Comparative particle size determination of phenacetin bulk powder by using Kubelka–Munk theory and principal component regression analysis based on near-infrared spectroscopy Makoto Otsuka * Department of Pharmaceutical Technology, Kobe Pharmaceutical University, Motoyama-Kitamachi 4-19-1, Higashi-Nada, Kobe 658-8558, Japan Accepted 6 January 2004 Available online 10 May 2004 Abstract Purpose: The purpose of this study is to investigate the effect of particle size on Kubelka – Munk theoretical light diffusion of NIR spectra. And a chemoinfometrical method for quantitative determination of particle size of phenacetin crystalline powder based on Fourier- transformed near-infrared (FT-NIR) spectroscopy was established. Method: The sample powders of phenacetin were obtained by sieving using 37 – 590 Am screens. NIR spectra were taken with a total 60 NIR data points by using a FT-NIR spectrometer. Results: The NIR absorption patterns were almost identical for the samples. However, the base line of the spectrum was observed to increase with decreasing sample powder particle size. The scatter coefficient constants (S) were calculated from NIR spectra based on Kubelka and Munk light scattering theory. The S values determined were found to be constant within the wavenumbers studied; i.e., 4000 – 10 000 cm 1 . However, this light scatter coefficient, S, for phenacetin particle was found to be inversely proportional to particle size. Subsequently, the principal component regression (PCR) analysis based on a three-principal component model was applied in the analyses of NIR spectra of phenacetin powder samples with various particle sizes. By applying this method, the particle size for phenacetin can be estimated form the light scatter coefficient, S. The resulting plot showed a linear relationship between the predicted and actual particle size with a slope of 0.9167, an intercept of 20.61, and a correlation coefficient of 0.9147. The loading vector of PC1 showed a plateau at 4500 – 10 000 cm 1 , and the score of PC1 increased with increase of particle size. Conclusion: Quantitative particle size evaluation of phenacetin crystalline powder using the PCR method based on NIR spectra was useful for practical purpose in pharmaceutical industry, and their background was clarified by using Kubelka –Munk scattering theory. D 2004 Elsevier B.V. All rights reserved. Keywords: Fourier-transformed near-infrared spectroscopy; Chemoinfometrics; Particle size; Phenacetin; Kubelka– Munk theory 1. Introduction In order to ensure the manufacture of safe and effica- cious pharmaceutical products, the production process validation is required in order to meet regulatory require- ments [1]. The pharmaceutical properties of bulk drug substances, such as the average particle size [2], crystal habit, and polymorphism, have to be equivalent to the investigational drug; these properties are usually checked during the manufacturing process of the bulk drug sub- stance. Because, these properties affect the dissolution rate [3], and bioavailability in humans have been required to influence the incidence of side effects [4]. Therefore, control of particle sizes of bulk drug prior to performing formulations is important in insuring the quality of phar- maceutical preparations. A few trial evaluations of the particle size after separation of the bulk drug from the preparations have been reported [5]. However, the particle size of the drug powder was changed during separation processes by using organic solvents. The Duyckaerts meth- od [6–9] was applied in evaluating the effect of particle size in bulk powder of pharmaceutical on the character- istics of a pharmaceutical preparation. The published eval- uation was based on the analysis of Fourier-transformed 0032-5910/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2004.01.025 * Tel.: +81-78-441-7531; fax: +81-78-441-7532. E-mail address: m-otsuka@kobepharma-u.ac.jp (M. Otsuka). www.elsevier.com/locate/powtec Powder Technology 141 (2004) 244– 250