Claus CornettUniversity of Copenhagen · Department of Pharmacy
Claus Cornett
MSc (spectroscopy/chemistry) Ph.D. (Pharmacy)
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144
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Introduction
NMR spectroscopy applied to all sorts of structure elucidation and determination of physical chemical properties of small molecules. Structure elucidation of drug metabolites. Structure elucidation of drug metabolites and metabolites thereof. Use of other analytical methods necessary to support these objects.
Improvement of the processing of timeseries NMR data and chemometric methods applied to quantitative Analytical Chemistry.
Publications
Publications (144)
An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a t...
Extracts of Synadenium glaucescens Pax are reported to contain biologically active compounds against bacterial and viral infections. This study aimed at isolating pure compounds from its bioactive extracts as well as evaluating their antibacterial efficacy. A phytochemical investigation of the root and stem barks involved total maceration in methan...
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharma...
The analgesic potential of Cannabis sativa L.—based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, ho...
Objective
To determine the synovial fluid (SF) concentrations of lidocaine and mepivacaine after intra-articular injection with clinically relevant doses to the distal interphalangeal (DIP), metacarpophalangeal (MCP), middle carpal (MC), and tarsocrural (TC) joint at two different time points after injection in order to be able to compare concentra...
Commiphora swynnertonii (Burtt) is traditionally used for medicinal purposes both in humans and animals in Tanzania. Previously, its leaves extract has been demonstrated antibacterial activity. However, there is limited information on identification of pure compounds responsible for its observed antibacterial activity. Therefore, this study was con...
The use of plants as sources of drug agents is attributed by factors among which are the easy accessibility to plants, less toxicity and little or no drug resistance. An improvement in both traditional medicine and drug discovery field necessitates investigation of pure compounds in any plant with medicinal value. Synadenium glaucescens Pax of the...
Commiphora swynnertonii (Burtt) is a medicinal plant with diverse traditional uses in Tanzania. However, there is limited information on isolation and cytotoxicity properties of bioactive compounds responsible for its pharmacological activities. Hence, this study attempted to isolate and assess toxicity properties of bioactive compounds from its le...
The leaves and stem woods of Synadenium glaucescens Pax. are traditionally used for treatment of various human diseases in Tanzania. However, there is limited information on the structural elucidation and toxicity properties of bioactive compounds responsible for their pharmacological properties. Thus, this study was aimed to elucidate and evaluate...
Newcastle Disease (ND) is a highly pathogenic disease of avian species which is caused by Newcastle Disease Virus (NDV). It is one of the major causes of mortality and morbidity to poultry industry in the third world countries. Currently, there is no treatment measures against ND; the only existing measure is vaccination, though it is incapable to...
A decreasing trend in narwhal (Monodon monoceros Linnaeus, 1758) abundance has been identified in a small population in Scoresby Sound, Southeast Greenland. We hypothesize that excessive hunting has affected life history and population dynamics of this population. Biological information and samples collected from the Inuit hunt, from satellite-tagg...
Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design...
Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quic...
PurposeAsthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of th...
Ethnopharmacological relevance:
Species of the genus Cinchona (Rubiaceae) have been used in traditional medicine, and as a source for quinine since its discovery as an effective medicine against malaria in the 17th century. Despite being the sole cure of malaria for almost 350 years, little is known about the chemical diversity between and within...
The current study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions and emulsions and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) were selected as model drugs. Self-diffusion nuclear m...
Introduction:
Authentication of herbal products to ensure efficacy and safety require efficient separation and quantification of constituents. Standard assays for Cinchona bark used for the treatment of malaria and production of quinine, either use only spectrophotometry to detect two pairs of diastereoisomers of quinine and cinchonine type alkalo...
Considerable inter- and intraspecific variation with respect to the quantity and composition of plant natural products exists. The processes that drive this variation remain largely unknown. Understanding which factors determine chemical diversity has the potential to shed light on plant defenses against herbivores and diseases and accelerate drug...
