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Discovery of falsified Symbicort 320/9 Turbohaler identified in the UK in 2013 demonstrated that falsified dry powder inhalers were also present in the European market. This work aimed to investigate the current situation of formoterol-containing dry powder inhalers in Europe and North Africa by assessing their aerodynamic performance profile.A total of eight registered formoterol-based dry powder inhalers over the European and North African markets were involved in this study, including the reference drug Foradil. Samples were prepared using a multistage liquid impinger (MsLI) and further analyzed by a validated HPLC-UV method to determine the delivered and the fine particle doses (FPDs). This study also examined the impact of freezing-thawing cycles on sample stability in terms of analytical purpose handling.No substandard dry powder inhalers were identified among the medicinal products involved in this work. The delivered dose (DD) of assessed drugs varied from 8.33 to 9.69 µg, while the FPD was between 1.86 and 3.35 µg. As expected, this work confirmed that the capsule composition and the barrier properties of the primary packaging can affect the FPD of dry powder for inhalation use.The FPD of products C and B was, respectively, 17.4 and 14.2% superior to Foradil, products D and H had the closest values compared to the original drug, and product F was 34.5% inferior. Additionally, this work showed that a high FPD can be achieved using HPMC capsules and moisture-impermeable primary packaging.

Vitamin D

Fracture toughness tests (compact tension) of a dual material composed of a structured Metal Matrix Composite (MMC) (martensitic steel and titanium carbides, named MS-TiC) surrounded by martensitic steel (MS) are simulated with a Discrete Elements Model (DEM) developed with the GranOO Workbench. The MMC structures are micro-lattices such as gyroid, octet-truss and Face and Body-Centered Cubic with Z-truss (FBCCZ). The volume fraction of these MMC inserts and their cell size are fixed, the influence of the cell orientation is studied. The aim of the study is to determine the configuration of topology (shape and cell orientation) which absorbs the most energy and is the most crack resistant. From experimental tests, the Young&rsquo, s moduli and the failure stresses of the MMC material and the metal are estimated, and thanks to beam network discretization, a local stiffness and a failure criterion are evaluated to finally obtain a crack propagation path. To verify the suitability of the DEM model, a Compact Tension (CT) experimental test on MMC specimens is performed and a stress intensity factor is computed. A good agreement with an error less than 10% is obtained between experimental and simulated KIc with values respectively equal to 35 and 37 MPam. From DEM simulations based on the CT tests, the FBCCZ cell absorbs the most energy at the crack propagation compared to other structures and the steel. The crack propagation length depends on the shape of the topology. The originality of the study lies in the modeling, with granular properties using DEM, of the mechanical and elastic fracture behavior of these topological structures classically solved by Finite Elements Method (FEM): the microscopic constitutive relations have been validated macroscopically by experimental tests on homogeneous MMC materials.

International audience

Vitamin D3 is a key micronutrient whose intakes are inadequate for most populations worldwide. Supplementation with medicines or food supplements is commonly prescribed to correct this imbalance and the quality of these products must be ensured. In this context, a generic methodology for the assay of vitamin D3 in oily formulations is proposed using supercritical fluid chromatography coupled to mass spectrometry (SFC-MS). It is in line with green analytical chemistry principles and combines the use of i) a fast and robust analytical method (4.0 min analysis time) ii) an easy sample preparation compatible with high throughput analysis (“dilute-and-shoot” approach) and iii) a relevant control strategy. Seventeen products from multiple manufacturers and encompassing a large content range were evaluated in this study. They were classified in four groups to streamline their processing considering the use of a matrix-matched calibration procedure. Matrix effect was thoroughly studied and was found to be low (99-106%), stable intra/inter-series and comparable between the different groups and types of matrices. The implemented control strategy was based on a three-level system suitability tests (SST). Level 1 SST: resolution of the critical pair that was above 1.5 for all analysis series. Level 2 SST: evaluation of the adequacy of the calibration for a QC sample in terms of recovery that was between 97-104% with a variability between 1-2%. Level 3 SST: method trueness that was between 95-102%. Sample analysis highlighted differences in types of products and dosage forms. This is the first study to propose a complete strategy for the quality control of vitamin D3 oily formulations and should prove useful in QC laboratories.

