Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

AEgIS at ELENA: outlook for physics with a pulsed cold antihydrogen beam.

The efficient production of cold antihydrogen atoms in particle traps at CERN's Antiproton Decelerator has opened up the possibility of performing direct measurements of the Earth's gravitational acceleration on purely antimatter bodies. The goal of the AEgIS collaboration is to measure the value of g for antimatter using a pulsed source of cold antihydrogen and a Moiré deflectometer/Talbot-Lau interferometer. The same antihydrogen beam is also very well suited to measuring precisely the ground-state hyperfine splitting of the anti-atom. The antihydrogen formation mechanism chosen by AEgIS is resonant charge exchange between cold antiprotons and Rydberg positronium. A series of technical developments regarding positrons and positronium (Ps formation in a dedicated room-temperature target, spectroscopy of the n=1-3 and n=3-15 transitions in Ps, Ps formation in a target at 10 K inside the 1 T magnetic field of the experiment) as well as antiprotons (high-efficiency trapping of [Formula: see text], radial compression to sub-millimetre radii of mixed [Formula: see text] plasmas in 1 T field, high-efficiency transfer of [Formula: see text] to the antihydrogen production trap using an in-flight launch and recapture procedure) were successfully implemented. Two further critical steps that are germane mainly to charge exchange formation of antihydrogen-cooling of antiprotons and formation of a beam of antihydrogen-are being addressed in parallel. The coming of ELENA will allow, in the very near future, the number of trappable antiprotons to be increased by more than a factor of 50. For the antihydrogen production scheme chosen by AEgIS, this will be reflected in a corresponding increase of produced antihydrogen atoms, leading to a significant reduction of measurement times and providing a path towards high-precision measurements.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.

Optimization and validation of a fast supercritical fluid chromatography method for the quantitative determination of vitamin D3 and its related impurities.

In the uprising context of green analytical chemistry, Supercritical Fluid Chromatography (SFC) is often suggested as an alternative to Normal Phase Liquid Chromatography. Indeed, SFC provides fast, efficient and green separations. In this report, the quantitative performances of SFC were challenged on a real-life case study: the Quality Control (QC) of vitamin D3. A rapid and green SFC method was optimized thanks to the Design of Experiments-Design Space (DoE-DS) methodology. It provided robust and high quality separation of the compounds within a 2min timeframe, using a gradient of ethanol as co-solvent of the carbon dioxide. The analytical method was fully validated according to the total error approach, demonstrating the compliance of the method to the specifications of U.S. Pharmacopeia (USP: 97.0-103.0%) and European Pharmacopeia (EP: 97.0-102.0%) for an interval of [50-150%] of the target concentration. In order to allow quantification of impurities using vitamin D3 as an external standard in SFC-UV, correction factors were determined and verified during method validation. Thus, accurate quantification of impurities was demonstrated at the specified levels (0.1 and 1.0% of the main compound) for a 70.0-130.0% dosing range. This work demonstrates the validity of an SFC method for the QC of vitamin D3 raw material and its application to real samples. Therefore, it supports the switch to a greener and faster separative technique as an alternative to NPLC in the pharmaceutical industry.

Towards a full integration of optimization and validation phases: An analytical-quality-by-design approach.

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.

[Doping, sport and addiction--any links?]. / Dopage, pratique sportive et addiction--quels liens?

Sport is widely encouraged as it is beneficial for health. However, high-performance sport is more and more associated to rather suspicious practices; doping is one of the best example. From a physician point of view, the use of doping agents is obviously a major concern because taking such products often induce serious adverse effects on health. The present manuscript aims to inform physicians about the most frequent doping practices. It also points out that intensive sport can generate an "addictive" behavior sharing with "common"addictions a loss of practice control, a lack of interest in other activities and even a sport's practice detrimental to athlete's health. Analysis of the doping issue needs to take this reality into account as some doping products display an established " addictive" effect.

Development of a quantitative approach using surface-enhanced Raman chemical imaging: first step for the determination of an impurity in a pharmaceutical model.