Local anaesthetics (LAs) are frequently used for diagnostic procedures in equine veterinary practice. The objective of this study was to investigate the physico-chemical stability and bacterial contamination of bupivacaine, lidocaine and mepivacaine used for lameness examinations in horses. The LAs were stored in 12 different groups at different te...
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 i...
Measuring both progestagens, androgens, corticosteroids as well as estrogens with a single method makes it possible to investigate the effects of endocrine-disrupting chemicals (EDCs) on the main pathways in the mammalian steroidogenesis. This paper presents two simple methods for the determination of the major steroid hormones in biological matrix...
Widely accepted in vitro methodologies for sustained release parenteral drug formulations remain to be established. Hydrogels have been proposed as a release matrix more closely resembling the in vivo conditions for formulations intended for subcutaneous administration. The perspective of the current work was to investigate the feasibility of devel...
Two co-amorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed towards their ease of amorphization and mechanism of co-amorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar...
Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50°C, 60°C, 70°C and 80°C as well as at 20°C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is therefore important to thoroughly investigate a possible reacti...
For parenteral biopharmaceuticals, subcutaneous diffusion and, in the case of solid implants or suspensions, dissolution may govern the clinical profile of the drug product. Insight into the dissolution and diffusion processes of biopharmaceuticals after parenteral administration is fundamental in the development of new protein drug formulations. U...
There is a growing need to increase our understanding of physicochemical stability of pharmaceuticals during manufacturing. The present study has investigated effects of excipients and processing conditions on the physicochemical properties of two weakly acidic model drugs (piroxicam and lornoxicam) in solid dosage pharmaceuticals. By means of soli...
Formation of superstructures in protein aggregation processes has been indicated as a general pathway for several proteins, possibly playing a role in human pathologies. There is a severe lack of knowledge on the origin of such species in terms of both mechanisms of formation and structural features. We use equine lysozyme as a model protein, and b...
Crystal structures are presented for two dihydrate polymorphs (DH-I and DH-II) of the non-steroidal anti-inflammatory drug sodium (S)-naproxen. The structure of DH-I is determined from twinned single crystals obtained by solution crystallization. DH-II is obtained by solid-state routes, and its structure is derived using powder X-ray diffraction, s...
The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed by sieving, drying, and compaction of the agglomerat...
The crystal structure of the tetrahydrate of the active pharmaceutical ingredient sodium naproxen is examined using single-crystal X-ray diffraction, supported by 13C and 23Na solid-state NMR. The structure has previously been reported to be a heminonahydrate, Na+(naproxen–)·4.5H2O. The average structure in space group C2 contains layers of naproxe...
A new HPLC system coupled with multiple detectors - Diode array detector (DAD), fluorescence detector (FLD), electrochemical amperometric detector (ADC) and mass spectrometry detector (MSD) was developed for the characterization and differentiation of tannin-containing herbal drugs included in The European Pharmacopoeia. The HPLC separation system...
This study aimed at determining if synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and healthy controls (HC) differ and are suitable disease models in pharmacological studies, and tested their response to some anti-inflammatory drugs. Synovial cells were isolated from synovial membrane or joint fluid. Cells were cultivat...
Purpose:
To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.
Methods:
Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure...
Purpose:
To understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context.
Methods:
Multi-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformati...
The present study puts forward a miniaturized high-throughput platform to understand influence of excipient selection and processing on the stability of a given drug compound. Four model drugs (sodium naproxen, theophylline, amlodipine besylate and nitrofurantoin) and ten different excipients were selected. Binary physical mixtures of drug and exci...
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 pol...
The ability of forensic laboratories to detect and identify unknown compounds is highly important since new, non-controlled designer drugs are appearing on the market with increasing frequency. In this study, the combined use of gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-quadrupole time of flight-mass s...
There is a need for an improved process understanding of solid dosage pharmaceuticals. In the present study, Raman spectroscopy together with partial least squares (PLS) regression was used to monitor the solid-state composition of piroxicam during processing in the presence of excipients. It was found that including variable selection in PLS regre...
