References of "Sacre, Pierre-Yves"
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See detailComparing the qualitative performances of handheld NIR and Raman spectrophotometers for the detection of falsified pharmaceutical products
Ciza Hamuli, Patient ULiege; Sacre, Pierre-Yves ULiege; Waffo Tchounga, Christelle ULiege et al

in Talanta (2019), 202

Over the last decade, the growth of the global pharmaceutical market has led to an overall increase of substandard and falsified drugs especially on the African market (or emerging countries). Recently ... [more ▼]

Over the last decade, the growth of the global pharmaceutical market has led to an overall increase of substandard and falsified drugs especially on the African market (or emerging countries). Recently, several methods using handheld/portable vibrational spectroscopy have been developed for rapid and on-field drug analysis. The objective of this work was evaluate the performances of various NIR and Raman handheld spectrophotometers in specific brand identification of medicines through their primary packaging. Three groups of drug samples (artemether-lumefantrine, paracetamol, and ibuprofen) were used in tablet or capsule forms. In order to perform a critical comparison, the analytical performances of the two analytical systems was compared statistically using three methods: hierarchical clustering algorithm (HCA), data-driven soft independent modeling of class analogy (DD-SIMCA) and hit quality index (HQI). The overall results show good detection abilities for NIR systems compared to Raman systems based on Matthews’s correlation coefficients, generally close to one. Raman systems are less sensitive to the physical state of the samples than the NIR systems, it also suffers of the auto-fluorescence phenomenon and the signal of highly dosed active pharmaceutical ingredient (e.g. paracetamol or lumefantrine) may mask the signal of low-dosed and weaker Raman active compounds (e.g. artemether). Hence, Raman systems are less effective for specific product identification purposes but are interesting in the context of falsification because they allow a visual interpretation of the spectral signature (presence or absence of API). [less ▲]

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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 detailField survey to evaluate the prevalence of poor quality anti-infective medicines in Cameroon
Waffo Tchounga, Christelle Ange ULiege; Ciza Hamuli, Patient ULiege; Sacre, Pierre-Yves ULiege et al

Conference (2019, May 20)

Poor quality medicines pose a threat to all health systems. It is obvious that they have harmful consequences not only from the point of view of public health, but also from the economic and socio ... [more ▼]

Poor quality medicines pose a threat to all health systems. It is obvious that they have harmful consequences not only from the point of view of public health, but also from the economic and socio-economic point of view [1]. Over the past 15 years, substandards and falsified drugs have received increasing attention in scientific publications. However, there is little reliable data determining their prevalence with accuracy due to the scarcity of well-designed studies identified as having good methodological quality as well as representative sampling strategy [2-4]. In this context, we have decided to evaluate the prevalence of poor quality anti-infective medicines in two Cameroon areas (Yaoundé and Douala), inspired by the Medicines Quality Assessment Reporting Guidelines (MEDGUARG) [3] and WHO recommendations [4] for the sampling strategy and the methodology. Our study will focus on the formal private sector. Pharmacies as well as drugs products will be sampled by a stratified random sampling strategy. The study will focus on two anti-infective medicines (ciprofloxacin and metronidazole 500mg tablets) in tablets, from 96 outlets in the cities of Yaoundé and Douala that are the two main cities (Yaoundé and Douala) of Cameroon representing almost 70% of private outlets of the country. Mystery shoppers will collect samples using a specific scenario. As a prelude to our field study, screening and dosage methods have to be developed and validated in Liège University. They se methods consist of vibrational spectroscopy (near infrared and Raman spectroscopy) as first screening techniques and HPLC for identification and assay. For vibrational spectroscopy, qualitative models will be developed for identification using chemometric tools. HPLC methods will be validated following the total error approach using accuracy profile as decision tool. The medicines collected will be first analysed visually (physical appearance tests), then field methods will be implemented (screening methods: Paper Analytical Devices (PADs), handled NIR device). Finally laboratory testing (assay and confirmation methods: HPLC reference method and pharmacotechnical tests) will be performed at LANACOME (Yaoundé, Cameroon). Suspect and unusual samples will be transported to Liège University for further analyses. All these methods will be applied according to a decision tree based on observed facts. The study will be submitted to the ethics committee of the Ministry of Health in Cameroon. An accurate and fast HPLC method for identification and quantification of both metronidazole and ciprofloxacin has been developed. Identification models for some brands of ciprofloxacin and metronidazole using handled NIR and Raman devices has been developed before implementation on field. This study will allow us to evaluate not only the prevalence of poor quality anti-infective medicines marketed in Cameroon but also outlets dispensing substandard and falsified medicines. They will be distinguished into sub-standard, degraded or falsified and classified according to their country of origin, manufacturer and city of sampling. The results will be notified to the drug regulatory authority in Cameroon and if poor quality medicines are detected, we will proceed with an alert to the WHO Global Surveillance System. The estimation of the prevalence of counterfeit and falsified anti-infective medicines would be extrapolated to the entire population and depending on the information obtained, evaluate the patient health risk exposed to substandard and falsified anti-infective medicines and develop capacity-building interventions in the fight against poor quality medicines. [less ▲]