This publication reports, for the first time, the development of a quantitative approach using surface-enhanced Raman chemical imaging (SER-CI). A pharmaceutical model presented as tablets based on paracetamol, which is the most sold drug around the world, was used to develop this approach. 4-Aminophenol is the main impurity of paracetamol and is actively researched in pharmaceutical formulations because of its toxicity. As its concentration is generally very low (<0.1%, w/w), conventional Raman chemical imaging cannot be used. In this context, a SER-CI method was developed to quantify 4-aminophenol assessing a limit of quantification below its limit of specification of 1000 ppm. Citrate-reduced silver nanoparticles were used as SERS substrate and these nanoparticles were functionalized using 1-butanethiol. Different ways to cover the tablets surface by butanethiol-functionalized silver nanoparticles were tested and a homogeneity study of the silver nanoparticles covering was realized. This homogeneity study was performed in order to choose the best way to cover the surface of tablets by silver colloid. Afterwards, the optimization of the SER-CI approach was necessary and different spectral intensity normalizations were tested. Finally, a quantitative approach using SER-CI was developed enabling to quantify 4-aminophenol from 0.025% to 0.2% in paracetamol tablets. This quantitative approach was tested on two different series of tablets using different batches of silver nanoparticles.

Improvement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: a case of a learning process.

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.

USE OF MICRO-DAMS IN POTATO FURROWS TO REDUCE EROSION AND RUNOFF AND MINIMISE SURFACE WATER CONTAMINATION THROUGH PESTICIDES.

The use of micro-dams in potato furrows is an interesting technology to reduce erosion and runoff in hilly areas. These phenomena are major sources of surface water contamination by nutrients and plant protection products (Gillijns et al., 2005). In 2011 Bayer CropScience set up a trial in collaboration with the Walloon Agricultural Research Centre (CRA-W) and ULg-Gembloux Agro-Bio Tech in Huldenberg (Belgium) to demonstrate this technique in potatoes. Micro-dams create barriers between furrows in order to encourage rainwater to infiltrate in the soil rather than to run off. The results from the trial over this year confirm that the application of micro-dams is effective in reducing erosion and runoff significantly. The total loss of plant protection products (PPP) to surface water is dramatically reduced and also strongly depends on the physic-chemical characteristics of the active ingredients. In addition, the technique tends to produce a higher yield of potato tubers as an effect of an optimised utilisation of the available rainwater and nutrients.

Application of an innovative design space optimization strategy to the development of LC methods for the simultaneous screening of antibiotics to combat poor quality medicines.

The poor quality of medicines is a crucial problem of public health. Therefore, it is important to have analytical tools to attend decisions of the legal authorities while combating this offense. In this context, the main objective of this study was to develop generic methods able to trace, screen and determine several antibiotics and common associated molecules by mean of liquid chromatographic techniques. For that purpose, an innovative Design Space optimization strategy was applied, targeting 16 antibiotics and 3 beta-lactamase inhibitors. The robustness of the developed method allowed using its use in an environment where operational factors such as temperature are not easy to control and eased its transfer to Ultra High Performance Liquid Chromatography. To demonstrate its ability to quantify the targeted molecules, the developed and transferred method was fully validated for two active ingredients commonly used in association, sulbactam and ceftriaxone, using the accuracy profile as decision tool. Based on this successful step, the method was then used for the quantitative determination of these two active ingredients in three pharmaceutical brands marketed in the Democratic Republic of Congo. Two out of the three pharmaceutical products did not comply with the specifications.

Detection of K(ATP) channels subunits in human term placental explants and evaluation of their implication in human placental lactogen (hPL) and human chorionic gonadotropin (hCG) release.

