in AUC values of 30-33 micrograms-hr/ml for mice and dogs after 20 and 7.5 mg/kg doses, respectively. The compound was eliminated rapidly. Half-life values for mice and dogs were about 7 and 2 hr, respectively. In vitro plasma binding measured 56% in mice, 46% in dogs, and 81% in humans. Fecal elimination was the major excretion pathway in mice after single iv doses of [14C]LY231514. Urine constituted the major route of excretion in dogs. Parent LY231514 accounted for the majority of urinary radiocarbon in mice (90%) and dogs (68%). Minor metabolites were found in urine, but the amounts were too small to isolate or identify. Based on an earlier observation that LY231514 photodegraded to produce reaction products having similar retention times as these minor urinary isolates, a photo-oxidation system was developed which in fact produced these metabolites. Subsequently, these photolytically-produced materials were used as standards to identify two novel in vivo metabolites formed by oxidation of the pyrrolo-pyrimidine ring system of LY231514. The oxidative transformations are similar to those observed for tryptophan and other indoles in that the pyrrole ring is oxidized to give an amide; further oxidation cleaves this ring, one ring carbon is lost, and a ketone is formed.

Recently an unknown degradation product of loracarbef (structure 1) was observed at low levels (--0.1%) in samples of the bulk drug substance that had been stored at 30°C for 36 months. Identification of this unknown was desired because of the potential for this unknown to form in the product during the shelf-life of the drug [1]. Isolation of such a minor impurity from limited quantities of sample is difficult and, therefore, more severe conditions were evaluated for generating higher levels of this degradation product. LC analysis with photodiode array detection indicated that this degradation product was present at higher levels in a sample of loracarbef stressed at 85°C for 8.5 months. Therefore, the degradation product (structure 4) and two other closely eluting degradation products (structures 5 and 6) were isolated concurrently from the 85°C stressed sample by preparative LC. Visualization of all three of these products under long wavelength UV indicated that they were fluorescent. MS and NMR spectroscopic characterization of these three products indicated the structures (structures 4-6) were derivatives of the highly fluorescent 2-hydroxy3-phenylpyrazine (structure 3). It is well established that [3-1actam antibiotics containing the phenyl glycine side chain will degrade under certain conditions to 2-hydroxy3-phenyl pyrazine (structure 3) [2-4]. Degradation studies of cefaclor (structure 2) [5] and other phenyl glycine-containing 13-1actams [4, 6] led to a proposed pathway for the formation of this pyrazine derivative (Scheme 1). The pathway to these 2-hydroxy-3-phenyl pyrazine derivatives involves hydrolysis of carbon-6 to reveal the masked aldehyde, and subsequent cyclization and aromatization leading to the pyrazine structure. In the case of the loracarbef, the sulphur at position 5 is replaced with a methylene, effectively blocking the possibility of hydrolysis leading to an aldehyde at position 6. Thus it was predicted that carbacepahlosporins such as loracarbef would not degrade to 2-hydroxy-3phenyl pyrazine derivatives. In agreement with this prediction, no pyrazine derivatives were detected in a previous study of the aqueous degradation of loracarbef [7]. The discovery that substituted pyrazines were formed during solid-state degradation of Ioracarbef indicates the existence of a novel degradation pathway to pyrazines, distinct from the established cephalosporin degradation pathway. This report describes the isolation, characterization and proposed mechanism of formation for

C-13 CP/MAS NMR and X-ray crystallography are used to characterize the structures of novel methylene Meldrum's acid precursors. Correlations are made between specific structural elements found in the X-ray crystal structure of I and its solid-state NMR spectrum. The complementary use of solid-state NMR is demonstrated as the structures of related analogs, II-IV, for which X-ray structures are not available, are characterized using these correlations.

Dirithromycin, a semisynthetic macrolide antibiotic, crystallizes in two anhydrous polymorphic forms, an amorphous form and at least nine stoichiometric solvate forms. Six of the known solvates are isomorphic, having nearly identical X-ray powder diffraction (XRPD) patterns. Differences are observed in the CP/MAS C-13 solid-state NMR spectra, which show resonances associated with the incorporated solvent molecules. Variable-temperature CP/MAS C-13 solid-state NMR spectra of the isomorphic solvates relate N,N-dimethylamine peak coalescence temperatures with steric hindrance of included solvent molecules. The crystal structure of the thermodynamically stable anhydrous polymorphic form, a 1-propanol solvate, and a cyclohexane trisolvate form are reported and compared to that of the previously reported acetonitrile trihydrate crystal form. The crystal packing, hydrogen-bonding networks, and molecular conformations are related to the spectroscopic properties of the various crystal forms and an amorphous form. The FTIR lactone carbonyl stretching frequency and the C-13 solid-state NMR chemical shift of the lactone carbon resonance are related to the presence or absence of hydrogen bonding to this group. This study shows the usefulness of these combined spectroscopic techniques for the study of solids with structures that have not been determined. Furthermore, the study demonstrates the wide range of crystallographic forms in which macrolide antibiotics exist.

