Claus Cornett | University of Copenhagen (original) (raw)

Papers by Claus Cornett

Journal of Pharmaceutical and Biomedical Analysis, Feb 1, 2004

2-Acetyl-2-decarboxamido-oxytetracycline (ADOTC) is a major impurity of oxytetracycline (OTC) pro... more 2-Acetyl-2-decarboxamido-oxytetracycline (ADOTC) is a major impurity of oxytetracycline (OTC) produced as a side product during fermentation. ADOTC was isolated from OTC and other impurities using preparative HPLC. The preparative column was an Xterra MS, C 18 chromatographic column (100 mm × 19 mm i.d., 5 m), and the mobile phase contained methanol-water (27:73 (v/v)) with 0.08 M formic acid added. The flow rate was 9.0 ml/min. It was possible to isolate few milligram ADOTC in a day. The compound was unambiguously identified using NMR and MS-MS. The anti-microbial activity against activated sludge bacteria was determined giving a potency of only 3% of that of OTC. With tetracycline-resistant bacteria, no anti-microbial activity was observed, indicating a mode of action similar to that of OTC.

Electrophoresis, Aug 1, 2009

A dual CD-CE method for chiral separation of enantiomers of pioglitazone, rosiglitazone and balag... more A dual CD-CE method for chiral separation of enantiomers of pioglitazone, rosiglitazone and balaglitazone was investigated for the purpose of optimizing the chiral separation. In a previous work a dual CD chiral CE method was used for investigation of glitazone compounds in drug substance and pharmaceutical formulation and the studies showed that all studied glitazones were racemic mixtures. This CE method could separate the enantiomers with a resolution (R S) of about 3. However, another study on single glitazone enantiomers pointed out that a higher R S is needed to achieve more accurate results for separation of a small amount of one enantiomer in the presence of a high amount of the other enantiomers. The focus of this investigation was thus directed toward the effect of CDs and the pH of the running buffer to achieve a better enantioseparation. Initially CE systems with each of heptakis(2,6-di-O-methyl)-b-CD (DM-b-CD) and heptakis (6-sulfobutylether)-b-CD (SB-b-CD) as single CD added were investigated at three different pH values (2.5, 5.0 and 9.3). After having chosen the best of these three pH values a dual CD system was further investigated and optimized. The optimization work was then focused on the concentration of the two CDs and the pH of the running buffer and was performed using factorial design experiments. A mixture of a DM-b-CD and SB-b-CD was found to be optimal and necessary to achieve enantioseparation with sufficiently high R S. In order to further verify the importance of the SB-b-CD, a CE system with the DM-b-CD added and substitution or partial substitution of the SB-b-CD by SDS was studied for comparison. 1 H-NMR studies were performed to get a more detailed understanding of the interactions between the glitazones and the CDs used.The optimized dual CD-CE method for chiral separation of the enantiomers of pioglitazone, rosiglitazone and balaglitazone using a running buffer containing 50 mM borate buffer pH 9.7, 12 mM of SB-b-CD and 3 mM of DM-b-CD provided a high R S (R S between 5.5 and 8.8).

Journal of Pharmaceutical and Biomedical Analysis, Nov 1, 2010

Reactions between active drug substances and excipients are of interest in the drug formulation p... more Reactions between active drug substances and excipients are of interest in the drug formulation process and should also be considered in the following storage of final preparations. Some excipients react more readily with certain chemical groups in drug substances and in the present paper the ester formation between a drug substance having a carboxylic acid moiety and some polyols are described. The drug substance cetirizine was chosen as the model substance as it is already marketed and used as a common drug for treatment of allergic reactions. Among the marketed products are oral solutions and oral drops containing excipients like sorbitol and glycerol. It was found that the carboxylic acid cetirizine readily reacts with sorbitol and glycerol to form monoesters. At a temperature as low as 40 degrees C, more than 1% of the cetirizine content was transformed into a monoester within 1 week using concentrations similar to those used in marketed preparations. The kinetic studies of the reaction performed at 40, 60 and 80 degrees C also revealed that the esters were unstable and they degraded especially at higher temperatures. Analysis of two marketed preparations having expiry dates in 2011 showed content of the cetirizine esters corresponding to a range from 0.1 to 0.3% of the declared cetirizine content.