Traditional dissolution testing determines drug release to the bulk, but does not enable an understanding of the events happening close to the surface of a solid or a tablet. UV imaging is a new imaging approach that can be used to study the dissolution behavior of chemical compounds. The UV imaging instrumentation offers recording of absorbance ma...
Results:
Basic physicochemical properties including their apparent solubility in aqueous buffer and vegetable oils of a series of 11 peptidomimetics varying with respect to chain length and degree of N-methylation were estimated. It was observed that the compounds in contact with water transformed into sticky, slowly dissolving semisolid materials...
The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin o...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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 carbox...
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.
The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynami...
Aim of the study:
The aim of this randomized and double blinded pilot clinical trial was to investigate the anti-diabetic efficacy of the Rauvolfia-Citrus (RC) tea in humans. We have earlier shown that a combination of calorie-restriction and chronic administration of the RC tea to the genetic diabetic (BKS-db) mice resulted in the normalization o...
1H NMR spectroscopy-based metabolic phenotyping was used to identify biomarkers in the plasma of patients with rheumatoid arthritis (RA). Forty-seven patients with RA (23 with active disease at baseline and 24 in remission) and 51 healthy subjects were evaluated during a one-year follow-up with assessments of disease activity (DAS-28) and 1H NMR sp...
The mitochondrial pH gradient across the inner-membrane is stabilised by buffering of the matrix. A low-molecular mass buffer compound has to be localised in the matrix to maintain its alkaline pH value. Taurine is found ubiquitously in animal cells with concentrations in the millimolar range and its pKa value is determined to 9.0 (25 degrees C) an...
We have determined the absorption, conjugation and excretion of naringenin-7-O-rutinoside (narirutin) compared to the corresponding glucoside in an orange juice matrix in human subjects. Healthy volunteers (eight men and eight women), in a double blind, randomised, crossover study, consumed orange juice with (1) natural content of naringenin-7-O-ru...
N-acylethanolamines (NAEs) are a group of lipid mediators synthesized in response to a number of physiological and pathological stimuli. Because of the low tissue concentrations of NAEs, analyses often include liquid extraction followed by solid-phase extraction and subsequent quantitation by LC/MS or GC/MS. Reported levels of NAEs vary considerabl...
α,β-Unsaturated esters of allylic alcohols have been shown to exhibit exciton coupling by circular dichroic spectroscopy. This coupling permits the establishment of the absolute configuration. The method was used to prove the absolute configuration at C-2 of archangelolide. Detailed NMR spectral studies of the prepared model structures may be used...
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 a...
Herbal drugs containing tannins are characterised in the European Pharmacopoeia by their tannin content analysed by the old, nonspecific, colorimetric Folin-Ciocalteu method. The result of the analysis is a single figure relating to the content of tannins, but this does not provide much information on the identity or status of the herbal drug.
In t...
The reaction between the high-dose drug substance 5-aminosalicylic acid (5-ASA) and the excipient citric acid during storage of an experimental enema preparation has been studied and three isobaric reaction products, i.e., an ester and an amide with non-symmetrically substituted citric acid moieties and a symmetrical amide, were identified by combi...
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...
In polymorph screening it is imperative to maximize the physicochemical diversity of solvents used in crystallization experiments. This is done in order to increase the probability of finding as many crystal forms of the compound as possible. When setting up a complete solid form screening scheme it is common practice to work with solvent subsets o...
The fluorescent dye thioflavin T (ThT) is commonly used for in situ amyloid fibril detection. In this work, we focused on the spectroscopic properties and chemical stability of ThT in aqueous solution as a function of pH, temperature, and dye concentration. A reversible hydroxylation process occurs in alkaline solutions, which was characterized usi...
The reactivity of citric acid towards drug substances in the solid state was examined using the beta-blocker carvedilol as a model compound. The reaction mixtures were analysed by LC-MS, the reaction products were isolated by preparative HPLC, and the structures were elucidated by microprobe NMR spectroscopy. Heating a mixture of solid carvedilol a...
