Understanding the impact of microcrystalline cellulose physicochemical properties on tabletability.

The quality by design (QbD) initiative is promoting a better understanding of excipient performance and the identification of critical material attributes (CMAs). Despite microcrystalline cellulose (MCC) being one of the most popular direct compression binders, only a few studies attempted identifying its CMAs. These studies were based either on a limited number of samples or on MCC produced on a small scale and/or in conditions that deviate from those normally encountered in production.

Estimation of the Time Interval between the Administration of Heroin and the Sampling of Blood in Chronic Inhalers.

To develop a model for estimating the time delay between last heroin consumption and blood sampling in chronic drug users. Eleven patients, all heroin inhalers undergoing detoxification, were included in the study. Several plasma samples were collected during the detoxification procedure and analyzed for the heroin metabolites 6-acetylmorphine (6AM), morphine (MOR), morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), according to a UHPLC/MSMS method.

A quality by design approach for longitudinal quality attributes.

The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior knowledge gathered during pharmaceutical development studies to provide a scientific rationale for the manufacturing process of a product and provide guarantee of future quality. This poses several challenges from a statistical standpoint and requires a shift in paradigm from traditional statistical practices.

Analytical procedure validation and the quality by design paradigm.

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a quality by design (QbD) approach, there have been many discussions on the opportunity for analytical procedure developments to follow a similar approach. While development and optimization of analytical procedure following QbD principles have been largely discussed and described, the place of analytical procedure validation in this framework has not been clarified. This article aims at showing that analytical procedure validation is fully integrated into the QbD paradigm and is an essential step in developing analytical procedures that are effectively fit for purpose.

A new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms.

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution.

Strategies for using the sheep ovarian cortex as a model in reproductive medicine.

Objective: To evaluate and compare the distribution and density of primordial follicles within a whole sheep ovary and to gain insight into how to overcome the impact of natural follicular heterogeneity on the experimental results.

Design: Histological study.

Setting: Academic research center.

Evaluation of the quantitative performances of supercritical fluid chromatography: from method development to validation.

Recently, the number of papers about SFC increased drastically but scientists did not truly focus their work on quantitative performances of this technique. In order to prove the potential of UHPSFC, the present work discussed about the different steps of the analytical life cycle of a method: from development to validation and application. Moreover, the UHPSFC quantitative performances were evaluated in comparison with UHPLC, which is the main technique used for quality control in the pharmaceutical industry and then could be considered as a reference.

An easy, convenient cell and tissue extraction protocol for nuclear magnetic resonance metabolomics.

Introduction: As a complement to the classic metabolomics biofluid studies, the visualisation of the metabolites contained in cells or tissues could be a very powerful tool to understand how the local metabolism and biochemical pathways could be affected by external or internal stimuli or pathologies. Therefore, extraction and/or lysis is necessary to obtain samples adapted for use with the current analytical tools (liquid NMR and MS). These extraction or lysis work-ups are often the most labour-intensive and rate-limiting steps in metabolomics, as they require accuracy and repeatability as well as robustness.

Robust method optimization strategy-a useful tool for method transfer: the case of SFC.

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.

Development of a liquid chromatographic method for the simultaneous quantification of curcumin, β-arteether, tetrahydrocurcumin and dihydroartemisinin. Application to lipid-based formulations.

A liquid chromatographic method was developed for the simultaneous separation of curcumin, β-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 (125mm×4mm, 5μm) using an isocratic elution with a mobile phase consisting of methanol-ammonium acetate (pH 4; 10mM) (80:20, v/v) at a flow rate of 0.

PAT tools for the control of co-extrusion implants manufacturing process.

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively.

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice.

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model relies on laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. By recapitulating the main features of the exudative form of human AMD, this assay has served as the backbone for testing antiangiogenic therapies.

Development and validation of an UHPLC-LTQ-Orbitrap MS method for non-anthocyanin flavonoids quantification in Euterpe oleracea juice.