See detailHANDHELD RAMAN SPECTROSCOPY: AN ESSENTIAL TOOL TO TACKLE THE SUBSTANDARD MEDICINES ISSUE?
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Dispas, Amandine ULiege et al

Conference (2019, May 20)

According to the World Health Organization, there is a growing concern about the quality of medicines around the world. Indeed, more and more substandard and falsified medicines are identified. That is ... [more ▼]

According to the World Health Organization, there is a growing concern about the quality of medicines around the world. Indeed, more and more substandard and falsified medicines are identified. That is why several spectroscopic techniques such as Raman, near- or mid-infrared spectroscopy, have gained great interest for this purpose. By means of chemometrics, interesting results have been shown in terms of elucidation of falsified medicines composition by hyperspectral imaging (L. Coic) and with benchtop spectrophotometers (O.Ye. Rodionova). However, these instruments are rather expensive, heavy and are not appropriated for low and middle-income countries. To circumvent these issues, several low-cost and middle-cost handheld spectrophotometers have been developed. In some cases of falsification, there is presence of a wrong or an absence of active pharmaceutical ingredient (API) that is often easy to prove with spectroscopy. However, the major part of the burden is constituted of lower dosed API that is trickier to evaluate in the field with conventional tools. In this study, the potential of handheld Raman spectroscopy to assay API in a solid dosage form was evaluated. For this purpose, fifteen formulations with a various proportion of mannitol and microcrystalline cellulose, seven level of concentration of ibuprofen (14 % – 26 % (m/m)) were produced thanks to a design of experiments, following the ICH Q3 guidelines. The calibration set was realized by analysing 3 tablets per formulation and each tablet was assayed using a previously validated benchtop NIR model. The PLS model was developed using PLS-Toolbox running in a Matlab® environment. The PLS model calibration has shown very nice results, with a R² of calibration / R² of cross-validation of 0.981 / 0.968 and a RMSECV of 0.83% (m/m). As explained, the validation set was projected on model and showed a RMSEP of 0.89 % (m/m). Then, the quantitative model has been validated following the total error approach with 4 series, 5 levels of concentration and 3 replicates. The acceptance limits were set at +/-15 % following the European Pharmacopeia criteria for uniformity of content. In a nutshell, handheld Raman spectrophotometer has shown very interesting results for studied formulation. Thanks to the 14 – 26 % (m/m) range, the model could be applied to get the quantitative information of the dosage of substandard medicines on the field. [less ▲]

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See detailVibrational spectroscopy in analysis of pharmaceuticals: Critical review of innovative portable and handheld NIR and Raman spectrophotometers
Deidda, Riccardo ULiege; Sacre, Pierre-Yves ULiege; Clavaud, Matthieu et al

in TrAC: Trends in Analytical Chemistry (2019), 114

The fast pace of changes occurring in the pharmaceutical world emphasizes the need for powerful technologies that allow checking the quality of pharmaceutical products. Infrared and Raman spectroscopies ... [more ▼]

The fast pace of changes occurring in the pharmaceutical world emphasizes the need for powerful technologies that allow checking the quality of pharmaceutical products. Infrared and Raman spectroscopies have shown great potentialities for drug analysis in the last decades and consequently caught the attention of the scientific world as well as of industrial developers, leading to major technological advancements. These fast, eco-friendly, and non-destructive techniques help gather essential information about the samples under examination with consistent advantages. This review focuses on the application of portable/handheld NIR and Raman spectrophotometers in the analysis of pharmaceutical products for both in-process and quality control tests. Moreover, several analytical methods developed by several authors are described in order to illustrate the applications explored until now. [less ▲]

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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 detailVibra-Santé Hub
De Bleye, Charlotte ULiege; Widart, Joëlle ULiege; Sacre, Pierre-Yves ULiege et al