The above article (DOI: 10.1002/cem.1107) was published online on 21 January 2008. An error was subsequently identified. Figures 2a, 2b and 2c should appear as below.
The print publication will incorporate the amendment identified by this erratum notice.
Near-infrared (NIR) spectroscopy is a well-established technique for solid-state analysis, providing fast, noninvasive measurements. The use of NIR spectroscopy for polymorph screening and the associated advantages have recently been demonstrated. The objective of this work was to evaluate the analytical potential of NIR spectroscopy for cocrystal...
Lansoprazole has been determined in the presence of its five related compounds by the Rapid Resolution RP-HPLC method, using Zorbax Eclipse XDB C18 4.6 mm × 50 mm, 1.8 µm particle size column at 25°C and acetonitrile-1% TEA (41.0:59.0 v/v) at pH 6.6 as mobile phase. The total time for chromatographic separation was approximately 3 min. Experimental...
An enantiospecific RP-HPLC method was developed and validated for the simultaneous determination of clopidogrel and four related compounds specified as impurities. Experimental design was applied during the method optimization (Full factorial 2(3) design) and robustness testing (Central Composite Face Centered design). Laboratory mixtures of clopid...
Diclofenac is widely used in the treatment of, for example, arthritis and muscle pain. The use of diclofenac has been associated with hepatotoxicity, which has been linked to the formation of reactive metabolites. Diclofenac can be metabolized to 4'-OH- and 5-OH-diclofenac, both of which are able to form quinone imines capable of reacting with, for...
Metabolite profiling relies on optimal precision of the acquired data, which requires, among others, a high signal-to-noise ratio (S/N). In addition, increased S/N will increase the likelihood of identification of new biomarkers. Here we introduce, for the first time in metabolite profiling studies by 1H NMR, an approach to enhance the precision of...
Many plants produce cyanogenic glucosides as part of their chemical defense. They are alpha-hydroxynitrile glucosides, which release toxic hydrogen cyanide (HCN) upon cleavage by endogenous plant beta-glucosidases. In addition to cyanogenic glucosides, several plant species produce beta- and gamma-hydroxynitrile glucosides. These do not release HCN...
Selecting a diverse set of solvents to be included in polymorph screening assignments can be a challenging task. As an aid to decision making, a database of 218 organic solvents with 24 property descriptors was explored and visualized using multivariate tools. The descriptors included, among others, log P, vapor pressure, hydrogen bond formation ca...
A Rapid Resolution Reversed Phase High-Performance Liquid Chromatography (RR RP-HPLC) method has been developed and validated for the simultaneous determination of atorvastatin and seven related compounds specified as impurities. Experimental design was used during method optimization (full factorial 3 design) and robustness testing (central compos...
The metabolism of methylseleninic acid, MeSeA in the gastro-intestinal tract was studied by incubation of MeSeA with homogenized intestinal epithelial cells from pigs. The major selenium-containing metabolite was identified by analysis of the supernatant of the incubated cells by LC-ICP-MS. The identity of the compound was established by LC-ESI-MS/...
A well-known method for quantification of isothiocyanates (ITCs) and their metabolites is the condensation reaction with 1,2-benzenedithiole to produce 1,3-benzodithiole-2-thione, which can be quantified by high-performance liquid chromatography. Standards of an ITC metabolite and 1,3-benzodithiole-2-thione are required for this assay but are not c...
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 e...
Although the antimicrobial tiamulin is extensively metabolized in pigs, the metabolism is not well investigated. In this work the NADPH dependent metabolism of tiamulin in liver microsomes from pigs has been studied. The tiamulin metabolites formed in the incubations were analysed using LC-MS, and three major metabolites were isolated using solid p...
Several studies have demonstrated that especially high taurine concentrations are found in tissues with high oxidative activity, whereas lower concentrations are found in tissues with primary glycolytic activity. Based on such observations, we have studied if taurine is involved in mitochondrial oxidation. Several pieces of information have demonst...