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See detailData processing of vibrational chemical imaging for pharmaceutical applications.
Sacre, Pierre-Yves ULg; De Bleye, Charlotte ULg; Chavez, Pierre-François ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (in press)

Vibrational spectroscopy (MIR, NIR and Raman) based hyperspectral imaging is one of the most powerful tools analyze pharmaceutical preparation. Indeed, it combines the advantages of vibrational ... [more ▼]

Vibrational spectroscopy (MIR, NIR and Raman) based hyperspectral imaging is one of the most powerful tools analyze pharmaceutical preparation. Indeed, it combines the advantages of vibrational spectroscopy to imaging techniques and allows therefore the visualization of distribution of compounds, crystallization processes. However, these techniques provide a huge amount of data that must be processed to extract the relevant information. This review presents fundamental concepts of hyperspectral imaging, the basic theory of the most used chemometric tools used to pre-process, process and post-process the generated data. The last part of the present paper focuses on pharmaceutical applications of hyperspectral imaging and highlights the data processing approaches to enable the reader making the best choice among the different tools available. [less ▲]

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See detailTowards a real time release approach for manufacturing tablets using NIR spectroscopy
Pestieau, Aude ULg; Krier, Fabrice ULg; Thoorens, Grégory et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 98

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See detailDevelopment of a quantitative approach using surface-enhanced Raman chemical imaging: First step for the determination of an impurity in a pharmaceutical model
De Bleye, Charlotte ULg; Sacre, Pierre-Yves ULg; Dumont, Elodie ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 90

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 ... [more ▼]

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. [less ▲]

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See detailDevelopment of a liquid chromatographic method for thesimultaneous quantification of curcumin, -arteether,tetrahydrocurcumin and dihydroartemisinin. Application to lipid-based formulations
Memvanga Bondo, Patrick; Mbinze Kindenge, Jérémie ULg; Rozet, Eric ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 88(-), 447-456

A liquid chromatographic method was developed for the simultaneous separation of curcumin, B-arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space ... [more ▼]

A liquid chromatographic method was developed for the simultaneous separation of curcumin, B-arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space methodology. The influence of the percentage of organic modifier, flow rate of the mobile phase and column temperature on the analytes separation was investigated. The optimal chromatographic separation was achieved on a C18 column (125 mm × 4 mm, 5 µm) using an isocratic elution with a mobile phase consisting of methanol:ammonium acetate (pH 4; 10 mM) (80/20, v/v) at a flow rate of 0.45 ml/min and a column temperature of 32.5◦C. This method was then validated for simultaneous quantification of curcumin and B -arteether contained in lipid-based formulations taking into account the B -expectation tolerance interval for the total error measurement. Finally, the suitability of the proposed liquid chromatographic method for routine analysis of curcumin and B -arteether loaded in lipid-based formulations has been proven. [less ▲]

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See detailImprovement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: A case of a learning process
Hubert, Cédric ULg; Lebrun, Pierre ULg; Houari, Sabah ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 88

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 ... [more ▼]

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. [less ▲]

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See detailRobust method optimization strategy – a useful tool for method transfer: the case of SFC
Dispas, Amandine ULg; Lebrun, Pierre ULg; Andri, Bertyl ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 88

The concept of Quality by Design (QbD) is now well established in pharmaceutical industry and should be applied to the development of any analytical methods. In this context, the key concept of Design ... [more ▼]