Poster (2018, December 19)

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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 ▲]

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See detailRaman chemical imaging, a new tool in kidney stone structure analysis: Case-study and comparison to Fourier Transform Infrared spectroscopy
Castiglione, Vincent ULiege; Sacre, Pierre-Yves ULiege; Cavalier, Etienne ULiege et al

Poster (2018, November 16)

The kidney stone’s structure might provide clinical information in addition to the stone composition. The Raman chemical imaging is a technology used for the production of two- dimension maps of the ... [more ▼]

The kidney stone’s structure might provide clinical information in addition to the stone composition. The Raman chemical imaging is a technology used for the production of two- dimension maps of the constituents’ distribution in samples. We aimed at determining the use of Raman chemical imaging in urinary stone analysis. Fourteen calculi were analyzed by Raman chemical imaging using a confocal Raman micro- spectrophotometer. They were selected according to their heterogeneous composition and morphology. Raman chemical imaging was performed on the whole section of stones. Once acquired, the data were baseline corrected and analyzed by MCR-ALS. Results were then compared to the spectra obtained by Fourier Transform Infrared spectroscopy. [less ▲]

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See detailTowards a spray-coating method for the detection of low-dose compounds in pharmaceutical tablets using surface-enhanced Raman chemical imaging (SER-CI)
Cailletaud, Johan ULiege; De Bleye, Charlotte ULiege; Dumont, Elodie ULiege et al

in Talanta (2018), 188

Surface-enhanced Raman chemical imaging (SER-CI) is a highly sensitive analytical tool recently used in the pharmaceutical field owing to the possibility to obtain high sensitivity along with spatial ... [more ▼]

Surface-enhanced Raman chemical imaging (SER-CI) is a highly sensitive analytical tool recently used in the pharmaceutical field owing to the possibility to obtain high sensitivity along with spatial information. However, the covering method of the pharmaceutical samples such as tablets with metallic nanoparticles is a major issue for SER-CI analyses due to the difficulty to obtain a homogeneous covering of tablet surface with the SERS substrates. In this context, a spray-coating method was proposed in order to fully exploit the potential of SER-CI. A homemade apparatus has been developed from an electrospray ionization (ESI) probe in order to cover the pharmaceutical tablets with the colloidal suspension in a homogeneous way. The silver substrate was pulled through the airbrush by a syringe pump which was then nebulized into small droplets due to the contact of the solution with the gas flow turbulence. A robust optimization of the process was carried out by adjusting experimental parameters such as the liquid flow rate and the spraying time. Besides, the performances of this spraying technique were compared with two others covering methods found in the literature which are drop casting and absorption coating. A homogeneity study, conducted by SER-CI and matrix assisted laser desorption/ ionization mass spectrometry imaging (MALDI-MSI) applied to the different covering techniques was performed. The influence of the metallic nanoparticles deposit on soluble compounds was also investigated in order to highlight the advantages of using this new spray coating approach. [less ▲]

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See detailA simple and easy-to-implement SERS approach overcoming the nanoparticle stabilisation by serum proteins: application to dopamine and PC-12 cells
Dumont, Elodie ULiege; De Bleye, Charlotte ULiege; Cailletaud, Johan ULiege et al

Conference (2018, September 11)

This lecture presents the different steps regarding the development of a label-free SERS analytical method that was able to overcome the nanoparticle stabilisation caused by serum proteins. It relied on ... [more ▼]

This lecture presents the different steps regarding the development of a label-free SERS analytical method that was able to overcome the nanoparticle stabilisation caused by serum proteins. It relied on the pre-aggregation of the SERS substrate, which was a suspension of gold nanoparticles. Furthermore, several applications of the developed methodology were presented: the quantification of dopamine in the culture medium of rat phaeochromocytoma PC-12 cells as well as the influence of calcium, potassium and dexamethasone on dopamine exocytosis from these cells. [less ▲]

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See detailTransfer of active pharmaceutical ingredients (API) Raman library from bench top towards handheld spectrometers
Clavaud, Matthieu ULiege; Sacre, Pierre-Yves ULiege; Hubert, Philippe ULiege et al

Conference (2018, September 09)

Over the last few years, manufacturers have made progress miniaturizing Raman spectrometers and trying to meet the practical needs of the end-users for raw material and finished goods identification. In ... [more ▼]