Xenobiotica, 1996

1. Metronidazole is metabolized by rat liver in vitro models to form a hydroxy metabolite, an ace... more 1. Metronidazole is metabolized by rat liver in vitro models to form a hydroxy metabolite, an acetic acid metabolite, a glucuronic acid conjugate, and a sulphate conjugate. 2. Four different in vitro systems for investigation of drug metabolism based on liver preparations from the male Wistar rat have been investigated. 3. An incubation system where liver slices are incubated in 12-well culture plates was evaluated with respect to metabolism of metronidazole. Optimal viability was observed for a time period of up to 24 h. The Michaelis-Menten parameters for the metabolism of metronidazole in liver slices were calculated and the intrinsic clearance values compared with the values determined in hepatocytes incubated in suspension. It was found that the intrinsic clearance with respect to formation of oxidative metabolites, the hydroxy metabolite, and the acetic acid metabolite correlated, whereas the intrinsic clearance with respect to formation of the glucuronic acid conjugate was lower in slices compared with hepatocytes. 4. The metabolism of metronidazole in liver slices, in hepatocytes in primary monolayer culture, in hepatocytes incubated in suspension, and in liver microsomes was compared. All the incubations were performed under identical incubation conditions including the same incubation medium. The trend observed was that the initial metabolic rates of the production of the hydroxy metabolite, the glucuronic acid metabolite, and the acetic acid metabolite of metronidazole were higher in microsomes than in the other liver preparations. The metabolic rates in hepatocytes in primary culture and in suspension with respect to the oxidative metabolites were higher than in liver slices. The metabolic turnover observed in liver slices was predicted to correlate with in vivo data earlier obtained for rat.

Journal of Clinical Medicine, Dec 30, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Planta Medica, Aug 1, 1988

Two novel cyclopentenoid cyanohydrin glycosides, (1 S,4 R)-and (1 R,4 S)-1-[6- O-(alpha- L-rhamno... more Two novel cyclopentenoid cyanohydrin glycosides, (1 S,4 R)-and (1 R,4 S)-1-[6- O-(alpha- L-rhamnopyranosyl)-beta- D-glucopyranosyloxy]-4-hydroxy-2-cyclopentene-1-carbonitrile, were isolated from seeds of the Indian medicinal plant HYDNOCARPUS PENTANDRA (F. Ham.) Oken (Flacourtiaceae) and characterized by optical rotations as well as (1)H-and (13)C-NMR spectra. The structural assignment is founded on these data and on degradation with alpha- L-rhamnosidase to the corresponding beta- D-glucopyranosides, epivolkenin and taraktophyllin, also present in the seeds in small amounts. Earlier reports of cyclopentenoid rhamnoglucosides from Passifloraceae are rejected.

European Journal of Pharmaceutics and Biopharmaceutics, Oct 1, 2012

The aim of the present study was to combine vibrational spectroscopy and chemometrics for investi... more The aim of the present study was to combine vibrational spectroscopy and chemometrics for investigating excipient-induced disproportionation of the calcium salt of atorvastatin into the corresponding free acid form in environments relevant to manufacturing and storage of solid dosage formulations. Of the excipients investigated, citric acid and polyacrylic acid were found to induce disproportionation. Moreover, it was also observed that exposure to high relative humidity, elevated temperatures, and milling all promoted disproportionation. The results suggest that disproportionation of drug salts in powders happens via a solution-mediated mechanism and that the choice of excipient has a considerable impact on the extent of disproportionation observed. Thus, careful attention must be paid to excipient selection during pharmaceutical development and exposure to stresses such as high humidity and mechanical activation should be minimized.

International Journal of Pharmaceutics, Dec 1, 1992

Exposure of 4-methoxy-2-(3-phenyI-2-propynyl)phenol (COl1828) to air and light (accelerated by te... more Exposure of 4-methoxy-2-(3-phenyI-2-propynyl)phenol (COl1828) to air and light (accelerated by temperature) yields 1-(2hydroxy-5-methoxyphenyl)-3-phenylpropynone as the major degradation product. With extraction, this product rapidly degrades to 5-methoxyaurone and 6-methoxyflavone. In addition, a mixture of dimeric and heterodimeric compounds that are not fully identified was observed. These results indicate the formation of a reactive ofthoquinone methide as an unstable intermediate. This hypothesis is supported by evidence that the aurone slowly isomerizes into the flavone in control samples.

