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See detailComparison of hyperspectral imaging techniques for the elucidation of falsified medicines composition
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Dispas, Amandine ULiege et al

in Talanta (2019), 198

Hyperspectral imaging has shown a high potential to analyze falsifications of solid pharmaceutical products since the last decade. Thanks to the non-destructive, ecological and non-invasive properties, it ... [more ▼]

Hyperspectral imaging has shown a high potential to analyze falsifications of solid pharmaceutical products since the last decade. Thanks to the non-destructive, ecological and non-invasive properties, it is a preferred technique for these kinds of applications. Moreover, thanks to the spectroscopic properties, it is possible to detect as well organic compounds as inorganic compounds in a single analysis. Therefore, we recommend using it as second-line laboratory analysis technique. Raman microscopy and Fourier Transform Infrared (FT-IR) microscopy are two interesting techniques that are complementary. In this study, the potential of the two hyperspectral imaging techniques is evaluated to elucidate the composition of falsified antimalarial tablets. Hyperspectral data are analyzed by Multivariate Curve Resolution-Alternating Least Square (MCR-ALS). The results obtained from this study show that Raman hyperspectral imaging seems to be more suited to detect low dosed compounds possibly due to a smallest sampling volume. It has been also possible to link formulations of falsified samples of two different brands. [less ▲]

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See detailCapillary electrophoresis and microscale thermophoresis in fragment-based drug discovery : development of screening bioassays towards FXIIa
Davoine, Clara ULiege; Farças, Elena; Thabault, Léopold et al

Poster (2019, March 24)

Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. One of the strategies in the search for safer antithrombotic therapies is to target coagulation ... [more ▼]

Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. One of the strategies in the search for safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa).[1] This strategy have two substantial advantages : 1. No bleeding risk 2. Additional anti-inflammatory effects After limited results with the traditional medicinal chemistry approach (inhibitors in the μM range) [2], we decided to apply fragment-based drug discovery approach (FBDD). In its first step, FBDD strongly depends on the ability to detect and gauge weak affinity binders. In the scope of validating the fragment hits, the most robust strategy is to apply orthogonal techniques. In this work, we investigate the suitability of microscale thermophoresis and capillary electrophoresis for the discovery of new fragments that bind FXIIa. [1] a) J.I.Weitz, Thromb Res, 141 Suppl 2 (2016) S40-45; b) J.C. Fredenburgh, P.L. Gross, J.I. Weitz, Blood, 129 (2017) 147-154; c) A.T. Long, E. Kenne, R. Jung, T.A. Fuchs, T. Renne, J Thromb Haemost, 14 (2016) 427-437. [2] a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194 [less ▲]

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See detailUpdate of the progresses and development prospects of the FEDER project Phare
Emonts, Paul ULiege; Penoy, Noémie ULiege; Rocks, Natacha ULiege et al

Scientific conference (2019, January 19)

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See detailAuthentication of falsified medicine tablets by handheld Raman spectroscopy class modeling
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege et al

Conference (2019, January 01)

Since last decades, the world has known significant changes in the pharmaceutical products sale. The emergence of the internet trade is an important issue because it is easy to sell medicines without ... [more ▼]

