International Journal of Pharmaceutics 388 (2010) 114–122 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology A novel method for the production of crystalline micronised particles Syed Anuar Faua’ad Syed Muhammad a,c , Tim Langrish a , Patricia Tang b , Handoko Adi b , Hak-Kim Chan b , Sergei G. Kazarian d , Fariba Dehghani a,∗ a School of Chemical and Biomolecular Engineering, University of Sydney, Australia b Faculty of Pharmacy, University of Sydney, Australia c Department of Bioprocess Engineering, Faculty of Chemical and Natural Resources Engineering, Universiti Teknologi Malaysia, Malaysia d Department of Chemical Engineering, Imperial College London, UK article info Article history: Received 15 September 2009 Received in revised form 19 December 2009 Accepted 21 December 2009 Available online 5 January 2010 Keywords: Supercritical CO2 Salbutamol sulphate Menthol Crystallisation Inhalation drug delivery abstract The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO 2 ) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated. Pure scCO 2 had no effect on the physical properties of amorphous salbutamol sulphate; however, scCO 2 modified with menthol at 150 bar and 50 ◦ C was efficient in converting amor- phous drug to crystalline form after 12 h of conditioning. The average particle size of powders decreased slightly after the conditioning process because of reducing agglomeration between particles by increas- ing surface roughness. Emitted dose measured by the fine particle fraction (FPF emitted ) of amorphous salbutamol sulphate was enhanced from 32% to 43% after conditioning with scCO 2 + menthol and its water uptake was significantly decreased. This study demonstrates the potential of scCO 2 + menthol for converting amorphous forms of powders to crystalline, while preserving the particle size. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. 1. Introduction More than 75% of pharmaceutical formulations use drugs in powder form (Roberts and Debenedetti, 2000). The crystallinity and particle size are key factors in drug stability and bioavail- ability. Methods such as spray drying, grinding, jet milling, and advanced liquid–liquid antisolvents are currently used for drug micronisation. Their broad application is limited due to use of high temperature operation (Tong and Chow, 2006), powders with broad particle size range, the use of organic solvents and their residues (Subra-Paternault et al., 2007), and the appearance of amorphous fractions (Brodka-Pfeiffer et al., 2003). Salbutamol sulphate is a  2 -sympathomimetic for the treat- ment of asthma, which is broadly used in inhalation and oral formulations (Corrigan et al., 2006a; Columbano et al., 2002; Brodka-Pfeiffer et al., 2003). It would be desirable to enhance the aerosol performance and the bioavailability of each drug to min- imise the dose and decrease the side effects of each drug. The micronised-crystalline salbutamol sulphate is produced by crys- tallisation followed by grinding and milling (Fages et al., 2004). Dry powder of crystalline salbutamol sulphate was also recently pro- ∗ Corresponding author. E-mail address: fdehghani@usyd.edu.au (F. Dehghani). duced by a liquid–liquid antisolvent using high gravity packed bed followed by spray drying (Chiou et al., 2007; Hu et al., 2008) and a sonocrystallisation technique (Dhumal et al., 2009). The aerosol performance of salbutamol sulphate was significantly enhanced, but large amounts of organic solvent were used in these processes. The amorphous form of micronsied salbutamol sulphate produced by spray drying of an aqueous solution exhibited poor aerosol per- formance (Chawla et al., 1994). The Gibbs free energy of amorphous solids is higher than crystalline forms, thus there is always a tendency for the glassy materials to recrystallise into the more stable crystalline form (Hancock and Zografi, 1994). The amorphous drug transforms into the thermodynamically stable crystalline state at ambient condi- tions when the glass-transition temperature (T g ) is below the room temperature. The rate of crystallisation can be explained by the William–Landel–Ferry equation (Williams et al., 1955) (WLF equa- tion) where the rate of the amorphous to crystalline transition (r) is defined as the ratio of the time for crystallisation ( cr ) at any tem- perature (T) to the time for crystallisation ( g ) at the T g which can be related by the following equation: log 10 r = log 10   cr  g  = -17.44(T - T g ) 51.6 + (T - T g ) (1) Thus by increasing the T (difference between process tempera- ture (T) and T g ) the rate of crystallisation is promoted. 0378-5173/$ – see front matter Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.12.047