Journal of Pharmaceutical and Biomedical Analysis 141 (2017) 180–191 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis j o ur nal ho me page: www.elsevier.com/lo cate/jpba Macro-Raman spectroscopy for bulk composition and homogeneity analysis of multi-component pharmaceutical powders Hui Wang a , David Barona a , Sulayman Oladepo a,b , Lisa Williams c , Susan Hoe c , David Lechuga-Ballesteros c , Reinhard Vehring a,∗ a Department of Mechanical Engineering, University of Alberta, Edmonton, AB T6G 2G8, Canada b Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia c Pearl Therapeutics Inc., Redwood City, CA, USA a r t i c l e i n f o Article history: Received 20 December 2016 Received in revised form 30 March 2017 Accepted 4 April 2017 Available online 23 April 2017 Keywords: Macro-Raman spectroscopy Bulk composition Effective sample volume Powder homogeneity a b s t r a c t A new macro-Raman system equipped with a motorized translational sample stage and low-frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi-component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi-pass cavity of the macro-Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02 L to about 0.4 L. A stochastic model simulating the random sam- pling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide ® 250 and Seretide ® 500 simulated for different sampling volumes with experimentally measured com- positions verified that the effective sample volume of a single point macro-Raman measurement in the multi-pass cavity of this instrument was between 0.3 L and 0.5 L. The macro-Raman system was also successfully used for blend uniformity analysis. It was concluded that demixing occurred in the binary mixture of l-leucine and d-mannitol from the observation that the sampling errors indicated by the stan- dard deviations of measured leucine mass fractions increased during mixing, and the standard deviation values were all larger than the theoretical lower limit determined by the simulation. Since sample volume was shown to have a significant impact on measured homogeneity characteristics, it was concluded that powder homogeneity analysis results, i.e., the mean of individual test results and absolute and relative standard deviations, must be presented together with the effective sample volumes of the applied testing techniques for any measurement of powder homogeneity to be fully meaningful. © 2017 Elsevier B.V. All rights reserved. 1. Introduction Pharmaceutical powders are commonly encountered solid dosage forms of medication in which one or more active pharma- ceutical ingredients are dispersed in a finely divided state with or without excipients [1–3]. Examples include drug powders in capsules [4], powders compressed into tablets [5], powder blends of respirable drugs and excipients contained in delivery devices like dry powder inhalers [6], and particle suspensions contained in pressurized metered dose inhalers [7]. Combination products containing formulations of several active drug ingredients and ∗ Corresponding author. E-mail address: reinhard.vehring@ualberta.ca (R. Vehring). excipients are frequently used to improve drug delivery efficiency, treat multiple symptoms or diseases, and reduce side effects [8–11]. Key properties of these multicomponent pharmaceutical pow- ders, such as particle size distribution, solubility, dispersibility, cohesive and adhesive forces, and biocompatibility need to be well characterized to make sure that the drugs can be released at the right sites and correct time to achieve the desired clinical effect [12–14]. Moreover, exact drug compositions, including concentra- tions of all active ingredients and excipients, must be precisely monitored and controlled before the products can be released to the market. Because of the potential for complex physical and chemical changes to occur to pharmaceutical powders during manufacture, storage, and even use [15], Raman spectroscopy has gained popu- larity in the pharmaceutical industry as a means of monitoring any http://dx.doi.org/10.1016/j.jpba.2017.04.003 0731-7085/© 2017 Elsevier B.V. All rights reserved.