Pharmaceutical regulatory bodies increasingly require the implementation of systematic approaches in pharmaceutical product development. Quality control methods play a key role in the control strategy of drugs manufacturing to assure their quality. A risk-based approach in the analytical method development is strongly recommended to ensure that the method performances fit the purpose of the method during its entire life-cycle. In the last decade, analytical quality by design (AQbD), as risk management oriented methodology, has been progressively integrated with method development for fulfilling this objective. This approach has successfully allowed the quality to be designed into the analytical processes by obtaining a deep understanding of the procedures. In this paper the AQbD workflow and its application in the development of methods to be used for pharmaceutical quality control have been treated and discussed. Recent publications regarding how AQbD has been applied in separation techniques were reviewed. The different development strategies have been also showcased, highlighting their advantages and disadvantages, in order to give a useful overview.

The pharmaceutical industry is highly regulated by quality policies. The concept of risk management is strongly integrated into the quality assurance system to ensure pharmaceuticals' quality and patients' safety. In the context of quality control, the detection of impurities in raw materials and finished products is a major concern. It can be challenging for analytical scientists to meet specificity/selectivity and sensitivity requirements. Obviously, separation techniques are widely used for the detection of impurities but the method development required to achieve Analytical Target Profile (ATP) concerns is often challenging. Therefore, to ensure pragmatic and systematic methods development and simultaneously manage the risk associated with analytical methods, the principles of Quality by Design (QbD) should be applied. This paper provides an overview of QbD principles and statistical strategies (mainly DoE-DS approach) which can be applied to impurity detection methods, as well as a review of the literature where QbD has been applied to these types of analytical methods.

The Discrete Element Method (DEM), also known as Distinct Element Method (DEM), is extensively used to study divided media such as granular materials. When brittle failure occurs in continuum such as concrete or ceramics, the considered media can be viewed as divided. In such cases, DEM offers an interesting way to study and simulate complex fracture phenomena such as crack branching, crack extension, crack deviation under coupled mode or crack lip closure with friction. The fundamental difficulty with DEM is the inability of the method to deal directly with the constitutive equations of continuum mechanics . DEM uses force–displacement interaction laws between particles instead of stress–strain relationships. Generally, this difficulty is bypassed by using inverse methods , also known as calibration processes, able to translate macroscopic stress–strain relationships into local force–displacement interaction laws compatible within DEM frameworks. However, this calibration process may be fastidious and really hard to manage. The presented work proposes to improve the Distinct Lattice Spring Model in order to deal with non-regular domains, by using Voronoi cells, which allow to completely fill the volume space of discrete domains. With this approach, the rotational effects must be included in the contact formulation, which enables the management of large rigid body rotations . This work also introduces a simple method to manage brittle fracture . Using non-regular domains avoids the cracks paths conditioning, and allows to reproduce quantitatively the Brazilian test, very popular in the rock mechanics community.

Summary This paper proposes an original method to simulate the electrical conduction in continuums with the Discrete Element Method (DEM). The proposed method is based on the graphs theory applied to electrical resistance network, where the resistance between two discrete elements is estimated through the notion of ‘transmission surface’ to assume the discrete domain as a continuous medium. In addition to the electrical conduction, the Joule heating of a DEM domain has also been developed to take full advantage of the electrical conduction. The proposed method has been implemented in the free DEM software named ‘GranOO’. The numerical results were compared against analytical approaches when applicable, or against Finite Element Method if the geometries become more complex or in case of dynamic loadings. The results are found satisfactory with errors around 3% for the electrical conduction and Joule heating of reasonably complex domains and loading cases. When it comes to more complex domains, such as electrical constriction, whilst the results remain close to those obtained with reference solutions (around 6%), they highlight the importance of taking care about the domains discretization. Finally, the proposed method is applied to detect cracks onset on a cylindrical rod torsion test to show how to take advantage of the proposed work. Copyright © 2016 John Wiley & Sons, Ltd.

Within the family of serotonin (5-HT) receptors, the 5-HT1A subtype is particularly interesting as it may be involved in various physiological processes or psychological disorders. The p-[18F]MPPF, a highly selective 5-HT1A antagonist, is used for in vivo studies in human or animal by means of positron emission tomography (PET) [1]. In order to selectively extract p-[18F]MPPF and its main metabolites from plasma, molecularly imprinted polymer (MIP) was prepared against these compounds by using the p-MPPF as template. For the control of the selectivity, non-imprinted polymer (NIP) was also synthesized without template. The MIP sorbent, packed in disposable extraction cartridges (DECs), was then evaluated as molecularly imprinted solid-phase extraction (MISPE) prior to the LC determination. The conditions of extraction were evaluated in order to obtain the highest selective retention of the p-[18F]MPPF and its metabolites on this MIP. The MIP selectivity was exploited in the loading and washing steps by adjusting the pH of plasma samples at a suitable value and by selecting mixtures for the washing step to limit the contribution of non-specific interactions. Other important parameters involved in the conditioning and elution steps were also studied. Finally, a pre-validation was carried out with optimal extraction conditions to demonstrate the performance of this MISPE-LC method as a generic method in the context of evaluation of new MISPE for p-[18F]MPPF and its potential for metabolites extraction from human plasma.

In France, approximately 500 deaths per year are related to sudden infant death syndrome (SIDS). After a 75% reduction of SIDS-related deaths in the 1990s, thanks to large prevention campaigns directing parents to put their infants to sleep on their back, the number of SIDS-related deaths remains stable. However, we estimate that 100-200 infant deaths per year in France could be prevented with better education on the risk factors for SIDS. In this prospective, descriptive monocentric study, we aimed to evaluate the level of expectant women's knowledge about SIDS. Questionnaires were distributed during a midwife consultation. A score on sleeping conditions, environmental and protective factors was determined with coefficients attributed according to their relevance to SIDS. Of 296 questionnaires distributed, 202 were completed and included in the analysis from March 1 to September 21, 2018. Scores were distributed from 2 to 46/50. The average score was 28.6/50. Information was principally obtained from media and not health professionals. When the information was delivered by a caregiver, in particular by a paediatrician, we observed better knowledge among these women. This study shows that it is important for health professionals to take the time to inform future mothers about the risk factors for SIDS, especially the least informed population groups such as young mothers and those from lower socioeconomic status, in order to reduce the number of avoidable infant deaths.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are considered as the most interesting cannabinoids in Cannabis sativa L. for the clinical practice. Since 2013, the Italian law allows pharmacists to prepare and dispense cannabis extracts to patients under medical prescription, and requires the evaluation of CBD and Δ9-THC content in cannabis extracts before sale. Cannabis olive oil extracts are prepared from dried female cannabis inflorescences, but a standard protocol is still missing. In this study, a fast RP-HPLC/UV method has been developed to quantify CBD and Δ9-THC in cannabis olive oil extracts. The analytical quality by design strategy has been applied to the method development, setting critical resolution and total analysis time as critical method attributes (CMAs), and selecting column temperature, buffer pH and flow rate as critical method parameters. Information from Doehlert Design in response surface methodology combined to Monte-Carlo simulations led to draw the risk of failure maps and to identify the method operable design region. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and then implemented in routine analysis. A control strategy based on system control charts was planned to monitor the developed method performances. Evaluation data were recorded over a period of one year of routine use, and both the CMAs showed values within the specifications in every analysis performed. Hence, a new risk evaluation for the future performances of the method was achieved by using a Bayesian approach based on the routine use data, computing the future distribution of the two CMAs. Finally, a study focusing on the monitoring of CBD and Δ9-THC concentrations in cannabis olive oil extracts was carried out. The developed method was applied to 459 extracts. The statistical analysis of the obtained results highlighted a wide variability in terms of concentrations among different samples from the same starting typology of cannabis, underlining the compelling need of a standardised procedure to harmonise the preparation of the extracts.

In this study, we describe the development of a SFC-MS method for the quality control of cannabis plants that could be potentially adulterated with synthetic cannabinoids. Considering the high number of already available synthetic cannabinoids and the high rate of development of novel structures, we aimed to develop a generic method suitable for the analysis of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as model compounds. Firstly, a suitable column was chosen after a screening phase. Secondly, optimal operating conditions were obtained following a robust optimization strategy based on a design of experiments and design space methodology (DoE-DS). Finally, the quantitative performances of the method were assessed with a validation according to the total error approach. The developed method has a run time of 9.4 min. It uses a simple modifier composition of methanol with 2% H2O and requires minimal sample preparation. It can chromatographically separate natural cannabinoids (except THC-A and CBD-A) from the synthetics assessed. Also, the use of mass spectrometry provides sensitivity and specificity. Moreover, this quality by design (QbD) approach permits the tuning of the method (within the DS) during routine analysis to achieve a desirable separation since the future compounds that should be analyzed could be unknown. The method was validated for the quantitation of a selected synthetic cannabinoid in fiber-type cannabis matrix over the range of 2.5% – 7.5% (w/w) with LOD value as low as 14.4 ng/mL. This generic method should be easy to implement in customs or QC laboratories in the context of counterfeit drugs tracking.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