Over the last few years, manufacturers have made progress miniaturizing Raman spectrometers and trying to meet the practical needs of the end-users for raw material and finished goods identification. In this study, library transfer from a donor benchtop Raman towards different Raman receiver devices, benchtop and handheld, was evaluated. The aim was to create a library of active pharmaceutical ingredients (API) on a lab spectrometer and to show that a transfer to different Raman systems using the Hit Quality Index (HQI) algorithm is possible. Consequently, library creation would be faster as well as the set-up of a device for routine measurements avoiding the acquisition of hundreds sample on each system, and allow optimizing method update strategy. A donor benchtop DXR SmartRaman (Thermo Fisher Scientific®) and receivers composed of a benchtop RXN1 (Kaiser Optical System®), and two handheld spectrometers respectively Truscan (Thermo Fisher Scientific®) and MIRA M-1 (Metrohm AG®) were selected. All spectrometers were equipped with a 785 nm near infrared excitation laser to avoid variation in laser differences. The Orbital-Raster-Scanning (ORS) technology available on the MIRA M-1 was initially evaluated. Understanding the effect of the ORS technique on APIs was a previous step before setting up a database transfer experiment. Subsequently, acetaminophen was used for library standardization to calibrate the x-axis of the Raman spectrometers. Finally, Raman spectra were pre-processed prior to computation of the HQI method. The results showed that transferring an API library from a benchtop Raman system towards handheld systems with HQI values higher than 90% is possible. Additionally, an HQI of maximum 75% was observed between the different APIs suggesting that the APIs were different enough allowing a transfer. [less ▲]

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See detailComparing the qualitative performances of handheld NIR and Raman spectrometers for the analysis of falsified pharmaceutical products.
Ciza Hamuli, Patient ULiege; Waffo Tchounga, Christelle ULiege; Coic, Laureen ULiege et al

Poster (2018, September)

The last decade has seen a significant growth of the pharmaceutical market of emerging countries to the point that it has induced many falsifications. Research activities have followed this growth but not ... [more ▼]

The last decade has seen a significant growth of the pharmaceutical market of emerging countries to the point that it has induced many falsifications. Research activities have followed this growth but not proportionately. Recently, several chemical analysis methods for the detection of counterfeit or falsified drugs have been developed using spectroscopic techniques. In this study, different spectrometers were used to collect near-infrared (NIR) and Raman spectral data sets of selected drugs to help improve existing methods. The objective of this work was to evaluate the qualitative performances of the NIR and Raman spectrometers; two benchtop equipment (NIR and Raman) and four handheld ones (three Raman and one NIR) were used. In particular, we made a critical comparison in the evaluation of the accuracy of the prediction. The predictive ability of the different equipments was compared statistically using chemometrics: clustering algorithm, soft modeling (DD-SIMCA) and hard modeling (PLS-DA). All these chemometric strategies were applied on each equipment. Clustering approaches, DD-SIMCA and PLSDA enabled us to compare the qualitative performances of handheld NIR and Raman equipment and to make a critical analysis of their use in the field of the detection of falsified drugs. [less ▲]

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See detailDetection of low-dose of piroxicam polymorphs in pharmaceutical tablets by surface-enhanced Raman chemical imaging and multivariate analysis
Cailletaud, Johan ULiege; De Bleye, Charlotte ULiege; Dumont, Elodie ULiege et al

Poster (2018, September)

In the pharmaceutical industry, the detection and the identification of polymorphic forms of an active pharmaceutical ingredient (API) is an important concern during the drug development and the ... [more ▼]