Journal of Agricultural and Food Chemistry, Jun 1, 1997

During investigation of the kinetics of skatole in pigs, it was observed that some pigs, which ar... more During investigation of the kinetics of skatole in pigs, it was observed that some pigs, which are poor metabolizers of skatole (3-methylindole), are incapable of forming a metabolite named MII. This lead to the hypothesis that incidents of boar taint in Danish pigs could at least be due partly to polymorphism in one of the P-450 isoenzymes responsible for the oxidative metabolism of skatole. To further investigate the metabolism of skatole in pigs, selected metabolites of skatole were isolated and identified. Three major metabolites of skatole were isolated from urine from pigs given [ 14 C]skatole (5 mg/kg). The metabolites were identified using mass spectroscopy (MS) and nuclear magnetic resonance (NMR) spectroscopy as 6-sulfatoxyskatole (MII), 3-hydroxy-3-methyloxindole (MIII), and the mercapturate adduct of skatole, 3-[(N-acetylcysteine-S-yl)methyl]indole (MX). MII and MIII are found both in plasma and urine, MX is only found in urine.

Journal of Pharmaceutical Sciences, Sep 1, 2010

Solid form screening is commonly performed using solvent-based crystallizations. However, less at... more Solid form screening is commonly performed using solvent-based crystallizations. However, less attention is paid to the role of secondary manufacturing, during which process-induced transformations of the active pharmaceutical ingredient (API) may occur, and potentially a new solid form may be discovered. In this study a new approach for effective solid form screening is presented. The technology combines well-plate-based crystallizations with miniaturized processing equipment, mimicking essential unit operations. Process-induced stresses (heat, solvent, shear, pressure) can be introduced directly to the well-plate unit. Theophylline and nifedipine were used as model compounds. Small-scale wet massing of theophylline resulted in an anhydrate-to-monohydrate transformation, followed by dehydration upon drying at 60 degrees C. Amorphous nifedipine was subjected to small-scale milling and compaction. Kinetic profiling of the milling operation enabled the detection of an intermediate, metastable polymorph (beta form), while the stable polymorph (alpha form) was the predominant form after 20 min of milling. Compaction of amorphous nifedipine at 100 MPa resulted in a complete conversion into the stable polymorph. The reported expanded approach is expected to maximize the outcome of solid form screening with minimal consumption of the compound of interest.

Journal of Analytical Atomic Spectrometry, 1992

Analytical Chemistry, Jan 3, 2007

Metabonomic approaches are believed to have the capability of revolutionizing diagnosis of diseas... more Metabonomic approaches are believed to have the capability of revolutionizing diagnosis of diseases and assessment of patient conditions after medical interventions. In order to ensure comparability of metabonomic 1H NMR data from different studies, we suggest validated sample preparation guidelines for human urine based on a stability study that evaluates effects of storage time and temperature, freeze-drying, and the presence of preservatives. The results indicated that human urine samples should be stored at or below -25 degrees C, as no changes in the 1H NMR fingerprints have been observed during storage at this temperature for 26 weeks. Formation of acetate, presumably due to microbial contamination, was occasionally observed in samples stored at 4 degrees C without addition of a preservative. Addition of a preserving agent is not mandatory provided that the samples are stored at -25 degrees C. Thus, no differences were observed between 1H NMR spectra of nonpreserved urines and urines with added sodium azide and stored at -25 degrees C, whereas the presence of sodium fluoride caused a shift of especially citrate resonances. Freeze-drying of urine and reconstitution in D2O at pH 7.4 resulted in the disappearance of the creatinine CH2 signal at delta 4.06 due to deuteration. A study evaluating the effects of phosphate buffer concentration on signal variability and assessment of the probability of citrate or creatinine resonances crossing bucket border (a boundary between adjacent integrated regions) led to the conclusion that a minimum buffer concentration of 0.3 M is adequate for normal urines used in this study. However, final buffer concentration of 1 M will be required for very concentrated urines.