The concept of Quality by Design (QbD) is now well established in pharmaceutical industry and should be applied to the development of any analytical methods. In this context, the key concept of Design Space (DS) was introduced in the field of analytical method optimization. In chromatographic words, the DS is the space of chromatographic conditions that will ensure the quality of peaks separation, thus DS is a zone of robustness. In the present study, the interest of robust method optimization strategy was investigated in the context of direct method transfer from sending to receiving laboratory. The benefit of this approach is to speed up the method life cycle by performing only one quantitative validation step in the final environment of method use. A Supercritical Fluid Chromatography (SFC) method previously developed was used as a case study in this work. Moreover, the interest of geometric transfer was investigated simultaneously in order to stress a little bit more the transfer exercise and, by the way, emphasize the additional benefit of DS strategy in this particular context. Three successful transfers were performed on two column geometries. In order to compare original and transferred methods, the observed relative retention times (RT) were modelled as a function of the predicted relative RT and of the method type (original or transferred). The observed relative RT of the original and transferred methods are not statistically different and thus the method transfer is successfully achieved thanks to the robust optimization strategy. Furthermore, the analytical method was improved considering analysis time (reduced five times) and peak capacity (increased three times). To conclude, the advantage of using a DS strategy implemented for the optimization and transfer of SFC method was successfully demonstrated in this work. [less ▲]

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See detailApplication of an innovative design space optimization strategy to thedevelopment of LC methods for the simultaneous screening of antibiotics to combat poor quality medicines
Mbinze Kindenge, Jérémie ULg; Dispas, Amandine ULg; Lebrun, Pierre ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 85

The poor quality of medicines is a crucial problem of public health. Therefore, it is important to haveanalytical tools to attend decisions of the legal authorities while combating this offense. In this ... [more ▼]

The poor quality of medicines is a crucial problem of public health. Therefore, it is important to haveanalytical 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 determineseveral antibiotics and common associated molecules by mean of liquid chromatographic techniques.For that purpose, an innovative Design Space optimization strategy was applied, targeting 16 antibioticsand 3 beta-lactamase inhibitors. The robustness of the developed method allowed using its use in anenvironment where operational factors such as temperature are not easy to control and eased its trans-fer to Ultra High Performance Liquid Chromatography. To demonstrate its ability to quantify the targetedmolecules, the developed and transferred method was fully validated for two active ingredients com-monly used in association, sulbactam and ceftriaxone, using the accuracy profile as decision tool. Basedon this successful step, the method was then used for the quantitative determination of these two activeingredients in three pharmaceutical brands marketed in the Democratic Republic of Congo. Two out ofthe three pharmaceutical products did not comply with the specifications [less ▲]

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See detailEvaluation of the residual solvent content of counterfeit tablets and capsules
Deconinck, Eric; Canfyn, Michael; Sacre, Pierre-Yves ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 81-82

A group of counterfeit samples of Viagra® and Cialis® were screened for their residual solvent content and compared to the content of the genuine products. It was observed that all counterfeit samples had ... [more ▼]

A group of counterfeit samples of Viagra® and Cialis® were screened for their residual solvent content and compared to the content of the genuine products. It was observed that all counterfeit samples had higher residual solvent contents compared to the genuine products. A more diverse range of residual solvents was found as well as higher concentrations. In general these concentrations did not exceed the international imposed maximum limits. Only in a few samples the limits were exceeded. A Projection Pursuit analysis revealed clusters of samples with similar residual solvent content, possibly enabling some future perspectives in forensic research. [less ▲]

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See detailImplementation of a Design Space Approach for Enantiomeric Separations in Polar Organic Solvent Chromatography
Nistor, Iolanda; Lebrun, Pierre ULg; Ceccato, Attilio ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 74

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 ... [more ▼]

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures. Good correlations were found between the observed data obtained after using a central composite design and the expected chromatographic behaviours predicted by applying the design of experiments-design space (DoE-DS) methodology. The critical quality attribute represented here by the separation criterion (Scrit) allowed assessing the quality of the enantioseparation. Baseline separation for the compounds of interest in an analysis time of less than 20 minutes was possible due to the original and powerful tools applied which facilitated an enhanced method comprehension. Finally, the advantage of the DoE-DS approach resides in granting the possibility to concurrently assess robustness and identify the optimal conditions which are compound dependent. [less ▲]

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See detailA validated GC-MS method for the determination and quantification of residual solvents in counterfeit tablets and capsules
Deconinck, Eric; Canfyn, Michaël; Sacre, Pierre-Yves ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 70

A fast headspace GC-MS method was developed and validated for the detection and quantification of residual solvents of all three ICH-classes in counterfeit tablets and capsules. The method was validated ... [more ▼]

