Production of ultrafine drug particles through rapid expansion of supercritical solution; a statistical approach Masoomeh Pourasghar a , Shohreh Fatemi a, ⁎, Alireza Vatanara b, ⁎⁎, Abdolhossein Rouholamini Najafabadi b a School of Chemical Engineering, Faculty of Engineering, University of Tehran, Tehran, Iran b Aerosol Research Laboratory, Pharmaceutics Department, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran abstract article info Article history: Received 5 September 2011 Received in revised form 17 March 2012 Accepted 24 March 2012 Available online 29 March 2012 Keywords: RESS process Lynestrenol Nano particles Supercritical CO 2 Performance of Rapid Expansion of Supercritical Solution (RESS) process, under different operation conditions, was conditions were evaluated through the analysis of the drug particle characteristics. The original particles of Lynestrenol with average size of 10 μm as a drug material were dissolved in supercritical CO 2 and then expanded rapidly through a nozzle with 0.6 mm diameter. The effect of temperature, pressure and fraction of solid co-solvent (menthol) was investigated by a two-level factorial experimental design. Our results showed that the pre-expansion pressure, temperature and solid co-solvent can significantly affect the morphology and size of the precipitated particles. In addition, the binary interaction effects of temperature– pressure and pressure–cosolvent were observed to apparently influence the size of outlet particles. In the temperature range from 45 to 60 °C, pressures from 15 to 30 MPa and the menthol fraction of 0 to 5 wt.%, the RESS process produced ultrafine Lynestrenol particles (from 58 to 326 nm) from its original particles as reflected by SEM and zetasizer analysis. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Approximately 80% of all pharmaceutical products are in the solid state [1]. The solid form drugs having low solubility in aqueous media are usually consumed at high doses and this might cause side effects in the human body. One method of enhancing the dissolution rate of a drug into the biological environment is to reduce the particle size [2]. In the pharmaceutical industry, several conventional techniques such as milling and grinding, spray-drying, freeze- drying, high-pressure homogenization, ball and air jet milling have been utilized for particle size reduction [3,4]. However all of these methods have several disadvantages in terms of thermal and chemical degradation of products due to the high temperatures and stresses, excessive solvent use and problems with disposal, solvent residues, high energy requirements, and broad particle size distri- butions [5–7]. To overcome this problem, several precipitation techniques based on supercritical fluid have been recently explored to micronized organic compounds. The preparation methods for ultrafine particle formation based on supercritical fluids are: rapid expansion of supercritical solutions (RESS), particle generation from gas saturated solution (PGSS), supercritical anti-solvent (SAS) and its numerous modifications [8–10]. The advantages of RESS process is getting fine particle size lower than 500 nm, whereas in PGSS the average size of the particles are around microns. In SAS process, organic solvents are required and the problem of incomplete removal of the solvents is occurred [11–13]. Carbon dioxide is mostly used as the supercritical fluid for pharmaceutical material processing. It is environmentally benign, non-flammable, non-toxic, and inexpensive. Carbon dioxide has mild critical pressure and temperature, i.e., Tc = 31.1 °C and Pc =7.37 MPa. Moreover, it can be removed from the final product by simple depressurization [14–18]. In the present study, formation of nano particles of Lynestrenol from its original source powder with 10 μm average size was investigated by RESS process. Lynestrenol is a synthetic oral progestagen associated with numerous effects of the natural proges- terone hormone. This material with molecular weight of 284 is an almost white and crystalline powder, practically insoluble in water and soluble in acetone and in alcohol [19]. Therefore it is expected to have solubility in supercritical carbon dioxide. The chemical structure of Lynestrenol is presented in Fig. 1 In this research, the RESS process was carried out at the temperature range of 45 to 60 °C, pressure range of 15 to 30 MPa and menthol weight fraction of 0 to 5% using an experimental design. The performance of RESS under different conditions was evaluated by analyzing the morphology and particle size characteristics. The effects of temperature, pressure and menthol on the average size of the formed particles to achieve the smallest particles have been discussed. Powder Technology 225 (2012) 21–26 ⁎ Corresponding author. Tel.: + 98 2161112229; fax: + 98 2166957784. ⁎⁎ Corresponding author. Tel.: + 98 2166959057; fax: + 98 2166461178. E-mail addresses: shfatemi@ut.ac.ir (S. Fatemi), vatanara@tums.ac.ir (A. Vatanara). 0032-5910/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2012.03.027 Contents lists available at SciVerse ScienceDirect Powder Technology journal homepage: www.elsevier.com/locate/powtec