Comparative static curing versus dynamic curing on tablet coating structures

International audienceCuring is generally required to stabilize film coating from aqueous polymer dispersion. This post-coating drying step is traditionally carried out in static conditions, requiring the transfer of solid dosage forms to an oven. But, curing operation performed directly inside the coating equipment stands for an attractive industrial application. Recently, the use of various advanced physico-chemical characterization techniques i.e., X-ray micro-computed tomography, vibrational spectroscopies (near infrared and Raman) and X-ray microdiffraction, allowed new insights into the film-coating structures of dynamically cured tablets. Dynamic curing end-point was efficiently determined after 4 h. The aim of the present work was to elucidate the influence of curing conditions on film-coating structures. Results demonstrated that 24 h of static curing and 4 h of dynamic curing, both performed at 60 degrees C and ambient relative humidity, led to similar coating layers in terms of drug release properties, porosity, water content, structural rearrangement of polymer chains and crystalline distribution. Furthermore, X-ray microdiffraction measurements pointed out different crystalline coating compositions depending on sample storage time. An aging mechanism might have occur during storage, resulting in the crystallization and the upward migration of cetyl alcohol, coupled to the downward migration of crystalline sodium lauryl sulfate within the coating layer. Interestingly, this new study clearly provided further knowledge into film-coating structures after a curing step and confirmed that curing operation could be performed in dynamic conditions

Comprehensive study of dynamic curing effect on tablet coating structure

International audienceThe dissolution method is still widely used to determine curing end-points to ensure long-term stability of film coatings. Nevertheless, the process of curing has not yet been fully investigated. For the first time, joint techniques were used to elucidate the mechanisms of dynamic curing over time from ethylcellulose (Aquacoat (R))-based coated tablets. X-ray micro-computed tomography (X mu CT), Near Infrared (NIR), and Raman spectroscopies as well as X-ray microdiffraction were employed as non-destructive techniques to perform direct measurements on tablets. All techniques indicated that after a dynamic curing period of 4 h, reproducible drug release can be achieved and no changes in the microstructure of the coating were any longer detected. X mu CT analysis highlighted the reduced internal porosity, while both NIR and Raman measurements showed that spectral information remained unaltered after further curing. X-ray microdiffraction revealed densification of the coating layer with a decrease in the overall coating thickness of about 10 pm as a result of curing. In addition, coating heterogeneity attributed to cetyl alcohol was observed from microscopic images and Raman analysis. This observation was confirmed by X-ray microdiffraction that showed that crystalline cetyl alcohol melted and spread over the coating surface with curing. Prior to curing, X-ray microdiffraction also revealed the existence of two coating zones differing in crystalline cetyl alcohol and sodium lauryl sulfate concentrations which could be explained by migration of these constituents within the coating layer. Therefore, the use of non-destructive techniques allowed new insights into tablet coating structures and provided precise determination of the curing end-point compared to traditional dissolution testing. This thorough study may open up new possibilities for process and formulation control

Développement de méthodologies chimiométriques sur des images hyperspectrales pour la détection de composés faiblement dosés : application à la microscopie Raman

Hyperspectral imaging is now considered as a powerful analytical tool in the pharmaceutical environment, both during development to ensure the drug product quality and to solve production issues on commercialized products.In this thesis, Raman microscopy is used to study the distribution of actives and excipients in a pharmaceutical drug product, by especially focusing on the identification of a low dose compound. This latter product is defined as a compound which has low spatial and spectra contributions, meaning that it is scattered in a few pixels of the image and that its spectral response is mixed with the other compounds of the formulation. While most chemometric tools are based on the decomposition of statistical moments (requiring sufficient variations between samples or image pixels), some limitations have been rapidly reached. The first part of this thesis highlights the difficulty to detect a low dose compound in a product by using independent component analysis or multivariate curve resolution. Different methodologies are proposed to circumvent these limitations. For both techniques, reduction of dimensions and filtering steps appears as critical parameters of the method. The second part of the thesis focusses on the signal space to determine absence/presence compound maps or to detect the compounds in an unknown formulation. The proposed methods are only based on the spectral space of each formulation compound. There are perfectly suitable to a low dose compound and should be well-adapted to other analytical techniques or to other environments.L’imagerie hyperspectrale est désormais considérée comme un outil analytique à part entière dans l’industrie pharmaceutique, aussi bien au cours du développement pour assurer la qualité d’un produit que pour résoudre des problématiques de production après la mise sur le marché du médicament. Dans ces travaux, la microscopie Raman est utilisée pour étudier la distribution en principes actifs et excipients au sein d’une forme pharmaceutique solide, en se focalisant tout particulièrement sur l’identification d’un composé faiblement dosé. Ce dernier est défini comme étant un produit ayant de faibles contributions spatiale et spectrale, signifiant qu’il est distribué dans quelques pixels de l’image avec une information spectrale peu présente dans un spectre de mélange. Alors que la plupart des algorithmes chimiométriques se basent sur la décomposition de moments statistiques, nécessitant une variation suffisante entre les échantillons (les pixels d’une image), les limites de ces outils pour résoudre ce cas spécifique sont rapidement atteintes.La première partie de la thèse met en évidence les difficultés de détection d’un composé faiblement dosé en utilisant l’analyse en composantes indépendantes et la résolution multivariée de courbes. Des méthodologies de travail sont proposées pour contourner ces limitations. Pour les deux techniques, les étapes de réduction de dimensions apparaissent comme des paramètres critiques de la méthode. La seconde partie de la thèse se focalise sur l’espace des signaux pour déterminer des cartes d’absence/présence de constituants ou pour détecter des constituants dans une formulation inconnue, en se basant sur des espaces spectraux portant une information relative aux constituants de la formulation. Les techniques proposées sont parfaitement adaptées à la détection d’un composé faiblement dosé et ces méthodes pourraient être adaptées à d’autres techniques de mesure ou d’autres domaines d’application