A fast headspace GC-MS method was developed and validated for the detection and quantification of residual solvents of all three ICH-classes in counterfeit tablets and capsules. The method was validated for ten solvents, selected based on an initial screening of counterfeit medicinal products. The considered solvents were ethanol, 2-propanol, acetone, ethylacetate, chloroform, carbon tetrachloride, benzene, toluene, dichloromethane and ethylbenzene. The proposed method uses a Phenomenex 624 capillary column (60 m x 0.32 mm; 1.8 µm film thickness) (Phenomenex, Torrance, USA) with an oven temperature program from 60°C (held for 5 min) to 270°C at 25 °C/min. 270°C is held for 10 min. The total run time is 23.4 minutes. The obtained method was fully validated by applying the “total error” profile. Calibration lines for all components were linear within the studied ranges. The relative bias and the relative standard deviations for all components were smaller than 5%, the -expectation tolerance limits did not exceed the acceptance limits of 10% and the relative expanded uncertainties were acceptable for all of the considered components. A method was obtained for the screening and quantification of residual solvents in counterfeit tablets and capsules, which will allow a fast screening of these products for the presence of residual solvents. [less ▲]

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See detailAPPLICATION OF DESIGN OF EXPERIMENTS AND DESIGN SPACE METHODOLOGY FOR THE HPLC-UV SEPARATION OPTIMIZATION OF APORPHINE ALKALOIDS FROM LEAVES OF Spirospermum penduliflorum THOUARS
Rafamantanana, Mamy; Debrus, Benjamin ULg; Raoelison, Guy et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 62

Spirospermum penduliflorum Thouars (Menispermaceae) is an endemic species of Madagascar traditionally used as vasorelaxant. Recently, two aporphine alkaloids known to possess antihypertensive activity ... [more ▼]

Spirospermum penduliflorum Thouars (Menispermaceae) is an endemic species of Madagascar traditionally used as vasorelaxant. Recently, two aporphine alkaloids known to possess antihypertensive activity (dicentrine and neolitsine) were isolated and identified from the leaves of this plant. In the present study, a HPLC-UV method allowing the separation of all alkaloids and the quantification of dicentrine in the alkaloidic extract of leaves was developed using design of experiments and design space methodology. Three common chromatographic parameters (i.e. the mobile phase pH, the initial proportion of methanol and the gradient slope) were selected to construct a full factorial design of 36 experimental conditions. The times at the beginning, the apex (i.e. the retention time) and the end of each peak were recorded and modelled by multiple linear equations. The corresponding residuals were normally distributed which confirmed that the models can be used for the prediction of the retention times and to optimize the separation. The optimal separation was predicted at pH 3, with a gradient starting at 32% of methanol and a gradient slope of 0.42%/min. Good agreement was obtained between predicted and experimental chromatograms. The method was also validated using total error concept. Using the accuracy profile approach, validation results gave a LOD and LOQ for dicentrine of 3 µg/ml and 10 µg/ml, respectively. A relative standard deviation for intermediate precision lower than 10% was obtained. This method was found to provide accurate results in the concentration range of 10 µg/ml to 75 µg/ml of dicentrine and is suitable for routine analysis. [less ▲]

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See detailClassification trees based on infrared spectroscopic data to discriminate between genuine and counterfeit medicines
Deconinck, Eric; Sacré, Pierre-Yves ULg; Coomans, Danny et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 57(1), 68-75

Classification trees built with the Classification And Regression Tree algorithm were evaluated for modelling infrared spectroscopic data in order to discriminate between genuine and counterfeit drug ... [more ▼]

Classification trees built with the Classification And Regression Tree algorithm were evaluated for modelling infrared spectroscopic data in order to discriminate between genuine and counterfeit drug samples and to classify counterfeit samples in different classes following the RIVM classification system. Models were built for two data sets consisting of the Fourrier Transformed Infrared spectra, the Near Infrared spectra and the Raman spectra for genuine and counterfeit samples of respectively Viagra® and Cialis®. Easy interpretable models were obtained for both models. The models were validated for their descriptive and predictive properties. The predictive properties were evaluated using both cross validation as an external validation set. The obtained models for both data sets showed a 100% correct classification for the discrimination between genuine and counterfeit samples and 83.3% and 100% correct classification for the counterfeit samples for the Viagra® and the Cialis® data set respectively. [less ▲]

