International Journal of Pharmaceutics 438 (2012) 287–295 Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics jo ur nal homep a ge: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Enhanced dissolution and oral bioavailability of aripiprazole nanosuspensions prepared by nanoprecipitation/homogenization based on acid–base neutralization Ying Xu a,b,1 , Xiaoyi Liu c,1 , Ruyue Lian a , Siji Zheng c , Zongning Yin b , Yi Lu a,∗ , Wei Wu a a School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery of Ministry of Education and PLA, Shanghai, 201203, PR China b West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China c Shanghai Zhong Xi Pharmaceutical (Group) Co., Ltd., Shanghai, 200065, PR China a r t i c l e i n f o Article history: Received 29 June 2012 Received in revised form 3 September 2012 Accepted 9 September 2012 Available online 16 September 2012 Keywords: Nanosuspensions Acid–base neutralization Aripiprazole Solubility Dissolution Oral bioavailability a b s t r a c t In this study, aripiprazole (APZ), a weak alkaline drug with pH-dependent solubility, was selected as model drug to examine the feasibility of preparing nanosuspensions using nanopre- cipitation/homogenization technique based on acid–base neutralization. The related substances in nanosuspensions prepared under optimal conditions were slightly increased as compared with APZ raw material. The resultant APZ nanosuspensions showed a mean particle size of 350 nm with polydispersion index (PI) value of 0.20. Good physical stability was kept for over 40 days. SEM observation showed the morphology of oval crystals with rough surface. Nanosuspensions significantly increased the solubility as well as the dissolution of APZ due to the decreased particle size. Differential scanning calorimetry and powder X-ray diffractometry confirmed the crystallinity of APZ in nanosuspensions. APZ nanosuspen- sions got maximum absorption rate and extent comparing with APZ commercial tablet and suspensions with relative bioavailability of 123.43 ± 12.98% and 171.41 ± 14.62%, respectively. This technique has the potential to prepare nanosuspensions of insoluble drugs with pH-dependent solubility. © 2012 Elsevier B.V. All rights reserved. 1. Introduction At present about 40% of the drugs under development and approximately 60% of the drugs coming directly from synthesis are poorly soluble (Keck and Müller, 2006). Generally, these poorly soluble drugs are plagued with low and highly variable bioavail- ability due to the dissolution rate-limited performance. Although some strategies like solid dispersion technology (Sun et al., 2008a,b; Zhang et al., 2008), complexing with cyclodextrins (Chen et al., 2012; Lu et al., 2009; Zhang et al., 2009), emulsions (Nakano, 2000) and nanoemulsions (Lu et al., 2012a), have showed good potential in bioavailability enhancement, they are limited by the physico- chemical properties of the drug molecules and only successful in some instances (Merisko-Liversidge et al., 2003; Patravale et al., 2004). Hence, there are still increasing requirements for innova- tive yet universal approaches to improve the bioavailability of poor water soluble drugs. Based on Noyes–Whitney equation (Noyes and Whitney, 1897), the dissolution rate of drugs is proportional to its surface area and ∗ Corresponding author. Tel.: +86 28 51980084; fax: +86 21 51980084. E-mail addresses: fd luyi@fudan.edu.cn (Y. Lu), wuwei@shmu.edu.cn (W. Wu). 1 These authors contributed equally to this work. their saturation solubility. Micronization is thus utilized to enhance the dissolution of poor water-soluble drugs, which however does not create sufficiently large surface to adequately enhance the dis- solution rate in most cases (Shegokar and Muller, 2010). In this regard, reducing the particle size of drugs to produce nanosuspen- sions, which is also called nanocrystals especially when it is dried, is quite advantageous. By definition, nanosuspension is colloidal dis- persion of nano-sized (typically between 200 nm and 500 nm) pure drug stabilized by suitable stabilizers (Gao et al., 2008; Keck and Müller, 2006; Patravale et al., 2004). It was estimated that reduc- ing the particle size from 10 m to 200 nm generally generate a 50-fold increase in specific surface area based on the assumption that the drug particles are near spherical (Merisko-Liversidge et al., 2003). Meanwhile, according to the Ostwald–Freundlich equation, solubility of drugs will increase when its particle size is reduced to nanoscale (Kesisoglou et al., 2007). Thus, the increased sur- face area together with the increased solubility due to particle size reduction will lead to increased dissolution and improved bioavailability for poor water-soluble drugs by the nanosuspen- sion technology (Liversidge and Conzentino, 1995; Liversidge and Cundy, 1995). Typically, nanosuspensions can be prepared by two types of methods: antisolvent precipitation of dissolved drugs (bottom-up) (Ali et al., 2009; Peltonen and Hirvonen, 2010) and comminution 0378-5173/$ – see front matter © 2012 Elsevier B.V. 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