title: Distribution of a low dose compound within pharmaceutical tablet by using multivariate curve resolution on Raman hyperspectral images.
abstract: In this work, Raman hyperspectral images and multivariate curve resolution-alternating least squares (MCR-ALS) are used to study the distribution of actives and excipients within a pharmaceutical drug product. This article is mainly focused on the distribution of a low dose constituent. Different approaches are compared, using initially filtered or non-filtered data, or using a column-wise augmented dataset before starting the MCR-ALS iterative process including appended information on the low dose component. In the studied formulation, magnesium stearate is used as a lubricant to improve powder flowability. With a theoretical concentration of 0.5% (w/w) in the drug product, the spectral variance contained in the data is weak. By using a principal component analysis (PCA) filtered dataset as a first step of the MCR-ALS approach, the lubricant information is lost in the non-explained variance and its associated distribution in the tablet cannot be highlighted. A sufficient number of components to generate the PCA noise-filtered matrix has to be used in order to keep the lubricant variability within the data set analyzed or, otherwise, work with the raw non-filtered data. Different models are built using an increasing number of components to perform the PCA reduction. It is shown that the magnesium stearate information can be extracted from a PCA model using a minimum of 20 components. In the last part, a column-wise augmented matrix, including a reference spectrum of the lubricant, is used before starting MCR-ALS process. PCA reduction is performed on the augmented matrix, so the magnesium stearate contribution is included within the MCR-ALS calculations. By using an appropriate PCA reduction, with a sufficient number of components, or by using an augmented dataset including appended information on the low dose component, the distribution of the two actives, the two main excipients and the low dose lubricant are correctly recovered.
authors.affiliation: Technologie Servier, Orléans, France. Electronic address: mathieu.boiret@fr.netgrs.com.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boiret
authors.affiliation: Grup de Quimiometria, Dept. Química Analítica, Universitat de Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: de Juan
authors.affiliation: IRSTEA, UMR ITAP 361, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gorretta
authors.affiliation: Technologie Servier, Orléans, France.
authors.forename: Yves-Michel
authors.initials: YM
authors.lastname: Ginot
authors.affiliation: IRSTEA, UMR ITAP 361, Montpellier, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Roger
mesh_terms: D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013059:Spectrum Analysis, Raman / Q000379:methods*; D013607:Tablets / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D013607:Tablets
keywords: Active and excipient distributions; Alternating least squares; Low dose compound; Multivariate curve resolution; Raman hyperspectral imaging