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See detailCritical Review of Near-Infrared Spectroscopic Methods Validations in Pharmaceutical Applications
De Bleye, Charlotte ULg; Chavez, Pierre-François ULg; Mantanus, Jérôme ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 69

Based on the large number of publications reported over the past five years, near-infrared spectroscopy (NIRS) is more and more considered an attractive and promising analytical tool regarding Process ... [more ▼]

Based on the large number of publications reported over the past five years, near-infrared spectroscopy (NIRS) is more and more considered an attractive and promising analytical tool regarding Process Analytical Technology and Green Chemistry. From the reviewed literature, few of these publications present a thoroughly validated NIRS method even if some guidelines have been published by different groups and regulatory authorities. However, as any analytical method, the validation of NIRS method is a mandatory step at the end of the development in order to give enough guarantees that each of the future results during routine use will be close enough to the true value. Besides the introduction of PAT concepts in the revised document of the European Pharmacopoeia (2.2.40) dealing with near-infrared spectroscopy recently published in Pharmeuropa, it agrees very well with this mandatory step. Indeed, the latter suggests to use similar analytical performance characteristics than those required for any analytical procedure based on acceptance criteria consistent with the intended use of the method. In this context, this review gives a comprehensive and critical overview of the methodologies applied to assess the validity of quantitative NIRS methods used in pharmaceutical applications. [less ▲]

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See detailGeneric systems for the enantioseparation of basic drugs in NACE using single-isomer anionic CDs
Rousseau, Anne ULg; Gillotin, Florian; Chiap, Patrice ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 54

The enantioseparation of ten basic drugs was evaluated in NACE systems using heptakis(2-O-methyl-3-O-acetyl-6-O-sulfo)-β-CD (HMAS-β-CD). For this purpose, a D-optimal design with 21 experimental points ... [more ▼]

The enantioseparation of ten basic drugs was evaluated in NACE systems using heptakis(2-O-methyl-3-O-acetyl-6-O-sulfo)-β-CD (HMAS-β-CD). For this purpose, a D-optimal design with 21 experimental points was applied. Four antifungal agents (econazole, isoconazole, miconazole, sulconazole), three local anesthetics (bupivacaine, mepivacaine and prilocaine), two sympathomimetics (salbutamol and terbutaline) and one β-blocker (carvedilol) were selected as basic model analytes. The influence on the enantiomeric resolution of anionic CD and BGE anion concentrations as well as the BGE anion nature was investigated. For all studied analytes, the enantiomeric resolution was shown to be significantly influenced by the CD concentration. Based on the observed results, a generic NACE system was recommended, namely 20 mM HMAS-β-CD and 10 mM ammonium camphorSO3- in methanol acidified with 0.75 M formic acid. Moreover, this NACE system was compared to previous conditions with heptakis(2,3-di-O-methyl-6-O-sulfo)-β-CD (HDMS-β-CD) or heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD). Finally, two generic systems using either HDAS-β-CD or HMAS-β-CD were proposed and evaluated for the enantioseparation of ketamine and norketamine after incubation of ketamine in phenobarbital-induced male rat liver microsomes systems. [less ▲]

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See detailApplication of a new optimization strategy for the separation of tertiary alkaloids extracted from Strychnos usambarensis leaves
Nistor, Iolanda ULg; Cao, Martine ULg; Debrus, Benjamin ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 56

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 ... [more ▼]

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 1mL/min during a 40.6 minutes 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 Strychnos usambarensis. [less ▲]

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See detailOptimisation and validation of a fast HPLC method for the quantification of sulindac and its related impurities
Krier, Fabrice ULg; Brion, Michaël; Debrus, Benjamin ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 54