When using an analytical method, defining an analytical target profile (ATP) focused on quantitative performance represents a key input, and this will drive the method development process. In this context, two case studies were selected in order to demonstrate the potential of a quality-by-design (QbD) strategy when applied to two specific phases of the method lifecycle: the pre-validation study and the validation step. The first case study focused on the improvement of a liquid chromatography (LC) coupled to mass spectrometry (MS) stability-indicating method by the means of the QbD concept. The design of experiments (DoE) conducted during the optimization step (i.e. determination of the qualitative design space (DS)) was performed a posteriori. Additional experiments were performed in order to simultaneously conduct the pre-validation study to assist in defining the DoE to be conducted during the formal validation step. This predicted protocol was compared to the one used during the formal validation. A second case study based on the LC/MS-MS determination of glucosamine and galactosamine in human plasma was considered in order to illustrate an innovative strategy allowing the QbD methodology to be incorporated during the validation phase. An operational space, defined by the qualitative DS, was considered during the validation process rather than a specific set of working conditions as conventionally performed. Results of all the validation parameters conventionally studied were compared to those obtained with this innovative approach for glucosamine and galactosamine. Using this strategy, qualitative and quantitative information were obtained. Consequently, an analyst using this approach would be able to select with great confidence several working conditions within the operational space rather than a given condition for the routine use of the method. This innovative strategy combines both a learning process and a thorough assessment of the risk involved.

International audience; Cemented carbide materials exhibit high hardness and fracture toughness. As a consequence they possess an excellent wear resistance that make them a material of choice for the manufacturing of cutting, drilling and forming tools. Cemented carbide materials are made of tungsten carbide (WC) grains embedded in a ductile metal phase, generally made of cobalt. The wear mechanism of the tungsten carbide and cobalt composites (WCsingle bondCo) operates in several successive steps: removal of the cobalt binder in the surface vicinity, plastic deformation and/or fracture of WC grains, debonding of WC grains and finally galling of workpiece material in the cavities freed of the WC grains. The present study focuses on the debonding step of the WCsingle bondCo wear mechanism.A micromechanical finite element is developed to study de sensitivity of a WC grain to be torn off the surface of a WCsingle bondCo composite structure. The model considers a single WC grain embedded in a homogeneous elementary volume of WCsingle bondCo material. The geometry of the WC grain is a rectangle which perimeter, width and length are based on statistical analyses of actual WCsingle bondCo die surfaces used in cold forming. Cohesive elements are used to model the junction between the grain and the elementary volume. The grain is torn off the surface when the fracture energy calculated within the cohesive element is totally consumed. The loadings applied on the grain are based on actual cold heading forming sequences. Various grain size, shape, orientation and friction conditions are tested. Results show that grain orientation, friction and WCsingle bondCo material toughness play a great role in WC grain removal. Equiaxed grains with small perimeter are less sensitive to debonding.

The understanding of the method is a major concern when developing a stability-indicating method and even more so when dealing with impurity assays from complex matrices. In the presented case study, a Quality-by-Design approach was applied in order to optimize a routinely used method. An analytical issue occurring at the last stage of a long-term stability study involving unexpected impurities perturbing the monitoring of characterized impurities needed to be resolved. A compliant Quality-by-Design (QbD) methodology based on a Design of Experiments (DoE) approach was evaluated within the framework of a Liquid Chromatography (LC) method. This approach allows the investigation of Critical Process Parameters (CPPs), which have an impact on Critical Quality Attributes (CQAs) and, consequently, on LC selectivity. Using polynomial regression response modeling as well as Monte Carlo simulations for error propagation, Design Space (DS) was computed in order to determine robust working conditions for the developed stability-indicating method. This QbD compliant development was conducted in two phases allowing the use of the Design Space knowledge acquired during the first phase to define the experimental domain of the second phase, which constitutes a learning process. The selected working condition was then fully validated using accuracy profiles based on statistical tolerance intervals in order to evaluate the reliability of the results generated by this LC/ESI-MS stability-indicating method. A comparison was made between the traditional Quality-by-Testing (QbT) approach and the QbD strategy, highlighting the benefit of this QbD strategy in the case of an unexpected impurities issue. On this basis, the advantages of a systematic use of the QbD methodology were discussed.

