Anal. Chem. 2003, 75, 1777-1785
Accelerated Articles
Spectroscopic Approach for On-Line Monitoring of Particle Size during the Processing of Pharmaceutical Nanoparticles John P. Higgins,* Steven M. Arrivo,† Gert Thurau, Robert L. Green, William Bowen, Andrew Lange, Allen C. Templeton, Denise L. Thomas, and Robert A. Reed
Merck Research Laboratories, Merck and Co., Inc., P.O. Box 4, WP78-110, West Point, Pennsylvania 19486
A novel application of near-infrared (near-IR) spectroscopy for the on-line determination of nanoparticle size of a drug compound in a high solids dispersion is described. The on-line spectroscopic technique provides real-time data for process monitoring and control and overcomes the limitations that are encountered using laboratorybased instrumentation for nanoparticle size determination. Near-IR spectroscopy is capable of providing an accuracy of 2.4 nm near the endpoint of particle production, where the volume-weighted D90 particle size is determined to be 200-220 nm. The accuracy is adequate for endpoint control, which minimizes excess processing and provides control over the particle size throughout nanoparticle production.
Particle size reduction of drug substances into the submicrometer size range has been recently developed as a viable approach for increasing the bioavailability of poorly water-soluble compounds.1-3 Reducing the particle size of the drug substance by media milling, wherein an aqueous suspension of a drug substance is milled by agitation with polystyrene media, can be used to reduce the particle size from ∼30 µm to ∼100-200 nm over the course of the process. The particle size distribution is * To whom correspondence should be addressed. E-mail: John_Higgins2@ Merck.com. Fax: 215-652-2821. † Current address: Pfizer Global Research & Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105. (1) Liversidge, G. G.; Cundy, K. C.; Bishop, J.; Czekai, D. “Surface modified drug nanoparticles.” U.S. Patent no. 5145684, 1991. (2) Muller, R. H.; Becker, R.; Kruss, B.; Peters, K. “Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution.” U.S. Patent no. 5858410, 1999. (3) Muller, R. H.; Peters, K.; Becker, R.; Kruss, B. Proc. Int. Symp. Controlled Release Bioact. Mater. 1996, 22, 574-575. 10.1021/ac0207980 CCC: $25.00 Published on Web 03/20/2003
© 2003 American Chemical Society
the critical process parameter that must be monitored and controlled before further formulation of the nanomilled drug substance. Herein we describe a novel on-line, real-time particle size analysis system based on near-IR spectroscopy that is capable of effectively monitoring particle size during the course of the process. Despite the routine use of near-IR spectroscopy in industrial process analysis, the application of the technique to monitor a submicrometer particle size distribution during the course of a manufacturing process has not been previously described. Moreover, the near-IR spectroscopic technique described in this report is the first example of an on-line spectroscopic approach that provides the precision necessary to distinguish particle size changes as small as 1-2 nm for nanoparticles with diameters of
