PHARMACEUTICAL NANOTECHNOLOGY A Screening Study of Surface Stabilization during the Production of Drug Nanocrystals BERNARD VAN EERDENBRUGH, 1 JAN VERMANT, 2 JOHAN A. MARTENS, 3 LUDO FROYEN, 4 JAN VAN HUMBEECK, 4 PATRICK AUGUSTIJNS, 1 GUY VAN DEN MOOTER 1 1 Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium 2 Department of Chemical Engineering, K.U. Leuven, W. de Croylaan 46, 3001 Leuven, Belgium 3 Center for Surface Chemistry and Catalysis, K.U. Leuven, Kasteelpark Arenberg 23, 3001 Leuven, Belgium 4 Metallurgy and Materials Engineering Department, K.U. Leuven, Kasteelpark Arenberg 44, 3001 Leuven, Belgium Received 20 March 2008; revised 8 July 2008; accepted 3 August 2008 Published online 19 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21563 ABSTRACT: In order to establish a knowledge base for nanosuspension production, a screening was performed on 13 different stabilizers at 3 concentrations for 9 structurally different drug compounds. Concerning the stabilizers tested, the group of semi-synthetic polymers was the least performant (stable nanosuspensions were obtained in only 1 out of 10 cases). For the linear synthetic polymers, better results were obtained with povidones, however poly(vinyl alcohol) did not result in adequate stabilization. The synthetic copolymers showed even higher success rates, resulting in nanosuspensions in two out of three cases when applied at a 100 wt% concentration (relative to the drug weight). Finally, the surfactants gave the best results, with TPGS being successful at concentrations of 25 or 100 wt% of the drug weight for all compounds tested. From the point of view of drug compound, large differences could be observed upon evaluation of the relative number of formulations of that compound resulting in nanosuspensions. It was found that the hydrophobicity of the surfaces, as estimated by the adsorbed amount of TPGS per unit of surface area of nanosuspensions stabilized with 25 wt% TPGS, was decisive for the agglomeration tendency of the particles and hence the ease of nano- suspensions stabilization. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2091–2103, 2009 Keywords: nanoparticles; nanotechnology; suspensions; stabilization; milling INTRODUCTION Because of the increasing number of drug candidates exhibiting low solubility and/or dis- solution rates, 1 nanosuspensions have rapidly become a valuable tool in the formulation area to obtain high dissolution rates and hence higher (oral) bioavailability. 2 Nowadays, awareness of nanosuspensions as a formulation option is becoming more and more widespread throughout the pharmaceutical developmental chain with possible considerations in computational, toxico- logical, preclinical, and clinical settings. 2 Nanosuspensions consist of stabilized submi- cron sized crystalline drug particles in a liquid Additional Supporting Information may be found in the online version of this article. Correspondence to: Guy Van den Mooter (Telephone: 32- 16330304; Fax: 32-16330305; E-mail: guy.vandenmooter@pharm.kuleuven.be) Journal of Pharmaceutical Sciences, Vol. 98, 2091–2103 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009 2091