A new application of surface-enhanced Raman scattering (SERS) in the field of plant material analysis is proposed in this study. The aim was to monitor the release of anatabine by methyl jasmonate (MeJa) elicited Bright Yellow-2 (BY-2) cells. Gold nanoparticles (AuNps) were used as SERS substrate. The first step was to study the SERS activity of anatabine in a complex matrix comprising the culture medium and BY-2 cells. The second step was the calibration. This one was successfully performed directly in the culture medium in order to take into account the matrix effect, by spiking the medium with different concentrations of anatabine, leading to solutions ranging from 250 to 5000 µg L−1. A univariate analysis was performed, the intensity of a band situated at 1028 cm−1, related to anatabine, was plotted against the anatabine concentration. A linear relationship was observed with a R2 of 0.9951. During the monitoring study, after the MeJa elicitation, samples were collected from the culture medium containing BY-2 cells at 0, 24 h, 48 h, 72 h and 96 h and were analysed using SERS. Finally, the amount of anatabine released in the culture medium was determined using the response function, reaching a plateau after 72 h of 82 µg of anatabine released/g of fresh weight (FW) MeJa elicited BY-2 cells.

The aim of the present study is to develop a strategy of numerical simulation to study the sequencing of two processes, when the modeling geometry assumptions differ. In this study, the first process is assumed continuous, leading to a plane strain model. The developed strategy of simulation takes advantages of this assumption to extrude, in the out-of-plane direction, the 2D mesh and the mechanical fields to create a 3D model corresponding to the second process. In a previous experimental study achieved by the authors, an edge-trimming/strip thickness reduction sequence was analyzed. The aim was to quantify the effect of the work hardening accumulated in the first step on the occurrence of cracks in the strips edges during the second one. The present study uses this experimental sequence to validate the proposed approach and to better understand the reasons of edge cracking, according to the plastic strain level and thickness reduction conditions. Finally, the proposed approach is used as a predictor, to quantify the effect of a major parameter in edge-trimming on the strips edges integrity, at the end of the full sequence.

Analytical methods capability evaluation can be a useful methodology to assess the fitness of purpose of these methods for their future routine application. However, care on how to compute the capability indices have to be made. Indeed, the commonly used formulas to compute capability indices such as Cpk, will highly overestimate the true capability of the methods. Especially during methods validation or transfer, there are only few experiments performed and, using in these situations the commonly applied capability indices to declare a method as valid or as transferable to a receiving laboratory will conduct to inadequate decisions. In this work, an improved capability index, namely Cpk-tol and the corresponding estimator of proportion of non-conforming results (π(Cpk-tol)) have been proposed. Through Monte-Carlo simulations, they have been shown to greatly increase the estimation of analytical methods capability in particular in low sample size situations as encountered during methods validation or transfer. Additionally, the usefulness of this capability index has been illustrated through several case studies covering applications commonly encountered in the pharmaceutical industry. Finally a methodology to determine the optimal sample size required to validate analytical methods is also given using the proposed capability metric.

The aim of this paper is to analyze the effect of cutting process on crack occurrence in metal forming, especially on strip edges. This study is performed within the field of cold rolling on an experimental testing stand by means of the Upsetting Rolling Test (URT). This test allows to reproduce cold rolling contact parameters such as forward slip, reduction ratio and friction coefficients. Specimens sampled near industrial strip edges are deformed using the URT. A first set of specimens is submitted to two successive passes using extreme forward slips each. A second set of specimens is annealed to reduce edge strain hardening due to the cutting process. The same deformation configurations as for the first set of specimens are applied. SEM micrographs and optical surface profiler topographies of trimmed and deformed specimen edges show that forward slip has a major effect on opening of cracks. In the case of heat treated specimens hardness is decreased, characterizing a quasi homogenous material state. No cracks appeared after all reduction passes, which shows a large influence of the cutting process.

A sensitive and accurate LC/MS method was developed for the monitoring of glucosamine (GLcN) dog plasmatic concentration. In this scope, relatively low plasmatic concentrations of GLcN were expected, ranging from 50 to 1000 ng/mL. Liquid chromatography coupled to simple quadrupole mass spectrometry detection (LC/MS) was selected bringing the selectivity and the sensitivity needed for this application. Additionally, a solid phase extraction (SPE) step was performed to reduce matrix and ion suppression effects. Due to the ionisable character of the compound of interest, a mixed-mode strong cation exchange (Plexa PCX) disposable extraction cartridge (DEC) was selected. The separation was carried out on a Zorbax SB-CN column (5 microm, 4.6mm i.d. x 250 mm), considering hydrophilic interaction liquid chromatography (HILIC). Indeed, the mobile phase was made of methanol and 5mM ammonium hydrogen carbonate buffer at pH 7.5 (95/5, v/v). The detection was led at m/z ratios of 180.0 and 417.0, for GLcN and IS, respectively. Reliability of the results was demonstrated through the validation of the method using an approach based on the accuracy profile allowing managing the risk associated to the use of these methods in routine analysis: it is thus guaranteed that each future result will fall in the +/-30% acceptance limits with a probability of at least 90%. Successful application of the method to a preliminary pharmacokinetic study illustrated the usefulness of the method for pre-clinical studies.