Journal of Analytical Atomic Spectrometry, 2016

A method for quantification of a pharmaceutical peptide in human plasma was developed using gradi... more A method for quantification of a pharmaceutical peptide in human plasma was developed using gradient elution LC-ICP-MS. A membrane desolvation (MD) system was applied to remove organic solvents from the eluent prior to the detection as SO + in the dynamic reaction cell (DRC) of the ICP-DRC-MS instrument and subsequent quantification by post-column isotope dilution (IDA). Plasma proteins were precipitated prior to analysis. Analytical figures of merit including linearity, precision, LOD, LOQ and accuracy were considered satisfactory for analysis of plasma samples. The selectivity of the developed method was demonstrated for five pharmaceutically relevant peptides: desmopressin, penetratin, substance P, PTH (1-34) and insulin. Preliminary experiments on an ICP-MS/MS system using oxygen to reduce the effect of organic solvents were also performed to compare sensitivity. The results of the study demonstrated that LC-ICP-MS post-column IDA may constitute a valuable additional tool in quantification of non-labelled peptides in the early drug development offering absolute quantification without need of species specific standards.

Pharmaceutical Research, Oct 1, 2010

Purpose To achieve an in-depth understanding of the underlying mechanism of the acceleration or d... more Purpose To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation. Methods The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynamic driving force of the phase transformation (e.g. supersaturation) at different temperatures was determined by measuring the solubility of the anhydrate and the hydrate. Results Both acceleration and deceleration effects of temperature on the phase transformation were observed. The mechanism of these temperature effects was studied by exploring the influence of temperature on supersaturation level and crystallization kinetics. Increasing temperature usually leads to accelerated phase transformation kinetics, but it simultaneously decreases supersaturation, which has the opposite effect on the kinetics of the phase transformation. The overall effect of temperature on the phase transformation is therefore determined by the combined effects of supersaturation and temperature on the nucleation and crystal growth kinetics of the hydrate. Conclusions By differentiating and comparing the effects of temperature and supersaturation on the anhydrate-to-hydrate phase transformation, a deeper understanding of the underlying principle of the acceleration and deceleration effects of temperature on the phase transformation has been achieved.

International journal of peptide & protein research, Jan 12, 2009

Molecular Pharmaceutics, Jun 20, 2011

Analytical Chemistry, Oct 15, 1999

The on-line separation and structure elucidation of naphthodianthrones, flavonoids, and other con... more The on-line separation and structure elucidation of naphthodianthrones, flavonoids, and other constituents of an extract from Hypericum perforatum L. using high performance liquid chromatography (HPLC) coupled on-line with ultraviolet−visible, nuclear magnetic resonance (NMR), and ...

Journal of Chromatography A, Apr 1, 1995

Metronidazole has previously been used as a probe when investigating cytochrome P450 isoenzymes a... more Metronidazole has previously been used as a probe when investigating cytochrome P450 isoenzymes and thus the pattern of metabolism of this drug has been extensively studied. However, in previous investigations the conjugates were determined by indirect methods. In this paper we present a high-performance liquid chromatographic (HPLC) system for the simultaneous determination of metronidazole, its major metabolites and their glucuronic acid conjugates in biological fluids. The separation is performed using bare silica dynamically modified with N-cetyl-N,N,N-trimethylammonium bromide contained in the mobile phase. The separation of the acidic metabolites of metronidazole is greatly improved with this system compared to other published reversed-phase HPLC systems intended for the same purpose. Glucuronides of metronidazole and its hydroxy metabolites have been synthesized in vitro using rat liver microsomes and preparative HPLC. The method developed makes it possible to determine the intact glucuronic acid conjugates of metronidazole and the hydroxy metabolite in human urine.

European Journal of Pharmaceutical Sciences, Sep 1, 1993

... Synthesis and structural elucidation of glutathione and N-acetyl-cysteine conjugates of 5-ami... more ... Synthesis and structural elucidation of glutathione and N-acetyl-cysteine conjugates of 5-amino salicylic acid Joan Jensena, Claus Cornetta, Carl Erik 0lsen ... Jacobsen, BA, Abildgaard, K., Rasmussen, HH, Christensen, LA, Fallingborg, J., Hansen, SH and Rasmussen, SN (1991 ...