Since last decades, the world has known significant changes in the pharmaceutical products sale. The emergence of the internet trade is an important issue because it is easy to sell medicines without passing any control. Moreover, in low- and middle-income countries (LMIC), the number of local pharmacies has grown, increasing the risk to have substandard or falsified medicines. Indeed, according to the World Health Organization (WHO) it is difficult to ensure quality medicines due to areas conflict, corrupted governments and poor health system [1]. For that reason, several analytical techniques have been developed since last decade. One of the most interesting tool is the Minilab, developed by the Global Pharma Health Fund (GPHF), which is a mobile mini-laboratory for fast drug quality control. Moreover, Raman spectroscopy has gained a great interest because it can be used at any step of analytical chain or on the fieldwork with handheld devices. However, spectroscopic data implies development of chemometrics models to gather relevant information. Several unsupervised techniques have already been used to authenticate drug products [2-3]. Due to the intrinsic properties of classification methods, class modeling is more appropriated to this kind of analysis. Indeed, falsified medicines can be quite different from the calibration set, so that, it does not have sense to attribute a class meanwhile it is dissimilar to the calibration set. In this study, the performances of two class-modeling techniques will be evaluated on handheld Raman spectra, to separate falsified medicines from authentic drugs. Three different generics of paracetamol, ibuprofen and artemether-lumefantrine with different dosage, dosage form and formulations were analyzed. Most of them were gathered in local Belgium pharmacies and other were gathered in Africa (artemether-lumefantrine formulations). Samples were analyzed with a handheld Raman spectrophotometer Pharma 21CFR part 11 qualified (Truscan RM, Thermo Scientific, USA) directly through the blister. In order to have a good representativeness of intra-batch variability, 10 tablets were analyzed per sample. The acquisition parameters were set to default. Two models were tested: one-class PLS (OC-PLS) [4] and the data driven-soft independent modeling class analogy (DD-SIMCA) [5]. All the computations were done in Matlab® (R2017b). The calibration and validation set was the same for each model and composed of 60 spectra for each, with different batch number. Because of the nature of each algorithm, there is a significant difference in terms of separation. Looking at Figure 1, the separation of dosage form for ibuprofen is much different between the two models. For the DD-SIMCA, it is more difficult to separate the long acting release from the soft capsule/coated tablet compared to the OC-PLS model. For the other API, similar results are obtained for the dosage and for the brand. It seems that the OC-PLS is more sensitive to the small spectral variabilities. In the case of artemether-lumefantrine formulations, the separation between samples is much more difficult. Indeed, the lumefantrine is a high Raman scatterer. This can explain that the signal of artemether and excipients is difficult to access. Elsewhere, in terms of development, the DD-SIMCA is much harder to optimize because there are more tunable parameters than for OC-PLS. Furthermore, both models are really influenced by spectral pretreatment. An optimization has to be done for each. The authentication of pharmaceutical products by handheld Raman spectroscopy has been possible thanks to class modeling. Both tested algorithms shown interesting results regarding the separation of samples depending on their characteristics. The optimization of data processing and pre-processing is the key-step to improve as sensitivity as specificity of both class modeling methods. [less ▲]

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See detailInsulin aggregation assessment by capillary gel electrophoresis without sodium dodecyl sulfate: Comparison with size-exclusion chromatography
Demelenne, Alice ULiege; NAPP, Aurore ULiege; Bouillenne, Fabrice ULiege et al

in Talanta (2019), 199

Size-exclusion chromatography (SEC) is a method of choice for the analysis of protein aggregates in pharmaceuticals. The United States and European Pharmacopoeias currently use a SEC method with an acidic ... [more ▼]

Size-exclusion chromatography (SEC) is a method of choice for the analysis of protein aggregates in pharmaceuticals. The United States and European Pharmacopoeias currently use a SEC method with an acidic pH mobile phase to assess the content of aggregates in insulin formulations. In this article, we analyzed aggregated human insulin samples and demonstrated that both methods under neutral conditions, namely neutral pH SEC (nSEC) and capillary gel electrophoresis (CGE), yield to similar aggregate content contrary to SEC under acidic conditions (aSEC). aSEC showed polymeric complexes that were not observed in nSEC and CGE. During method development, the effect on SEC profiles of arginine and acetonitrile were highlighted. In CGE, the effect of SDS on disruption of non-covalent insulin aggregates was confirmed and the benefit of sodium deoxycholate addition in sieving gel was discussed. The three methods were applied to the analysis of an insulin formulation and similar results to those obtained for human insulin as raw material were observed. Finally, the CGE method was used to study the stability of human insulin under different storage conditions. In view of the obtained results one may question the relevance of the current pharmacopoeia method to study insulin aggregates by emphasizing the importance of the mobile phase composition and pH in SEC. The new CGE method developed is an easy method for studying non-covalent aggregates of insulin, which could be applied to other proteins. © 2019 Elsevier B.V. [less ▲]