INTRODUCTION: ATP-sensitive potassium channels (KATP channels) have been identified in a variety of tissues. Nevertheless, the presence and role of such metabolism-sensitive K+ channels still remain to be unraveled in the reproductive system. METHODS: The study evaluates the presence of KATP channel subunits in human term placental explants by immunohistochemistry, proximity ligation assay, Western blot and RT-PCR techniques. The potential involvement of KATP channels in human placental lactogen (hPL) and human chorionic gonadotrophin (hCG) release has been assessed radioimmunologically from human term placental explants incubated in the presence of different KATP channel modulators. RESULTS: Immunolocalization of the KATP channel subunits documented both the Kir6.2 and SUR2 subunits in the syncytiotrophoblast of human term placenta. Their colocalization was demonstrated by proximity ligation assay and their presence was further confirmed by immunoblotting and RT-PCR. Kir6.1 subunit was immunolocalized in blood vessels media. SUR1 was not expressed at the mRNA level. Incubation of human term placental explants in the presence of increasing concentrations of modulators of KATP channels such as glibenclamide, tolbutamide, pinacidil or diazoxide did not affect the measured hCG and hPL secretory rates. DISCUSSION: Our study reports, for the first time, the presence of the KATP channel subunits Kir6.2 and SUR2 in the human term syncytiotrophoblast. However, under the present experimental conditions, the activation or inhibition of these putative KATP channels by different pharmacological agents did not affect the hPL and hCG secretory rate of human term placental explants. CONCLUSION: The present findings suggest that the human term syncytiotrophoblast might be endowed with KATP channels. Further studies should clarify their implication in the syncytiotrophoblast ionic homeostasis and hormone regulation.

Application of an innovative design space optimization strategy to the development of liquid chromatographic methods to combat potentially counterfeit nonsteroidal anti-inflammatory drugs.

In the context of the battle against counterfeit medicines, an innovative methodology has been used to develop rapid and specific high performance liquid chromatographic methods to detect and determine 18 non-steroidal anti-inflammatory drugs, 5 pharmaceutical conservatives, paracetamol, chlorzoxazone, caffeine and salicylic acid. These molecules are commonly encountered alone or in combination on the market. Regrettably, a significant proportion of these consumed medicines are counterfeit or substandard, with a strong negative impact in countries of Central Africa. In this context, an innovative design space optimization strategy was successfully applied to the development of LC screening methods allowing the detection of substandard or counterfeit medicines. Using the results of a unique experimental design, the design spaces of 5 potentially relevant HPLC methods have been developed, and transferred to an ultra high performance liquid chromatographic system to evaluate the robustness of the predicted DS while providing rapid methods of analysis. Moreover, one of the methods has been fully validated using the accuracy profile as decision tool, and was then used for the quantitative determination of three active ingredients and one impurity in a common and widely used pharmaceutical formulation. The method was applied to 5 pharmaceuticals sold in the Democratic Republic of Congo. None of these pharmaceuticals was found compliant to the European Medicines Agency specifications.

Application of a new optimization strategy for the separation of tertiary alkaloids extracted from Strychnos usambarensis leaves.

The HPLC separation of six alkaloids extracted from Strychnos usambarensis leaves has been developed and optimized by means of a powerful methodology for modelling chromatographic responses, based on three steps, i.e. design of experiments (DoE), independent component analysis (ICA) and design space (DS). This study was the first application of a new optimization strategy to a complex natural matrix. The compounds separated are the isomers isostrychnopentamine and strychnopentamine, 10-hydroxyusambarine and 11-hydroxyusambarine, also strychnophylline and strychnofoline. Three LC parameters have been optimized using a multifactorial design comprising 29 experiments that includes 2 center point replicates. The parameters were the percentage of organic modifiers used at the beginning of a gradient profile which consisted in different proportions of methanol (MeOH) and acetonitrile (MeCN), the gradient time to reach 70% of organic modifiers starting from the initial percentage and the percentage of MeCN found in the mobile phase. Subsequent to the experimental design application, predictive multilinear models were developed and used in order to provide optimal analytical conditions. The optimum assay conditions were: methanol/acetonitrile-sodium pentane sulfonate (pH 2.2; 7.5 mM) (33.4:66.6, v/v) at a mobile phase flow rate of 1 ml/min during a 40.6 min gradient time. The initial organic phase contained 3.7% MeCN and 96.3% MeOH. The method showed good agreement between the experimental data and predictive value throughout the studied parameters space. Improvement of the analysis time and optimized separation for the compounds of interest was possible due to the original and powerful tools applied. Finally, this study permitted the acquisition of isomers profiles allowing the identification of the optimal collecting period of S. usambarensis.

Innovative high-performance liquid chromatography method development for the screening of 19 antimalarial drugs based on a generic approach, using design of experiments, independent component analysis and design space.

