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Développement De Méthodes De Dépistage Des Médicaments De Contrefaçon Et Des Produits Adultérés Par LC-MS/MS

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Développement De Méthodes De Dépistage Des Médicaments De Contrefaçon Et Des Produits Adultérés Par LC-MS/MS Université de Montréal Développement de méthodes de dépistage des médicaments de contrefaçon et des produits adultérés par LC-MS/MS par Philippe Lebel Département de chimie Faculté des arts et sciences Mémoire présenté à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Maître ès sciences (M.Sc.) en chimie Décembre 2014 © Philippe Lebel, 2014 Résumé Ce projet de maitrise implique le développement et l’optimisation de deux méthodes utilisant la chromatographie liquide à haute performance couplée à la spectrométrie de masse en tandem (HPLC-MS/MS). L'objectif du premier projet était de séparer le plus rapidement possible, simultanément, 71 médicaments traitant la dysfonction érectile (ED) et 11 ingrédients naturels parfois retrouvés avec ces médicaments dans les échantillons suspectés d’être adultérés ou contrefaits. L'objectif du deuxième projet était de développer une méthode de dépistage permettant l'analyse rapide simultanée de 24 cannabinoïdes synthétiques et naturels pour une grande variété d'échantillons tels que les mélanges à base de plantes, des bâtons d'encens, de sérums et de cannabis. Dans les deux projets, la séparation a été réalisée en moins de 10 min et cela en utilisant une colonne C18 à noyau solide 100 2,1 mm avec des particules de 2,6 µm de diamètre couplée à un système MS avec trappe ionique orbitale fonctionnant en électronébulisation positive. En raison du nombre élevé de composés dans les deux méthodes et de l’émergence de nouveaux analogues sur le marché qui pourraient être présents dans les échantillons futurs, une méthode de dépistage LC-MS/MS ciblée/non-ciblée a été développée. Pour les deux projets, les limites de détection étaient sous les ng/mL et la variation de la précision et de l’exactitude étaient inférieures de 10,5%. Le taux de recouvrement à partir des échantillons réels variait entre 92 à 111%. L’innovation des méthodes LC-MS/MS développées au cours des projets est que le spectre de masse obtenu en mode balayage lors de l'acquisition, fournit une masse exacte pour tous les composés détectés et permet l'identification des composés initialement non-ciblés, comme des nouveaux analogues. Cette innovation amène une dimension supplémentaire aux méthodes traditionnellement utilisées, en permettant une analyse à haute résolution sur la masse de composés non-ciblés. Mots-clés : Médicaments traitant la dysfonction érectile; Flavonoids; Inhibiteurs de phosphodiestérase de type 5; Éjaculation prématurée; Échantillon contrefait; médicaments illégaux; Supplément alimentaire adultéré; échantillon adultéré; cannabinoides synthétiques et naturelles; LC-MS; Spice i Abstract This master’s project involved the development and optimization of two rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. The objective of the first project was to simultaneously separate, as rapidly as possible, 71 erectile dysfunction (ED) treatment drugs and 11 natural ingredients sometimes found alongside ED drugs present in suspected adulterated or counterfeit samples. The objective of the second project was to develop a screening method allowing rapid, simultaneous analysis of 24 synthetic and natural cannabinoids for a wide variety of samples such as herbal smoking mixtures, incense sticks, serums and Cannabis plant material. In both projects, the separations were achieved in ≤ 10 min using 2.6 µm fused-core C18 particles packed into a 100 2.1 mm column coupled to an LTQ Orbitrap XL mass spectrometer operated in positive electrospray mode. Because of the very high number of compounds in both methods and the knowledge that future analogues are always immerging on the market that could thus be present in samples, a targeted/untargeted LC-MS/MS screening method was developed. For both projects, detection limits were in the sub ng/mL range and intra- and inter-assay precisions were below 10.5%. Recovery from real samples ranged from 92 to 111%. The innovation of the developed LC-MS/MS methods is that the full scan event in the MS acquisition provides accurate masses for all detected species and thus allows post-analysis identification of initially untargeted compounds, i.e., the immerging analogues. This innovation adds an additional dimension to traditional MS/MS methods, allowing high mass resolution of untargeted compounds. Keywords : Erectile dysfunction drugs; Flavonoids; Phosphodiesterase type 5 inhibitors; Premature ejaculation; Counterfeit samples; illicit drugs; Adulterated dietary supplements, Synthetic and natural cannabinoids; LC-MS; adulterated samples; Spice ii Table des matières Résumé ......................................................................................................................................... i Abstract ....................................................................................................................................... ii Table des matières...................................................................................................................... iii Liste des figures ......................................................................................................................... vi Liste des tableaux ..................................................................................................................... viii Liste des abréviations ................................................................................................................. ix Remerciements ........................................................................................................................... xi 1. Introduction ............................................................................................................................. 1 1.1 Les médicaments contrefaits pour traiter la dysfonction érectiles .................................... 2 1.2 Les cannabinoides ............................................................................................................. 4 1.3 Objectifs des projets .......................................................................................................... 7 2. Instrumentation ....................................................................................................................... 8 2.1 Chromatographie liquide à haute performance ................................................................. 9 2.2 Spectrométrie de masse ................................................................................................... 15 3. Partie expérimentale.............................................................................................................. 21 3.1 Préparation des échantillons ........................................................................................... 22 3.2 Détermination des paramètres expérimentaux du spectromètre de masse ...................... 23 3.3 Optimisation de la méthode LC-MS ............................................................................... 31 3.3.1 Phase stationnaire..................................................................................................... 31 3.3.2 Phase mobile ............................................................................................................ 32 3.4 Performance de la méthode ............................................................................................. 32 3.4.1 Paramètres analytiques ............................................................................................. 32 3.4.2 Étude de stabilité ...................................................................................................... 34 3.4.3 Validation croisées ................................................................................................... 34 4. Analyse des médicaments traitant la dysfonction érectile .................................................... 36 4.1 Abstract ........................................................................................................................... 38 iii 4.2 Introduction ..................................................................................................................... 39 4.3 Materials and methods .................................................................................................... 40 4.3.1 Reagents and standards ............................................................................................ 40 4.3.2 Samples and sample preparation .............................................................................. 50 4.3.3 LC-MS/MS operating conditions ............................................................................. 51 4.3.4 Method performance ................................................................................................ 52 4.4 Results and discussion .................................................................................................... 53 4.4.1 Selectivity ................................................................................................................ 54 4.4.2 Solution stability ...................................................................................................... 58 4.4.3 Matrix effects and carryover .................................................................................... 58 4.4.4 Linearity, detection limit, quantification limit and recovery ................................... 59 4.4.5 Precision and accuracy ............................................................................................. 60 4.4.6 Analysis of samples ................................................................................................
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