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See detailHighly sensitive and selective separation of intact parathyroid hormone and variants by sheathless CE-ESI-MS/MS.
Nyssen, Laurent ULiege; Fillet, Marianne ULiege; Cavalier, Etienne ULiege et al

in Electrophoresis (2019)

Parathyroid hormone (PTH) is a common clinical marker whose quantification relies on immunoassays, giving variable results as batch, brand, or target epitope changes. Sheathless CE-ESI-MS, combining CE ... [more ▼]

Parathyroid hormone (PTH) is a common clinical marker whose quantification relies on immunoassays, giving variable results as batch, brand, or target epitope changes. Sheathless CE-ESI-MS, combining CE resolution power and low-flow ESI sensitivity, was applied to the analysis of PTH in its native conformation in the presence of related forms. Fused silica and neutral-coated capillaries were investigated, as well as preconcentration methods such as transient isotachophoresis (t-ITP), field-amplified sample injection (FASI) and electrokinetic supercharging (EKS). The method for the separation of PTH and its variants was first developed using fused-silica capillary with UV detection. An acidic background electrolyte (BGE) was used to separate 1-84 PTH (full length), 7-84 PTH and 1-34 PTH. Acetonitrile was added to the BGE to reduce peptide adsorption onto the capillary wall and t-ITP was used as analyte preconcentration method. The method was then transferred to a sheathless CE-ESI-MS instrument. When using a fused silica capillary, CE-MS was limited to mug/mL levels. The use of a neutral coating combined with FASI or EKS allowed a significant increase in sensitivity. Under these conditions, 1-84 PTH, 7-84 PTH and 1-34 PTH were detected at concentrations in the low ng/mL (FASI) or pg/mL (EKS) range. This article is protected by copyright. All rights reserved. [less ▲]

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See detailDevelopment of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies.
Palazzo, Claudio; Laloy, Julie; Delvigne, Anne Sophie et al

in European Journal of Pharmaceutical Sciences (2019), 9(127), 52-59

Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies ... [more ▼]

Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies prematurely born. No efficacy treatment is available to the present day. Estetrol (E4), a major estradiol metabolite, has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Liposome and DCL formulations were prepared and were physiochemically characterized. Stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells, as well as hemocompatibility of the nanovectors were performed in vitro. In vitro BBB passage was evaluated using human BBB cell line (hCMEC/D3). All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Therefore, the formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. [less ▲]

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See detailUltra-high-performance liquid chromatography-mass spectrometry method for neutrophil gelatinase-associated lipocalin as a predictive biomarker in acute kidney injury
Ion, Valentin ULiege; Nys, Gwenaël ULiege; COBRAIVILLE, Gaël ULiege et al

in Talanta (2019), 195

Neutrophil gelatinase associated lipocalin (NGAL) is a protein that was found to be overexpressed in acute kidney injury (AKI). The rise in NGAL concentration, both in urine or plasma, appears earlier ... [more ▼]

Neutrophil gelatinase associated lipocalin (NGAL) is a protein that was found to be overexpressed in acute kidney injury (AKI). The rise in NGAL concentration, both in urine or plasma, appears earlier than for other classical renal function markers such as serum creatinine, thus making it a suitable marker for early pathology detection. The aim of this study was to develop a method involving tryptic digestion, solid phase extraction and LC-MS/MS analysis to analyze NGAL in plasma medium using an isotope labeled surrogate protein, containing NGAL signature tags, as internal standard (QPrEST). The method was validated for the analysis of NGAL in an analytical range from 50 to 1250 ng/mL using two different proteotypic peptides. The method was further used to quantify the NGAL in human plasma samples for whom elevated NGAL values were expected. NGAL values were between 190.8 and 242.6 ng/mL for control group and between 228.1 and 3526.2 ng/mL for patient group. This study proved that the selection of the right internal standard is of utmost importance in targeted proteomics studies as the digestion steps might cause high variability. This study also confirmed that, although NGAL is highly resistant to proteases such as trypsin, the method could be fully validated according to FDA guidelines and subsequently used to assess NGAL levels in patient plasma with high analytical confidence. © 2018 [less ▲]