An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE-ICA-DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE-ICA-DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE-ICA-DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study.

Determination of binary polymorphic mixtures of fluconazole using near infrared spectroscopy and X-ray powder diffraction: a comparative study based on the pre-validation stage results.

The aim of the present study was to develop near infrared (NIR) and X-ray powder diffraction methods (XRPD) able to determine pure crystalline form II of fluconazole in a binary polymorphic mixtures containing forms II and III. In order to give a first performance estimation of both methods, these latters were pre-validated using accuracy profiles, a statistical approach based on ß-expectation tolerance intervals. Both methods showed a good trueness, precision and accuracy and their ß-expectation tolerance intervals were fully included within the acceptance limits. The comparative study was carried out using statistical analysis based on the work of Bland and Altman. A good agreement between the two methods was demonstrated indicating the interchangeability of NIR method with XRPD method.

Innovative methodology to transfer conventional GC-MS heroin profiling to UHPLC-MS/MS.

Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good sensitivity and reproducibility, and allows the use of large databases. Despite those benefits, recently introduced analytical techniques, such as ultra-high-pressure liquid chromatography (UHPLC), could offer better chromatographic performance, which needs to be considered to increase the analysis throughput for heroin profiling. With the latter, chromatographic conditions were optimized through commercial modeling software and two atmospheric pressure ionization sources were evaluated. Data obtained from UHPLC-MS/MS were thus transferred, thanks to mathematical models to mimic GC-MS data. A calibration and a validation set of representative heroin samples were selected among the database to establish a transfer methodology and assess the models' abilities to transfer using principal component analysis and hierarchical classification analysis. These abilities were evaluated by computing the frequency of successful classification of UHPLC-MS/MS data among GC-MS database. Seven mathematical models were tested to adjust UHPLC-MS/MS data to GC-MS data. A simplified mathematical model was finally selected and offered a frequency of successful transfer equal to 95%.

Acetaminophen determination in low-dose pharmaceutical syrup by NIR spectroscopy.

The aim of the present study was first to develop a robust near infrared (NIR) calibration model able to determine the acetaminophen content of a low-dose syrup formulation (2%, w/v). Therefore, variability sources such as production campaigns, batches, API concentration, syrup basis, operators and sample temperatures were introduced in the calibration set. A prediction model was then built using partial least square (PLS) regression. First derivative followed by standard normal variate (SNV) were chosen as signal pre-processing. Based on the random subsets cross-validation, 4 PLS factors were selected for the prediction model. The method was then validated for an API concentration ranging from 16 to 24 mg/mL (1.6-2.4%, w/v) using an external validation set. The 0.26 mg/mL RMSEP suggested the global accuracy of the model. The accuracy profile obtained from the validation results, based on tolerance intervals, confirmed the adequate accuracy of the results generated by the method all over the investigated API concentration range. Finally, the NIR model was used to monitor in real time the API concentration while mixing syrups containing various amounts of API, a good agreement was found between the NIR method and the theoretical concentrations.

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion.

AIMS/HYPOTHESIS: Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. METHODS: Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (betaSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival. RESULTS: Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca(2+) stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, in betaSOCS2 mice proinsulin maturation is impaired, leading to an altered structure of insulin secretory granules and augmented levels of proinsulin. The latter is likely to be due to decreased production of prohormone convertase 1 (PC1/3), which plays a key role in proinsulin cleavage. CONCLUSIONS/INTERPRETATIONS: SOCS2 was shown to be a potent regulator of proinsulin processing and insulin secretion in beta cells. While its constitutive production is insufficient to induce overt diabetes in this mouse model, it causes glucose intolerance. Thus, increased SOCS2 production could be an important event predisposing to beta cell failure.

Active content determination of non-coated pharmaceutical pellets by near infrared spectroscopy: method development, validation and reliability evaluation.

