Pharmaceutical Nanotechnology Comparison of Methods for Predicting Dissolution and the Theoretical Implications of Particle-Size-Dependent Solubility KEVIN C. JOHNSON Intellipharm, LLC, Niantic, Connecticut 06357 Received 16 January 2011; revised 29 July 2011; accepted 9 September 2011 Published online 11 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22778 ABSTRACT: Experimental dissolution data of cilostazol suspensions and hydrocortisone pow- ders were simulated using either the Wang–Flanagan equation (1999. J Pharm Sci 88:731–738; 2002. J Pharm Sci 91:534–542) or the method of Johnson and coworkers (1989. Int J Pharm 51:9–17; 1993. Pharm Res 10:1308–1314; 1996. Pharm Res 13:1795–1798; 2003. Drug Dev Ind Pharm 29:833–842). Both methods were able to simulate experimental data with similar ac- curacy. For the method of Johnson and coworkers (1989. Int J Pharm 51:9–17; 1993. Pharm Res 10:1308–1314; 1996. Pharm Res 13:1795–1798; 2003. Drug Dev Ind Pharm 29:833–842), a single set of hydrodynamic assumptions was able to simulate both cilostazol and hydrocorti- sone with similar accuracy. For the Wang–Flanagan equation (1999. J Pharm Sci 88:731–738; 2002. J Pharm Sci 91:534–542), significantly different diffusion layer thicknesses gave the best simulations for cilostazol and hydrocortisone, but a single value of 38 : m provided good overall simulation of dissolution. The general computational method was enhanced to make solubility dependent on particle size, according to the Ostwald–Freundlich equation; it was also able to simulate Ostwald ripening. The enhanced computational method provided no way to explain the large increase in bioavailability of cilostazol in dogs when the drug was dosed as a nanopar- ticle versus micronized preparation. The method provides a computational tool for exploring theoretical implications and explaining the behavior of nanoparticles. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:681–689, 2012 Keywords: diffusion layer thickness; dissolution; dynamic simulation; mathematical model; nanoparticles; Ostwald–Freundlich equation; Ostwald ripening; particle size; solubility INTRODUCTION Several commercially available software prod- ucts simulate drug dissolution. These include GastroPlus TM (Simulations Plus, Inc., Lancaster, CA), Intellipharm R  PKCR (Intellipharm, LLC, Ni- antic, CT), PK-Sim R  (Bayer Technology Services GmbH, Leverkusen, Germany), and Simcyp R  (Sim- cyp Limited, Sheffield, UK). Simcyp R  applies the Wang–Flanagan method 1,2 to simulate dissolution, whereas GastroPlus TM offers the option of using ei- ther the Wang–Flanagan method 1,2 or the method of Johnson and coworkers. 3–6 One of the objectives of this study was to compare the two methods in their capability to predict the dissolution of polydisperse powders under nonsink conditions over a large range of pharmaceutically relevant drug particle sizes. Ide- Correspondence to: Kevin C. Johnson (Telephone: +860-691- 0142; E-mail: kjohnson29@snet.net) Journal of Pharmaceutical Sciences, Vol. 101, 681–689 (2012) © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association ally, a combination of theory and hydrodynamic as- sumptions is sought to allow accurate prediction of dissolution in vitro and in the gastrointestinal tract. A second objective was to provide insight into the poorly understood mechanisms by which nanopar- ticles improve the absorption of poorly soluble drugs. 7–10 This investigation was undertaken by in- corporating particle-size-dependent solubility based on the Ostwald–Freundlich equation 8–10 into the gen- eral computational method for simulating the disso- lution of polydisperse powders. It is unclear whether the commercially available programs named above handle particle-size-dependent solubility and, if so, how. 8 This report describes a method to simulate particle-size-dependent solubility as well as Ostwald ripening. 11 THEORY Equations 1 and 2 represent enhanced versions of the equations used by Johnson and coworkers 3–6 and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 2, FEBRUARY 2012 681