Euterpe oleracea fruits have gained much attention because of their phenolic constituents that have shown potential health benefits. The aim of this work was to quantify the major non-anthocyanin flavonoids (NAF) in the fruit juice by an accurate method coupling ultra-high pressure liquid chromatography with a linear ion trap-high resolution Orbitrap mass spectrometry system (UHPLC-LTQ-Orbitrap MS). Fruits were processed to juice, and then the juice was lyophilized and defatted.

Enzymatic but not compensated Jaffe methods reach the desirable specifications of NKDEP at normal levels of creatinine. Results of the French multicentric evaluation.

The French Society of Clinical Biochemistry conducted this study to compare the accuracy and performances of the best creatinine enzymatic assays and the compensated Jaffe methods from the same manufacturers. Creatinine was measured in 3 serum pools with creatinine levels of 35.9±0.

Fast microwave-assisted extraction of rotenone for its quantification in seeds of yam bean (Pachyrhizus sp.).

The aim of this study was to find if fast microwave-assisted extraction could be an alternative to the conventional Soxhlet extraction for the quantification of rotenone in yam bean seeds by SPE and HPLC-UV. For this purpose, an experimental design was used to determine the optimal conditions of the microwave extraction. Then the values of the quantification on three accessions from two different species of yam bean seeds were compared using the two different kinds of extraction.

Implementation of a design space approach for enantiomeric separations in polar organic solvent chromatography.

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.

Application of design of experiments and design space methodology for the HPLC-UV separation optimization of aporphine alkaloids from leaves of Spirospermum penduliflorum Thouars.

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.

Comparison of acid and enzymatic methods for inulin dosage: analytical performances and impact on glomerular filtration rate evaluation.

Among issues susceptible to hamper a reliable measurement of inulin clearance, those regarding the dosage of inulin are largely neglected. We have compared the analytical performances of 2 commonly used methods of inulin dosage (one "acid" and one "enzymatic" method) and studied their potential impact on the glomerular filtration rate (GFR) value given by inulin clearance. Repeatability, uncertainty and the beta-expectation limits were evaluated from pre-determined serum and urine pools of inulin.

Design space approach in the optimization of the spray-drying process.

From a quality by design perspective, the aim of the present study was to demonstrate the applicability of a Bayesian statistical methodology to identify the Design Space (DS) of a spray-drying process. Following the ICH Q8 guideline, the DS is defined as the "multidimensional combination and interaction of input variables (e.g.

Evaluating the reliability of analytical results using a probability criterion: a Bayesian perspective.

Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the individual results that will be generated during the routine application of the method. Regulatory guidelines provide a general framework to assess the validity of a method, but none address the issue of results reliability.

Development and validation of a ultra-high-performance liquid chromatography-UV method for the detection and quantification of erectile dysfunction drugs and some of their analogues found in counterfeit medicines.

Pharmaceutical counterfeiting is a permanently growing problem. Control laboratories are constantly analysing counterfeit medicines. In industrialised countries, one of the main counterfeited class of medicines are erectile dysfunction drugs.

A multicentric evaluation of IDMS-traceable creatinine enzymatic assays.

Chronic kidney disease definition is based on glomerular filtration rate (GFR) estimations which are derived from creatinine-based equations. The accuracy of GFR estimation is thus largely dependent of those of serum creatinine assays. International recommendations highlight the need for traceable creatinine assays.

Validation, transfer and measurement uncertainty estimation of an HPLC-UV method for the quantification of artemisinin in hydro alcoholic extracts of Artemisia annua L.

Malaria is the world's most important parasitic infection with 500 millions cases annually and almost 2 millions death per year. This disease is more present in Sub-Saharan Africa where 90% of the infections are found. Artemisinin and its semi synthetic derivatives (artemether, artesunate) have actually the most powerful activity on malaria, even in its complicated forms and resistance cases.

Application of new methodologies based on design of experiments, independent component analysis and design space for robust optimization in liquid chromatography.

HPLC separations of an unknown sample mixture and a pharmaceutical formulation have been optimized using a recently developed chemometric methodology proposed by W. Dewé et al. in 2004 and improved by P.