In the pharmaceutical industry, the detection and the identification of polymorphic forms of an active pharmaceutical ingredient (API) is an important concern during the drug development and the manufacturing process. The necessity to detect polymorphic forms especially at low concentrations is an area of particular interest in pharmaceutical applications due the difference of physico-chemical properties exhibited by the polymorphs. The polymorphic behavior of drugs can affect the therapeutic efficacy of the drug substance and can also have an impact from an intellectual property (IP) standpoint. Indeed, much effort are expended by the regulatory authorities to determine if the polymorph present in the final product is covered by a patent for IP rights aspects. Various analytical techniques can be used for polymorph detection and characterization such as X-ray powder diffraction (XRPD), solid-state nuclear magnetic resonance spectroscopy (ssNMR) and vibrational spectroscopy. Despite low sensitivity and long image acquisition times, Raman microscopy is well suited to the analysis of polymorphic forms since it enables the acquisition of spectral and spatial information at the same time. This technique can be combined with surface-enhanced Raman scattering (SERS), resulting in surface-enhanced Raman chemical imaging (SER-CI). SER-CI is a promising tool for the detection and the visualization of low-dose compounds or impurities in tablets taking account of the high sensitivity of this technique. Consequently, we firstly focused on the development of a reproducible spray-coating method to control the deposition of SERS nanoparticles on pharmaceutical samples in order to fully exploit the potential of SER-CI. Besides, this spraying technique, coupled with SER-CI, was applied to model tablets consisting of one excipient and a 10% (w/w) API concentration. Piroxicam, a non-steroidal anti-inflammatory drug which presents three polymorphic forms was used as a model API. The model formulation was a binary mixture of the form β and the form α2 polymorphs of piroxicam. Using SER-CI and multivariate analysis, it was possible to detect the β form polymorph in these model tablets below 1% (w/w) while reducing the image acquisition time. To conclude, the combination of the spray-coating method and SER-CI enabled the detection of low-dose of piroxicam polymorphs in model pharmaceutical formulations. This approach can serve as a potential way for the development of methods validation for semi-quantitative and quantitative analyses [less ▲]

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See detailSolving composition of falsified artemether/lumefantrine formulation by hyperspectral imaging
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege et al

Poster (2018, September)

The emerging internet trade and its potential significant profitability cause falsified drugs to be one of the major public health issues of the 21st century. Although some preventing measures - such as ... [more ▼]

The emerging internet trade and its potential significant profitability cause falsified drugs to be one of the major public health issues of the 21st century. Although some preventing measures - such as the new European Parliament Directive 2011/62/UE - have been taken during the last decade, drugs are subject to more frequent monitoring from the authorities. New techniques thus have to be developed in order to help them investigate the relationships between falsified drugs and industries. Some preliminary tests such as visual inspection or colorimetric testing can be performed in order to check drug authenticity. When these tests are inconclusive, spectroscopy and hyperspectral imaging can be used to provide more information, especially to characterize the composition of presumed falsified samples. The efficiency of this technique has no longer to be proven. Vibrational hyperspectral imaging has many advantages such as the non-destruction of the sample and the possibility to combine spectral and spatial information. Once obtained, the hyperspectral data may be decomposed in its various spectral (qualitative) and spatial (quantitative) components using resolution algorithms such as MCR-ALS. The resolution of the spectral component allows the elucidation of the complete formulation composition without a priori knowledge, including mineral and organic compounds. This composition may be used as a production fingerprint for further forensic investigations. In this study, six artemether/lumefantrine formulations (two batches of Combiart 20/120 and four batches of Coartem 20/120) have been analyzed for falsification suspicion. First, a handheld Raman spectroscopic analysis has been performed confirming the falsification. The analysis confirmed the supposed absence of active compounds. In order to complete the knowledge of the formulations, one tablet per sample has been further analyzed by hyperspectral imaging. The MCR-ALS decomposition of the hyperspectral data cube shows that five out of the six samples (2 Combiart and 3 Coartem) have the same composition. Those samples are composed by two active compounds: sildenafil and ciprofloxacine chlorhydrate monohydrate at traces level by same excipients (organic and inorganic). This finding seems to indicate that despite different brand names, packaging and tablet shapes, these samples come from the same production. [less ▲]

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See detailForensic formulation fingerprinting of falsified medicine by Raman hyperspectral imaging
Sacre, Pierre-Yves ULiege; Coic, Laureen ULiege; Avohou, Tonakpon Hermane ULiege et al

Conference (2018, September)

With the Medicrime convention (in 2010) and the European Parliament directive 2011/62/UE (in 2011), the notion of pharmaceutical crime appeared allowing effective, proportionate, and deterring sanctions ... [more ▼]

