Research paper Near InfraRed Spectroscopy homogeneity evaluation of complex powder blends in a small-scale pharmaceutical preformulation process, a real-life application I. Storme-Paris a,b , I. Clarot c , S. Esposito d , J.C. Chaumeil d , A. Nicolas c , F. Brion b,e , A. Rieutord b , P. Chaminade a, * a Groupe de Chimie Analytique de Paris-Sud, EA 4041, IFR 141, School of Pharmacy, Univ Paris-Sud, Châtenay-Malabry, France b APHP, Robert Debré University Children Hospital, Pharmacy Department, Paris, France c Laboratory of Analytical Chemistry and Drug Bioanalyses, School of Pharmacy, Univ Nancy I, France d Research and Development Department, Agence Générale des Equipements et Produits de Santé (AGEPS), Paris, France e School of Pharmacy, Univ Paris Descartes, Paris, France article info Article history: Received 14 May 2008 Accepted in revised form 16 November 2008 Available online 25 November 2008 Keywords: Near InfraRed Spectroscopy Chemometrics Powder blend homogeneity Paediatrics Colimycin Tobramycin abstract Near InfraRed Spectroscopy (NIRS) is a potentially powerful tool for assessing the homogeneity of indus- trial powder blends. In the particular context of hospital manufacturing, we considered the introduction of the technique at a small pharmaceutical process scale, with the objective of following blend homoge- neity in mixtures of seven components. This article investigates the performance of various NIRS-based methodologies to assess powder blending. The formulation studied is prescribed in haematology unit, as part of the treatment for digestive decon- tamination in children receiving stem-cell transplantation. It is composed of the active pharmaceutical ingredients (APIs) colimycin and tobramycin and five excipients. We evaluated 39 different blends com- posing 14 different formulations, with uncorrelated proportions of constituents between these 14 formu- lations. The reference methods used to establish the NIRS models were gravimetry and a High Performance Liquid Chromatography method coupled to an Evaporative Light Scattering Detection. Unsupervised and supervised qualitative and quantitative chemometric methods were performed to assess powder blend homogeneity using a bench top instrument equipped with an optical fibre. For qual- itative evaluations, unsupervised Moving Block Standard Deviation, autocorrelation functions and Partial Least Square Discriminant Analysis (PLS-DA) were used. For quantitative evaluations, Partial Least Square Cross-Validated models were chosen. Results are expressed as API, and major excipient percentages of theoretical values as a function of blending time. The 14 different formulations were only satisfactorily discriminated by supervised algorithms, such as an optimised PLS-DA model. The homogeneity state was demonstrated after 16 min of blending, quantifying three components with a precision between 1.2% and 1.4% w/w. This study demonstrates, for the first time, the effective implementation of NIRS for blend homogeneity evaluation, as early as the preformulation step in a small hospital manufacturing unit. It shows how NIRS involving sampling with an optic fibre can be useful to characterise, optimise and control a small-scale mixing processes on the basis of the distribution of APIs and excipients during blending. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction 1.1. Clinical and pharmaceutical context In the haematology unit of the Robert Debré Children’s Hospital, children receiving bone marrow transplantation are concomitantly treated for digestive decontamination to prevent bacterial spread. The current formulation is poorly palatable, leading to non-compli- ance by most of our paediatric patients. This jeopardised patient outcome and consequently, the AGEPS (the Department for Drug Development of Paris Hospitals) has formulated oral powders for paediatric digestive decontamination. These preparations were composed of two APIs i.e. colimycin (C, 0.1 w/w) and tobramycin (T, 0.2 w/w), with five excipients: sucrose, citric acid, colloidal sil- ica, magnesium stearate, and flavourings. The role of the AGEPS is to develop and manufacture pharma- ceutical forms intended for distribution to the hospital pharmacies. When the needs do not justify industrial manufacture by the AGE- PS, individual accredited hospital pharmacies have themselves to 0939-6411/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2008.11.002 * Corresponding author. Groupe de Chimie Analytique de Paris-Sud, EA 4041, IFR 141, School of Pharmacy, Univ Paris-Sud, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France. Tel.: +33 (0) 1 46 83 54 59; fax: +33 (0) 1 46 83 54 58. E-mail address: pierre.chaminade@u-psud.fr (P. Chaminade). European Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 189–198 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb