International Journal of Pharmaceutics 439 (2012) 1–7 Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics jo ur nal homep a ge: www.elsevier.com/locate/ijpharm Surfactant choice and the physical stability of nanosuspensions as a function of pH Maria D. Donoso, Roy J. Haskell, Richard R. Schartman ∗ Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA a r t i c l e i n f o Article history: Received 11 June 2012 Received in revised form 20 August 2012 Accepted 6 September 2012 Available online xxx Keywords: Nanoparticle Suspension Aggregation Salt Amorphous Surfactant a b s t r a c t Nanosuspensions of the example compounds ketoconazole and itraconazole were shown to aggregate upon reducing the pH to levels comparable to that known to exist in the stomach. Manipulation of the surfactant/polymer ratio in the suspension vehicle did not elucidate the cause of the aggregation. X-ray diffraction on ketoconazole solids failed to identify a form change as causative. Ultimately, ketoconazole intrinsic dissolution rate experiments implicated surface salt formation between ketoconazole and the vehicle surfactant as the cause of the aggregation. The generality of the phenomenon is discussed. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Multiple mechanisms have been identified by which suspen- sions are made physically stable. For example, polymers may be utilized to stabilize suspensions sterically (Napper and Netschey, 1971; Grasso et al., 2002). In this context, the word steric does not imply that aggregation is inhibited by the intermolecular colli- sion of surface-adsorbed polymers. Rather, the term implies that at least one of two different mechanisms is operating. The first mecha- nism works in a fashion akin to osmosis. As two particles that have polymer chains extending from the particles’ surfaces approach, the local concentration of solvent between the particles becomes lower than that of the bulk. The resulting chemical potential differ- ence works to drive solvent between the particles and keep them separated. The second “steric” mechanism relies on entropy to maintain particle separation. As particles with adsorbed polymer approach, the number of configurations that the polymer chains can assume is reduced, which through the Boltzmann relationship implies a reduction in entropy. A lower entropy in turn implies that parti- cle approach in such a situation is thermodynamically unfavorable (Grasso et al., 2002). Surface charge is yet another mechanism by which suspensions may be stabilized. The theoretical description of this was laid down ∗ Corresponding author. Tel.: +1 203 677 6769; fax: +1 203 677 7072. E-mail address: richard.schartman@bms.com (R.R. Schartman). by Deryagin, Landau, Verwey, and Overbeek in what has come to be called the DLVO theory (Deryagin, 1940; Deryagin and Landau, 1941a,b; Verwey and Overbeek, 1948; Kruyt, 1952). Haines and Martin (1961a,b,c) and Martin (1961) applied the theory to pharma- ceutical suspensions and explained how to avoid the formation of a hard non-redispersible cake when a suspension settles. Through proper adjustment of surface charge, it is possible to flocculate suspended particles and thus avoid cake formation. One would expect knowledge of the above mechanisms to be useful in the design of nanosuspension formulations. An exami- nation of the literature however shows that nanosuspensions are formulated in a largely empirical manner (Van Eerdenbrugh et al., 2009; Lee et al., 2008; Juhnke et al., 2010; Bodmeier and Chen, 1990). One popular formulation method involves the use of a poly- mer in combination with a charged surfactant. Presumably, optimal performance of an orally dosed suspension would require the sus- pension to be physically stable over the range of pH encountered in the gastrointestinal tract. However, it will be shown below that nanosuspensions of the example compounds itraconazole and ketoconazole were physically unstable toward acidification. In this paper we show that the reason for the instability is due to simple surface chemistry rather than a failure of one of the more complex mechanisms outlined above. 2. Materials and methods The structures of all compounds used in this study are provided in Fig. 1. 0378-5173/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2012.09.012