The European Pharmacopoeia describes a liquid chromatography (LC) method for the quantification of sulindac, using a quaternary mobile phase including chloroform and with a rather long run time. In the ... [more ▼]

The European Pharmacopoeia describes a liquid chromatography (LC) method for the quantification of sulindac, using a quaternary mobile phase including chloroform and with a rather long run time. In the present study, a new method using a short sub-2μm column, which can be used on a classical HPLC system, was developed. The new LC conditions (without chloroform) were optimised by means of a new methodology based on design of experiments in order to obtain an optimal separation. Four factors were studied: the duration of the initial isocratic step, the percentage of organic modifier at the beginning of the gradient, the percentage of organic modifier at the end of the gradient and the gradient time. The optimal condition allows the separation of sulindac and of its 3 related impurities in six minutes instead of 18 min. Finally, the method was successfully validated using an accuracy profile approach in order to demonstrate its ability to accurately quantify these compounds. [less ▲]

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See detailDetermination 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
Ziemons, Eric ULg; Bourichi, H.; Mantanus, Jérôme ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 55

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 ... [more ▼]

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 form 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 β-expectation tolerance intervals. Both methods showed a good trueness, precision and accuracy and their β-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. [less ▲]

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See detailAdvances in validation, risk and uncertainty assessment of bioanalytical methods
Rozet, Eric ULg; Marini Djang'Eing'A, Roland ULg; Ziemons, Eric ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 55

Bioanalytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that ... [more ▼]

Bioanalytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them. Even if several guidelines exist to help perform bioanalytical method validations, there is still the need to clarify the meaning and interpretation of bioanalytical method validation criteria and methodology. Yet, different interpretations can be made of the validation guidelines as well as for the definitions of the validation criteria. This will lead to diverse experimental designs implemented to try fulfilling these criteria. Finally, different decision methodologies can also be interpreted from these guidelines. Therefore, the risk that a validated bioanalytical method may be unfit for its future purpose will depend on analysts personal interpretation of these guidelines. The objective of this review is thus to discuss and highlight several essential aspects of methods validation, not only restricted to chromatographic ones but also to ligand binding assays owing to their increasing role in biopharmaceutical industries. The points that will be reviewed are the common validation criteria, which are selectivity, standard curve, trueness, precision, accuracy, limits of quantification and range, dilutional integrity and analyte stability. Definitions, methodology, experimental design and decision criteria are reviewed. Two other points closely connected to method validation are also examined: incurred sample reproducibility testing and measurement uncertainty as they are highly linked to bioanalytical results reliability. Their additional implementation is foreseen to strongly reduce the risk of having validated a bioanalytical method unfit for its purpose. [less ▲]

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See detailDO PLACEBO BASED VALIDATION STANDARDS MIMIC REAL BATCH PRODUCTS BEHAVIOUR? CASE STUDIES
Bouabidi, A.; Talbi, M.; Bouklouze, A. et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 55

Analytical methods validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application. Validation usually involves validation standards ... [more ▼]

Analytical methods validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application. Validation usually involves validation standards or quality control samples that are prepared in placebo or reconstituted matrix made of a mixture of all the ingredients composing the drug product except the active substance or the analyte under investigation. However, one of the main concerns that can be made with this approach is that it may lack an important source of variability that come from the manufacturing process. The question that remains at the end of the validation step is about the transferability of the quantitative performance from validation standards to real authentic drug product samples. In this work, this topic is investigated through three case studies. Three analytical methods were validated using the commonly spiked placebo validation standards at several concentration levels as well as using samples coming from authentic batch samples (tablets and syrups). The results showed that, depending on the type of response function used as calibration curve, there were various degrees of differences in the results accuracy obtained with the two types of samples. Nonetheless the use of spiked placebo validation standards was showed to mimic relatively well the quantitative behaviour of the analytical methods with authentic batch samples. Adding these authentic batch samples into the validation design may help the analyst to select and confirm the most fit for purpose calibration curve and thus increase the accuracy and reliability of the results generated by the method in routine application. [less ▲]

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