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See detailSelectivity evaluation of phenyl based stationary phases for the analysis of amino acid diastereomers by liquid chromatography coupled with mass spectrometry
Moldovan, R.-C.; Bodoki, E.; Servais, Anne-Catherine ULiege et al

in Journal of Chromatography A (2019)

D-amino acids (AA) analysis is becoming more and more relevant for metabolomics, therefore new analytical tools need to be developed. A common approach to achieve AA enantioseparation is chiral ... [more ▼]

D-amino acids (AA) analysis is becoming more and more relevant for metabolomics, therefore new analytical tools need to be developed. A common approach to achieve AA enantioseparation is chiral derivatization. Among the chiral derivatization reagents, (+) or (-)-1-(9-fluorenyl) ethyl chloroformate ((+) or (-)-FLEC) has proved to be one of the most versatile. Suitable chiral selectivity for FLEC derivatives of amino acids could be obtained in reversed-phase HPLC using nonpolar stationary phases (C4, C8 and C18) and tetrahydrofuran (THF) based mobile phases. This study is meant to provide alternatives to the use of THF as organic modifier by evaluating the selectivity obtained on two phenyl based stationary phases for 19 FLEC-DL-AA pairs of diastereomers using UHPLC-MS. Several mobile phases consisting of ammonium acetate and different common organic solvents (acetonitrile (ACN), methanol (MeOH), 2-propanol (IPA)) were tested using gradient elution. Experimental design was employed for the optimization of the separation conditions. In the optimized conditions, complete chiral separation can be achieved for 18 out of 19 FLEC-DL-AAs in less than 30 min. © 2019 Elsevier B.V. [less ▲]

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See detailDevelopment of fragments screening bioassays towards thrombin and FXIIa using capillary electrophoresis
Davoine, Clara ULiege; Farças, Elena; Bouckaert, Charlotte et al

Poster (2018, December 19)

In this communication, we will report the development of a capillary electrophoresis approach for the screening of fragments towards thrombin and FXIIa. We performed direct and competitive ACE-binding ... [more ▼]

In this communication, we will report the development of a capillary electrophoresis approach for the screening of fragments towards thrombin and FXIIa. We performed direct and competitive ACE-binding assays for the screening of molecules at physiological pH. [less ▲]

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See detailQuality control of therapeutic oligonucleotides using HILIC-UV and CZE-UV
Gou, Marie-Jia ULiege; Demelenne, Alice ULiege; Parulski, Chloé et al

Poster (2018, December 19)

Detailed reference viewed: 13 (3 ULiège)
See detailQuality control and aggregation follow-up of insulin formulations
Demelenne, Alice ULiege; Napp, Aurore ULiege; Radermecker, Régis ULiege et al

Conference (2018, December 19)

The prevalence of diabetes is increasing every year making insulin formulations widely prescribed medicines. Fast and efficient methods to assess the quality of such biopharmaceutical products are thus ... [more ▼]

The prevalence of diabetes is increasing every year making insulin formulations widely prescribed medicines. Fast and efficient methods to assess the quality of such biopharmaceutical products are thus required, more particularly methods to assess the content of API and potential aggregates. We started our study on insulin aggregation using the European Pharmacopeia method. Since methods to assess aggregate content are often contradictory, we also developed original and orthogonal methods using size-exclusion chromatography (SEC) and capillary gel electrophoresis (CGE). It was demonstrated that methods under neutral conditions (SEC and CGE) yield to similar aggregate content contrary to pharmacopeia SEC method that works under acidic conditions. Ion-mobility Q-TOF mass spectrometer was also used to confirm the presence and the identity of insulin dimers. Then, we applied the three methods to the analysis of an insulin formulation and similar results to those obtained for human insulin as raw material were observed. We also used the CGE method to study the stability of human insulin under different storage conditions. Finally, we used UHPLC and mass spectrometry to quantify insulin formulation from different supply chains. We demonstrated that all the analyzed formulations had a potency between 95.0 % and 105.0 % of the potency stated on the label. This was useful to dispel doubts regarding issues in insulin cold chain supply recently described in the litterature. [less ▲]