With the Medicrime convention (in 2010) and the European Parliament directive 2011/62/UE (in 2011), the notion of pharmaceutical crime appeared allowing effective, proportionate, and deterring sanctions against the falsifiers. However, to be able to apply these sanctions, the authorities must collect information allowing them to go up to the manufacturing sites. This is however extremely complex at a global scale. The opportunity to link several falsification cases is one more brick laid in building the investigation. Hyperspectral imaging is not a new analytical tool and has been used in many research papers some of them about falsified medicines. However, the time has come to re-evaluate its place in the suspect formulation workflow. From our point of view, after a formulation is confirmed falsified (or substandard) by a first line investigation (e.g. visual inspection, handheld Raman or colorimetric testing), hyperspectral imaging should always be performed when possible (solid pharmaceutical forms). Indeed, in a single imaging analysis, one may access qualitative, semi-quantitative and distributional homogeneity of organic and inorganic constituents of the formulation. These inform on the risk of taking the medicine but most of all it provides a unique fingerprint of the production allowing the linking of falsification cases. To illustrate this, six artémether/luméfantrine formulations (two batches of Combiart 20/120 and four batches of Coartem 20/120) have been analyzed for falsification suspicion. Handheld Raman spectroscopic analysis rapidly confirmed the falsification and possibly the absence of active compound. Once confirmed falsified, one tablet of each formulation underwent Raman hyperspectral imaging on the whole sample surface. A chemometric analysis of the spectral data revealed the presence of traces of two active compounds (sildenafil and ciprofloxacine chlorhydrate monohydrate) and the same excipients (organic and inorganic) in five formulations (2 Combiart and 3 Coartem) allowing us to link these cases. [less ▲]

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See detailBayesian securing of the pharmaceutical supply chain
Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege; Lebrun, Pierre ULiege et al

Conference (2018, September)

Introduced in 2011, the European Union Falsified Medicines Directive asks for an enhanced security of the pharmaceutical supply chain. In this frame, manufacturers must apply safety measures to enable the ... [more ▼]

Introduced in 2011, the European Union Falsified Medicines Directive asks for an enhanced security of the pharmaceutical supply chain. In this frame, manufacturers must apply safety measures to enable the verification of authenticity and identification of individual packs. This is the so-called serialization of the pharmaceutical supply chain. However, these measures are only dedicated to the analysis of the secondary packaging and do not enable the analysis of the product’s quality. Therefore, we propose an end-to-end strategy based on spectroscopic fingerprints and risk-oriented statistical models for the verification of the quality of medicines along the supply chain. They can provide a precise description of the chemical composition of samples, and hence can be used to fingerprint a pharmaceutical product. A representative set of these spectra is sampled from each batch at release using appropriate devices. This sample is used to build a statistical tolerance band, that is assumed to contain a high proportion, say at least 90% of the future spectra of the product. The construction of such a band relies on the newly emerging chemometrics techniques such as functional data analysis (e.g. Bayesian wavelet or splines regressions). The upper and lower limits of the tolerance band are used as threshold or reference spectra for the conformity of a new spectrum. This allows us to declare the conformity of a product with a certain probability confidence. Compared to classical measures (p-values, Hit Quality Indexes), this functional data analysis and risk-oriented approach enables to detect very small perturbations of the spectrum caused, for example by degradation, batch inversion, etc. The computed tolerance band may be stored in a cloud server and accessed throughout the supply chain to check the conformity of the product itself. The spectral serialization of pharmaceutical batches is another brick in the wall of pharmaceutical supply chain securing. [less ▲]

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See detailDevelopment of a SERS strategy to overcome the nanoparticle stabilisation effect in serum-containing samples: Application to the quantification of dopamine in the culture medium of PC-12 cells
Dumont, Elodie ULiege; De Bleye, Charlotte ULiege; Cailletaud, Johan ULiege et al

in Talanta (2018), 186

The analysis of serum samples by surface-enhanced Raman spectroscopy (SERS) has gained ground over the last years. However, the stabilisation of colloids by the proteins contained in these samples has ... [more ▼]

The analysis of serum samples by surface-enhanced Raman spectroscopy (SERS) has gained ground over the last years. However, the stabilisation of colloids by the proteins contained in these samples has restricted their use in common practice, unless antibodies or aptamers are used. Therefore, this work was dedicated to the development of a SERS methodology allowing the analysis of serum samples in a simple and easy-to-implement way. This approach was based on the pre-aggregation of the colloid with a salt solution. Gold nanoparticles (AuNPs) were used as the SERS substrate and, owing to its physiopathological importance, dopamine was chosen as a model to implement the SERS approach. The presence of this neurotransmitter could be determined in the concentration range 0.5 to 50 ppm (2.64 – 264 µM) in the culture medium of PC-12 cells, with a R² of 0.9874, and even at lower concentrations (0.25 ppm, 1.32 µM) in another matrix containing fewer proteins. Moreover, the effect of calcium and potassium on the dopamine exocytosis from PC-12 cells was studied. Calcium was shown to have a predominant and dose-dependent effect. Finally, PC-12 cells were exposed to dexamethasone in order to increase their biosynthesis and release of dopamine. This increase was monitored with the developed SERS approach. [less ▲]

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