Tin octoate is used as a catalyst in the synthesis of polydimethylsiloxane (PDMS), a room temperature vulcanizing (RTV) silicone rubber. This rubber is largely used in the medical field due to its great biocompatibility. In this framework, a high-speed and costless analytical method for the determination of stannic ions, Sn(IV), in the presence of stannous ions, Sn(II), has been developed. The separation of these two ions was carried out using differential pulse polarography (DPP). For this purpose, the tin species contents in the catalyst is quantitatively extracted under inert condition to avoid any changes in the ratio Sn(IV)/Sn(II). Polarography showed well-shaped oxidation and reduction peaks respectively at -650 and -860mV for stannous ions. The peak of the stannic ion was well separated and appeared at -1210mV. Many parameters such as extraction process, extraction time, pH, chelating agents and polarographic conditions were optimized. We have also demonstrated that no oxidation of the stannous ions occurred during the sample preparation. The dosing range considered in this study extends between 10 and 40mug/mL, corresponding to 6.8% and 27.2% of the degradation product (Sn(IV)) in the catalyst, regarding to the sampling. Finally this method was successfully validated using the total error concept.

This paper deals with an original study on serration, supposed to be the result of residual stresses in the strip metal edge, due to edge trimming and revealed during the cold rolling process. The aim of this research work is to predict the formation of serration and the finite element methodology will be used to model edge trimming. The first part of this paper focuses on the simulation of the process using two fracture criteria and the Lemaitre’s damage model which have been implemented into a Vectorized User MATerial (VUMAT). The configuration of the damage model coupled to a fracture criterion is also considered. A 2D numerical model of edge trimming is created to validate the accuracy of the implemented models by comparison of the crack profiles obtained by finite element simulation with those obtained in industrial conditions. The second part of this work concerns the 3D model of edge trimming. A special attention is given to the meshing of this model to obtain a realistic crack profile and an accurate residual stress state on the strip edge.

This paper is focused on the basic study and optimization of short time (

A comparative study of chemical bath deposition (CBD) of ZnS, CdS, and a mixture of (Cd,Zn)S buffer layers has been carried out on electrodeposited CuIn(S,Se)2 (CISSe) and coevaporated Cu(In,Ga)Se2 (CIGS) absorbers. For an optimal bath composition with the ratio of [Zn]/[Cd] = 25, efficiencies higher than those obtained with CdS and ZnS recipes, both on co-evaporated CIGS and electrodeposited CISSe, have been obtained independent of the absorber used. In order to better understand the (Cd,Zn)S system and its impact on the increased efficiency of cells, predictions from the solubility diagrams of CdS and ZnS in aqueous medium were made. This analysis was completed by in situ growth studies with varying bath composition by quartz crystal microbalance (QCM). The morphology and composition of the films were studied using scanning electron microscopy (SEM) and X-ray photoelectron spectra (XPS) techniques. Preliminary XPS studies showed that films are composed of a mixture of CdS and Zn(O,OH) phases and not a pure ternary Cd1 − xZnxS compound. The effect of the [Zn]/[Cd] molar ratio on properties of the corresponding CISSe and CIGS solar cells was investigated by current voltage [J(V)] and capacitance voltage [C(V)] characterizations. The origin of optimal results is discussed. Copyright © 2008 John Wiley & Sons, Ltd.

In the field of Cu(Ga,In)(S,Se) 2 photovoltaic technology, zinc sulphide based buffer layers prepared by Chemical Bath Deposition (CBD) have already demonstrated their potential to replace CdS. This paper aims on a better understanding of deposition mechanism of the Zn(S,O,OH) buffer layers. First, the influence of deposition parameters is studied from solution chemistry considerations by constructing solubility diagrams of ZnS, ZnO, and Zn(OH) 2 . Experimental studies are then carried out by the in situ quartz crystal microgravimetry (QCM) technique. A global equation for the growth rate is derived from these experiments. The morphology and composition of Zn(S,O,OH) films are then determined using scanning electron microscopy and X-ray photoelectron spectroscopy techniques. Electro-deposited-CIS/Zn(S,O,OH)/ZnO and co-evaporated-CIGS/Zn(S,O,OH)/ZnO cells were prepared with efficiencies similar to that of reference CBD CdS buffer layers.