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See detailStrategies for the study of plant virus-based virus-like particles (VLP) displaying human papillomavirus (HPV) L2 epitope
Yazdani, Razieh; Shams-Bakhsh, Masoud; Thelen, Nicolas ULiege et al

Poster (2018, December 19)

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See detailDevelopment and optimization of a derivatization protocol for phenethylamine compounds using FITC-CE-LIF method
Emonts, Paul ULiege; Dispas, Amandine ULiege; Ninane, Caroline et al

Poster (2018, December 19)

In the framework of the development of an innovative microfluidic system based on capillary electrophoresis separation, we optimized a fluorescein isothiocyanate (FITC) derivatization protocol for Laser ... [more ▼]

In the framework of the development of an innovative microfluidic system based on capillary electrophoresis separation, we optimized a fluorescein isothiocyanate (FITC) derivatization protocol for Laser Induced Fluorescence (LIF) detection. The microfluidic device will present a high sensitivity thanks to the fluorescence detection and an innovative hydrodynamic injection approach. To highlight the analytical performances of this microfluidic system, we will use synthetic cathinones (and some derivatives) as targeted compounds. They present a panel of closely related structures and isobaric compounds. In addition to analytical challenges, this category of drugs is a current topic regarding to public health. Indeed synthetic cathinones were described as the second most frequently seized group of new psychoactive substances in EU in 2016. Moreover some of them are currently sell on internet as bath salts without any legislation. In this context, fast, easy and reliable analytical tools are required to track and quantify these compounds. In the present study, we initiated the optimization of the derivatization of model compounds (phenethylamine family) using FITC. The panel of model analytes includes primary and secondary amino groups to be representative of future real samples. Design of experiments strategy was used to optimize the derivatization protocol in order to reach an easy sample preparation and to maximize the derivatization efficiency. Finally, the CE developed method will be transferred to the microfluidic system. Then separation performances comparison of traditional CE-LIF vs µCE-LIF will allow to highlight the advantages of microfluidics such as the lower amount of sample required, the gain in time and money, the significant decrease of solvent and its compact size. [less ▲]

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See detailDevelopment of graphical user interface (GUI) for database building and for falsification applications
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Dispas, Amandine ULiege et al

Scientific conference (2018, December 19)

Inside a research unit, there are several kind of information which are gathered in a continuous flow from operators. It is important to centralize all of the information not to lose any interesting ... [more ▼]

Inside a research unit, there are several kind of information which are gathered in a continuous flow from operators. It is important to centralize all of the information not to lose any interesting result. Because of the cost and/or the non-applicability of commercial database software, it is interesting to build its own one. Indeed, in the case of spectroscopic data, the use of a market database software is not user-friendly because, stored data cannot be directly manipulated in multivariate analyses applications. The database under development actually contains the data of various pharmaceutical samples (genuine and falsified) obtained on several spectroscopic devices. For this application, a Matlab® graphical user interface (GUI) is being developed. It provides the access to spectroscopic data for any operator and allows the automatic implementation of new instruments and/or new formulation groups. Moreover, in case of falsification suspicion, another GUI has been developed to provide qualitative information regarding the composition of the medicines. It is an interesting tool because it provides an instantaneously visual comparison between reference database and the unknown spectrum. Moreover, statistical tools, as Hit Quality Index or correlation coefficient, can provide a numerical result to quantify the match between spectra. In the future, results from other kind of techniques (e.g. HPLC, dissolution curves, photos) will be added to centralize samples information. [less ▲]

Detailed reference viewed: 26 (8 ULiège)
See detailDevelopment of capillary electrophoresis bioassays for the screening of fragments : application to thrombin and FXIIa
Davoine, Clara ULiege; Farças, Elena; Bouckaert, Charlotte et al

Poster (2018, November 23)

In this communication, we will report the development of a capillary electrophoresis approach for the screening of fragments towards thrombin and FXIIa. We performed direct and competitive ACE-binding ... [more ▼]

In this communication, we will report the development of a capillary electrophoresis approach for the screening of fragments towards thrombin and FXIIa. We performed direct and competitive ACE-binding assays for the screening of molecules at physiological pH. [less ▲]

Detailed reference viewed: 9 (1 ULiège)