Real-time predictions of drug release and end point detection of a coating operation by in-line near infrared measurements

International audienc

Raman Hyperspectral Imaging: An essential tool in the pharmaceutical field

Resulting from the combination of Raman spectroscopy and optical microscopy, Raman hyperspectral imaging has proven to be an indispensable tool in the pharmaceutical field. This article will broach a number of Raman hyperspectral imaging applications that were developed in our laboratory, in order to demonstrate the significance of the technique

Utilisation de la spectrométrie Raman dans le domaine pharmaceutique

This document sets out the theoretical and practical fundamentals to guide users in the imple- mentation of Raman spectroscopy in industry or the university-hospital sector. It describes the principle of this technique and currently available instruments. Since Raman spectrometers are used in a regulated context, the methodology of instru- ment qualification is discussed. Different types of applications encountered in the pharmaceutical field are presented: process monitoring, searching for and detecting counterfeits, and identifying raw materials on receipt

Critical review of surface-enhanced Raman spectroscopy applications in the pharmaceutical field

Surface-enhanced Raman spectroscopy (SERS) is a sensitive analytical tool used in the pharmaceutical field in recent years. SERS keeps all the advantages of classical Raman spectroscopy while being is more sensitive allowing its use for the detection and the quantification of low-dose substances contained in pharmaceutical samples. However, the analytical performance of SERS is limited due to the difficulty to implement a quantitative methodology correctly validated. Nevertheless, some studies reported the development of SERS quantitative methods especially in pharmaceutical approaches. In this context, this review presents the main concepts of the SERS technique. The different steps that need to be applied to develop a SERS quantitative method are also deeply described. The last part of the present manuscript gives a critical overview of the different SERS pharmaceutical applications that were developed for a non-exhaustive list of pharmaceutical compounds with the aim to highlights the validation criteria for each application

Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by Hot-Melt Extrusion using transmission Raman spectroscopy: A feasibility study.

The development of a quantitative method determining the crystalline percentage in an amorphous solid dispersion is of great interest in the pharmaceutical field. Indeed, the crystalline Active Pharmaceutical Ingredient transformation into its amorphous state is increasingly used as it enhances the solubility and bioavailability of Biopharmaceutical Classification System class II drugs. One way to produce amorphous solid dispersions is the Hot-Melt Extrusion (HME) process. This study reported the development and the comparison of the analytical performances of two techniques, based on backscattering and transmission Raman spectroscopy, determining the crystalline remaining content in amorphous solid dispersions produced by HME. Principal Component Analysis (PCA) and Partial Least Squares (PLS) regression were performed on preprocessed data and tended towards the same conclusions: for the backscattering Raman results, the use of the DuoScan™ mode improved the PCA and PLS results, due to a larger analyzed sampling volume. For the transmission Raman results, the determination of low crystalline percentages was possible and the best regression model was obtained using this technique. Indeed, the latter acquired spectra through the whole sample volume, in contrast with the previous surface analyses performed using the backscattering mode. This study consequently highlighted the importance of the analyzed sampling volume.Mycomel

Dosages quantitaifs de principes actifs dans les formes solides par spectroscopie proche infrarouge: Application pratique au test d'uniformité de teneur des comprimés

L'augmentation du nombre de dosages à réaliser dans l'industrie pharmaceutique conduit à rechercher des méthodes alternatives. La spectroscopie proche infrarouge répond précisément à cette demande en permettant des dosages rapides, non destructifs et respectueux de l'environnement. Le texte publié dans SFSTP Pharma Pratiques en 2010 énonçait la méthodologie à suivre pour développer une technique de dosage de substance active dans une formulation solide de type comprimé par spectroscopie proche infrarouge. Il est apparu intéressant d'illustrer et de compléter les différentes étapes de cette méthodologies au travers d'exemples