All analysts face the same situations as method validation is the process of proving that an analytical method is acceptable for its intended purpose. In order to resolve this problem, the analyst refers to regulatory or guidance documents, and therefore the validity of the analytical methods is dependent on the guidance, terminology and methodology, proposed in these documents. It is therefore of prime importance to have clear definitions of the different validation criteria used to assess this validity. It is also necessary to have methodologies in accordance with these definitions and consequently to use statistical methods which are relevant with these definitions, the objective of the validation and the objective of the analytical method. The main purpose of this paper is to outline the inconsistencies between some definitions of the criteria and the experimental procedures proposed to evaluate those criteria in recent documents dedicated to the validation of analytical methods in the pharmaceutical field, together with the risks and problems when trying to cope with contradictory, and sometimes scientifically irrelevant, requirements and definitions.

It is recognized that the purpose of validation of analytical methods is to demonstrate that the method is suited for its intended purpose. Validation is not only required by regulatory authorities, but is also a decisive phase before the routine use of the method. For a quantitative analytical method the objective is to quantify the target analytes with a known and suitable accuracy. For that purpose, first, a decision about the validity of the method based on prediction is proposed: a method is declared proper for routine application if it is considered that most of the future results generated will be accurate enough. This can be achieved by using the "beta-expectation tolerance interval" (accuracy profile) as the decision tool to assess the validity of the analytical method. Moreover, the concept of "fit-for-purpose" is also proposed here to select the most relevant response function as calibration curve, i.e. choosing a response function based solely on the predicted results this model will allow to obtain. This paper reports four case studies where the results obtained with quality control samples in routine were compared to predictions made in the validation phase. Predictions made using the "beta-expectation tolerance interval" are shown to be accurate and trustful for decision making. It is therefore suggested that an adequate way to conciliate both the objectives of the analytical method in routine analysis and those of the validation step consists in taking the decision about the validity of the analytical method based on prediction of the future results using the most appropriate response function curve, i.e. the fit-for-future-purpose concept.

This paper presents a thermodynamic study of Chemical Bath Deposition (CBD) of zinc sulphide based films in aqueous ammonia solutions. The aim is a better understanding of ammonia and temperature effects on the deposition conditions and films composition. The formation of solid phases has been predicted by means of the precipitation conditions of ZnO, Zn(OH) 2 and ZnS as a function of temperature between 298 and 333 K. Films have been deposited according to calculated diagrams and preliminary results on solar cells based on electrodeposited CuIn(S,Se) 2 layers have been demonstrated. Composition and thickness of the films have been extracted to link the theoretical study with experiments.

When developing a new formulation, the development, calibration and validation steps of analytical methods based on vibrational spectroscopy are time-consuming. For each new formulation, real samples must be produced and a "reference method" must be used in order to determine the Active Pharmaceutical Ingredient (API) content of each sample. To circumvent this issue, the paper presents a simple approach based on the film-casting technique used as a calibration tool in the framework of hot-melt extrusion process. Confocal Raman microscopic method was successfully validated for the determination of itraconazole content in film-casting samples. Then, hot-melt extrusion was carried out to produce real samples in order to confront the results obtained with confocal Raman microscopy and Ultra High Performance Liquid Chromatography (UHPLC). The agreement between both methods was demonstrated using a comparison study based on the Bland and Altman's plot.

This paper presents recent investigations in the field of lubricant escapes from asperities. This phenomenon, named Micro Plasto Hydrodynamic Lubrication (MPHL), induces friction variation during metal forming processes. A better understanding of MPH lubrication would lead to a better management of friction, which is a central element in most sheet metal forming processes. To fulfil that goal, experiments were conducted in plane strip drawing using a transparent upper tool in order to observe lubricant flow around macroscopic pyramidal cavities. These experiments were then numerically reproduced with two complementary Finite Element models. The numerical results are discussed in this paper and show good agreement with experimental measurements.

Bisphenol A (BPA) is well known for its use in plastic manufacture and thermal paper production despite its risk of health toxicity as an endocrine disruptor in humans. Since the publication of new legislation regarding the use of BPA, manufacturers have begun to replace BPA with other phenolic molecules such as bisphenol F (BPF) and bisphenol B (BPB), but there are no guarantees regarding the health safety of these compounds at this time. In this context, a very simple, cheap and fast surface-enhanced Raman scattering (SERS) method was developed for the sensitive detection of these molecules in spiked tap water solutions. Silver nanoparticles were used as SERS substrates. An original strategy was employed to circumvent the issue of the affinity of bisphenols for metallic surfaces and the silver nanoparticles surface was functionalized using pyridine in order to improve again the sensitivity of the detection. Semi-quantitative detections were performed in tap water solutions at a concentrations range from 0.25 to 20 μg L(-1) for BPA and BPB and from 5 to 100 μg L(-1) for BPF. Moreover, a feasibility study for performing a multiplex-SERS detection of these molecules was also performed before successfully implementing the developed SERS method on real samples.

IF=2.124; International audience; This paper focuses on the analysis of surfaces resulting from thickness reduction of aluminium strips, provided with lubricant reservoirs, and deformed with different lubricant viscosities and drawing velocities, by a specific experimental drawing process. During reduction, the lubricant is pressurized and may escape from its initial cavities and supply the neighbouring ones. The nature of the lubrication regime is thus locally changed and may vary from boundary to hydrodynamic. The deformed surfaces are measured by means of a Vertical Scanning Interferometer then analysed in terms of arithmetic roughness and developed roughness profile length. Since these two parameters are found not accurate enough to identify regions where different lubrication phenomena occurred, a method based on roughness peaks and valleys curvature radii estimation, recently developed by some of the present authors, is applied.The acquired surfaces are assumed as fractal surfaces and a multiscale decomposition of the peaks and valleys curvature radii of roughness profile is performed, for each experimental test. Then the analysis of the deformed surfaces is achieved and the effects of the different testing conditions on the curvature radii are highlighted. During this study, this method has been of great help to qualitatively define the different contacts nature, i.e. severe or not, and to link the different regions to a lubrication regime.

The CIS by electrodeposition (CISEL) project between Electricite de France (EDF), Centre National de la Recherche Scientifique (CNRS)/Ecole Nationale Superieure de Chimie de Paris (ENSCP) and Saint-Gobain Recherche (SGR) aims at developing a low-cost electrodeposition process for Cu(In,Ga)(S,Se) 2 (CIGS) solar cells. The process is characterized by two main steps: (i) deposition of the precursor film and (ii) thermal annealing. This process enables the preparation of a large range of sulfur containing absorbers, with S/(S+Se) atomic ratio from 0% to more than 90%. The films are single phase over the whole composition range. The influence of Sulfur content on the microstructure has been shown with grain sizes decreasing with increasing sulfur content. Efficient solar cells can be obtained from all the different precursor compositions, with efficiencies of over 10% on lab cells on sulfur-rich absorbers, and 6–7% on 30×30 cm 2 devices. The homogeneity of 15×15 cm 2 substrates is also discussed.

This paper reviews the state of the art in using electrodeposition to prepare chalcopyrite absorber layers in thin film solar cells. Most of the studies deal with the direct preparation of Cu(In,Ga)Se 2 films, and show that the introduction of gallium in the films is now becoming possible from single bath containing all the elements. Electrodeposition can also be used to form precursor films with stacked layer structures, of pure elements or of combinations with binary or even ternary films. Thermal annealing treatments are of dramatic importance to provide suitable electronic quality to the layers. They are often done in the presence of a chalcogen (selenium or sulfur) over pressure and there is a tendency to use rapid thermal processes. Less studies are devoted to complete solar cell formation. Significant progresses have been made in the recent period with several groups achieving cell efficiencies around 8–10% on different substrates. A record efficiency of 11.3% is reported for a cell with an absorber presenting a band gap of 1.47 eV. First results on the manufacturability of the corresponding process to large areas are presented.

A copper hydroxynitrate of stoichiometry Cu2(OH)3NO3, analogous to the layered double hydroxide family, was synthesized by the so-called controlled double jet precipitation technique, and by hydrolysis of urea in the presence of copper nitrate. Special attention has been focused on the size, morphology and agglomeration tendency of the particles. The aim of this work is to define the optimum precipitation conditions in terms of quality and dispersability of the recovered product. Such platelet-like particles can be used as anisotropic fillers in nanocomposite materials. Several reaction parameters such as flow and concentration of the reactant solutions, design of the reactor and addition of a growth modifier were studied. r 2003 Published by Elsevier Science B.V.