A robust near infrared (NIR) method able to quantify the active content of pilot non-coated pharmaceutical pellets was developed. A protocol of calibration was followed, involving 2 operators, independent pilot batches of non-coated pharmaceutical pellets and two different NIR acquisition temperatures. Prediction models based on Partial Least Squares (PLS) regression were then carried out. Afterwards, the NIR method was fully validated for an active content ranging from 80 to 120% of the usual active content using new independent pilot batches to evaluate the adequacy of the method to its final purpose. Conventional criteria such as the R(2), the Root Mean Square Error of Calibration (RMSEC), the Root Mean Square Error of Prediction (RMSEP) and the number of PLS factors enabled the selection of models with good predictive potential. However, such criteria sometimes fail to choose the most fitted for purpose model. Therefore, a novel approach based on accuracy profiles of the validation results was used, providing a visual representation of the actual and future performances of the models. Following this approach, the prediction model using signal pre-treatment Multiplicative Scatter Correction (MSC) was chosen as it showed the best ability to quantify accurately the active content over the 80-120% active content range. The reliability of the NIR method was tested with new pilot batches of non-coated pharmaceutical pellets containing 90 and 110% of the usual active content, with blends of validation batches and industrial batches. All those batches were also analyzed by the HPLC reference method and relative errors were calculated: the results showed low relative errors in full accordance with the results obtained during the validation of the method, indicating the reliability of the NIR method and its interchangeability with the HPLC reference method.

Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice.

AIMS/HYPOTHESIS: Due to their ability to regulate various signalling pathways (cytokines, hormones, growth factors), the suppressor of cytokine signalling (SOCS) proteins are thought to be promising therapeutic targets for metabolic and inflammatory disorders. Hence, their role in vivo has to be precisely determined. METHODS: We generated transgenic mice constitutively producing SOCS-3 in skeletal muscle to define whether the sole abundance of SOCS-3 is sufficient to induce metabolic disorders and whether SOCS-3 is implicated in physiological roles distinct from metabolism. RESULTS: We demonstrate here that chronic expression of SOCS-3 in skeletal muscle leads to overweight in mice and worsening of high-fat diet-induced systemic insulin resistance. Counter-intuitively, insulin sensitivity in muscle of transgenic mice appears to be unaltered. However, following constitutive SOCS-3 production, several genes had deregulated expression, among them other members of the SOCS family. This could maintain the insulin signal into skeletal muscle. Interestingly, we found that SOCS-3 interacts with calcineurin, which has been implicated in muscle contractility. In Socs-3 transgenic muscle, this leads to delocalisation of calcineurin to the fibre periphery. Relevant to this finding, Socs-3 transgenic animals had dilatation of the sarcoplasmic reticulum associated with swollen mitochondria and decreased voluntary activity. CONCLUSIONS/INTERPRETATION: Our results show that constitutive SOCS-3 production in skeletal muscle is not in itself sufficient to induce the establishment of metabolic disorders such as diabetes. In contrast, we reveal a novel role of SOCS-3, which appears to be important for muscle integrity and locomotor activity.

Moisture content determination of pharmaceutical pellets by near infrared spectroscopy: method development and validation.

The aim of the present study was to develop and validate a near infrared method able to accurately determine a moisture content of pharmaceutical pellets ranging from 1% to 8% in order to check their moisture content conformity. A calibration and validation set were designed for the conception and evaluation of the method adequacy. An experimental protocol was then followed, involving two operators, independent production campaign batches and different temperatures for data acquisition. On the basis of this protocol, prediction models based on partial least squares (PLS) regression were then carried out. Conventional criteria such as the R(2), the root mean square errors of calibration and prediction (RMSEC and RMSEP) as well as the number of PLS factors enabled the selection of three preliminary models. However, such criteria did not clearly demonstrate the model's ability to give accurate predictions over the whole analyzed water content range. Consequently, a novel approach based on accuracy profiles which allow the selection of the most fitted model for purpose was used. According to this novel approach, the model using multiplicative scatter correction (MSC) pre-treatment was obviously the most suitable. Indeed, the resulting accuracy profile clearly showed that this model was able to determine moisture content over the range of 1-8% with a very acceptable accuracy. The present study confirmed that NIR spectroscopy could be used in the PAT concept as a non-invasive, non-destructive and fast technique for moisture content determination in pharmaceutical pellets. In addition, facing the limit of the classical and commonly used criteria, the use of accuracy profiles proved to be useful as a powerful decision tool to demonstrate the suitability of the proposed analytical method.