International Journal of Pharmaceutics 377 (2009) 148–152 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Nanodispersions of taxifolin: Impact of solid-state properties on dissolution behavior Alexander N. Shikov a , Olga N. Pozharitskaya a , Inna Miroshnyk b , Sabiruddin Mirza b,∗ , Irina N. Urakova a , Samuli Hirsjärvi b , Valery G. Makarov a , Jyrki Heinämäki b , Jouko Yliruusi b , Raimo Hiltunen c a St Petersburg Institute of Pharmacy, 47/5 Piskarevsky prospect, 195067 St Petersburg, Russia b Division of Pharmaceutical Technology, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5E), FI-00014 University of Helsinki, Helsinki, Finland c Division of Pharmaceutical Biology, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5E), FI-00014 University of Helsinki, Helsinki, Finland article info Article history: Received 23 December 2008 Received in revised form 12 April 2009 Accepted 29 April 2009 Available online 6 May 2009 Keywords: Nanoparticles Taxifolin Lyophilization Nanodispersion Solid-state properties Drug release kinetics abstract Nanosizing is an advanced formulation approach to address the issues of poor aqueous solubility of active pharmaceutical ingredients. Here we present a procedure to prepare a nanoparticulate formulation with the objective to enhance dissolution kinetics of taxifolin dihydrate, a naturally occurring flavonoid with antioxidant, anti-inflammatory, and hepatoprotective activities. Polyvinylpirrolidone was selected as a carrier and the solid nanodispersions of varying compositions were prepared by a co-precipitation technique followed by lyophilization. The formulation technology reported herein resulted in aggregate- free, spherical particles with the mean size of about 150 nm, as observed by scanning electron microscopy and measured by photon correlation spectroscopy. Furthermore, the co-precipitation process caused taxifolin dihydrate to convert into an amorphous form as verified by X-ray powder diffraction, differential scanning calorimetry, hot stage microscopy and Raman spectroscopy. Finally, in vitro dissolution behavior of the nanodispersion of taxifolin was shown to be superior to that of either pure drug or a drug–polymer physical mixture, reaching 90% of taxifolin released after 30min. Such enhanced drug release kinetics from the nanodispersion was attributed to both the reduced particle size and the loss of crystallinity. © 2009 Elsevier B.V. All rights reserved. 1. Introduction The poor solubility of active pharmaceutical ingredients (APIs) in water and their low dissolution rate in the aqueous gastro-intestinal fluids often leads to insufficient bioavailability and is one of the most difficult and non-solved problems in pharmaceutical tech- nology. The common approaches used to address the issues of poor aqueous solubility include, for instance, salt formation (Stahl and Wermuth, 2002), particle size reduction (Merisko-Liversidge et al., 2003), and solid dispersion formulations (Chiou and Riegelman, 1971; Pozharitskaya et al., 1999; Leuner and Dressman, 2000), whereby an API is homogeneously dispersed within a carrier. Solid dispersions are particularly regaining interest within the pharmaceutical industry as they enable to obtain a physi- cally stable formulation of an API in amorphous state (Van den Mooter et al., 2000; Forster et al., 2002; Miller et al., 2008; Tong and Zografi, 2001). Within the polymeric matrix, the API can be present in two forms: solid solution (molecularly dis- persed) or nanodispersed with particle sizes preferably lower than ∗ Corresponding author. Tel.: +358 919159151; fax: +358 919159144. E-mail address: sabir.mirza@helsinki.fi (S. Mirza). URL: http://www.pharmtech.helsinki.fi/english/frontpage.htm (S. Mirza). 500 nm (amorphous/crystalline material) (Karavas et al., 2007). Polyvinylpyrrolidone (PVP; Fig. 1B), a freely water soluble amor- phous polymer, has been most widely used as a carrier for such solid dispersion systems. Flavonoids are naturally occurring substances possessing some positive effects on human health (Harborne, 1994). These sub- stances with variable polyphenolic structures are found in numerous food products, such as fruit, vegetables, nuts and bev- erages (coffee, tea, red wine), as well as in different parts of herbs (Hollman and Katan, 1997; Nijeveldt et al., 2001). Flavonoid tax- ifolin (2(R), 3(S)- 3 ′ ,4 ′ ,5,7-tetrahydroxyflavanonol) (Fig. 1A) is widely distributed in the rind of Siberian and Dahurian larchs (Larix sibirica Leder. and L. gmelini Rupr. (Rupr.), syn. L. Dahurica Turoz) (Teselkin et al., 2000). Taxifolin significantly dilates blood ves- sel, improves microcirculation, increases cerebral blood flow, and inhibits platelet aggregation activity. It has been widely used in the treatment of cerebral infarction and sequela, cerebral throm- bus, coronary heart disease and angina pectoris (Landolfi et al., 1984; Tzen et al., 1991). In recent years taxifolin also has shown anti-inflammatory, antioxidant, and hepatoprotective activities (Plotnikov et al., 2005). Flavonoids are slightly soluble in water and show a slow dissolu- tion rate from solid oral dosage forms, restricting their clinical use. Hence, the purpose of this study was to enhance dissolution rate of 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.04.044