The oral route is most preferred for chronic drug therapy. Poor oral bioavailability has the consequences of more variable and poorly controlled plasma concentrations and drug effects, in addition to possibly increased product cost. In this review, the most common causes of low oral bioavailability are categorized, and formulation strategies to improve bioavailability are summarized. Various methods that can be used to help identify the cause of low bioavailability are discussed. The focus of this article is on poor membrane permeation and presystemic degradation problems; solubility/dissolution rate problems are discussed only briefly. Poor membrane permeation and presystemic degradation problems are typically encountered in the efforts to develop oral proteins, peptides, and peptide mimics. Formulation strategies reviewed include the use of metabolism inhibitors, membrane permeation enhancers, ion pairing and complexation, and particulate carriers. Also reviewed are lipid and surfactant formulations, which have been shown to increase bioavailability by various mechanisms and which are only beginning to be understood and optimized.

□ The aqueous degradation of the carbacephalosporin loracarbef under moderately acidic conditions (pH range, 2.7 – 4.3) is described. Structures of a total of 10 compounds isolated by preparative reversed-phase HPLC have been proposed. Five of these 10 degradation compounds arose from hydrolysis of the /3-lactam ring followed by structural changes in the six-membered heterocyclic ring. Four compounds form from intermolecular reactions of loracarbef to form dimeric structures with peptide linkages. The remaining compound resulted from oxidation of the primary amine to a hydroxylamine. Pathways for the formation of these compounds from the parent loracarbef are proposed.

The acidic aqueous degradation of cefaclor, an orally administered cephalosporin antibiotic, has been investigated. The most prominent peak in the high-performance liquid chromatography profile of a degraded solution of cefaclor was isolated by preparative high-performance liquid chromatography. Mechanistically, the formation of this degradent from cefaclor involves a condensation of two cefaclor degradation products in which both products have undergone contraction from a six-membered cephem ring to a five-membered thiazole ring, presumably via a common episulfonium ion intermediate.

Zatosetron is being tested clinically as an antianxiety agent; it is a highly selective antagonist of the serotonin 5-HT3 receptor, with minimal agonist activity. The disposition of [14C]zatosetron was studied in five healthy men after a single oral dose (46.2 mg). Serum levels of radioactivity and parent drug peaked in 3-8 hr. About 15% more radioactivity was measured in red blood cells than in plasma. In serum, the parent compound represented about 85% of the radioactivity, zatosetron-N-oxide represented 10%, and N-desmethyl-zatosetron and 3-hydroxy-zatosetron each represented 2-3%. The t1/2 of zatosetron was 25-37 hr. About 75% of zatosetron added to human plasma became reversibly bound to protein. Concentrations of zatosetron in saliva were generally 10-50% higher than those in serum. About 80% of the administered radioactivity was eliminated in urine and 20% in feces; radioactivity was measurable in the excreta for 10-12 days after drug administration. The major route of metabolism of zatosetron was a stereoselective N-oxidation to form 8-alpha-methyl, 8-beta-oxo zatosetron (zatosetron N-oxide). In urine, approximately 45% of the radioactivity was unchanged zatosetron, 35% was zatosetron N-oxide, 10% was N-desmethyl-zatosetron, and 5% was 3-hydroxy-zatosetron. In feces, 30% of the radioactivity was unchanged zatosetron, and 70% was N-desmethyl-zatosetron. Overall, approximately 60% of the administered zatosetron was metabolized in humans. In a separate multiple-dose study, the disposition of zatosetron was found to be similar to that in the single-dose study.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure of antibiotic A41030AAnn H. Hunt, Douglas E. Dorman, Manuel Debono, and R. Michael MolloyCite this: J. Org. Chem. 1985, 50, 12, 2031–2035Publication Date (Print):June 1, 1985Publication History Published online1 May 2002Published inissue 1 June 1985https://pubs.acs.org/doi/10.1021/jo00212a005https://doi.org/10.1021/jo00212a005research-articleACS PublicationsRequest reuse permissionsArticle Views97Altmetric-Citations10LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

The structure of the novel nucleoside antibiotic A201A has been determined by a combination of chemical and spectroscopic methods. It is composed of 6-dimethylaminopurine, 3-amino-3-deoxyribose, p-hydroxy-alpha-methylcinnamic acid, a novel unsaturated hexofuranose and 3,4-di-O-methylrhamnose. Structures have also been assigned to several related minor factors simultaneously isolated from the fermentation broth. These unique nucleosides have very interesting similarities and differences in structure with the known antibiotics puromycin and hygromycin A.

AbstractPure pencillin N α‐sulfoxide (1) and penicillin N β‐sulfoxide (2) were obtained by HPLC and tested as substrates for deacetoxycephalosporin C synthetase (DXCS). Neither one of the sulfoxides was utilized under conditions of conversion of penicillin N (8) to deacetoxycephalosporin C (9). The cephalosporin C α and β‐sulfoxides (3 and 4, resp.) were also prepared. Relative stabilities of the sulfoxides 3 and 4 are discussed by interpretation of the 13C‐NMR spectra.

The physicochemical characterization and proof of structure are reported for several new macrolide antibiotics related to tylosin which have been obtained by fermentation of mutant strains of Streptomyces fradiae.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and identification of a polar sulfamethazine metabolite from swine tissueDeborah D. Giera, Riaz F. Abdulla, John L. Occolowitz, Douglas E. Dorman, James L. Mertz, and Robert F. SieckCite this: J. Agric. Food Chem. 1982, 30, 2, 260–263Publication Date (Print):March 1, 1982Publication History Published online1 May 2002Published inissue 1 March 1982https://pubs.acs.org/doi/10.1021/jf00110a011https://doi.org/10.1021/jf00110a011research-articleACS PublicationsRequest reuse permissionsArticle Views81Altmetric-Citations21LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts