Crystallization of micro particles of sulindac using rapid expansion of supercritical solution Ali Zeinolabedini Hezave, Feridun Esmaeilzadeh n Department of Chemical and Petroleum Engineering, Shiraz University, P.O. Box 7134851154, Namazi Square, Shiraz, Iran article info Article history: Received 16 November 2009 Received in revised form 13 July 2010 Accepted 15 July 2010 Communicated by: S. Veesler Available online 3 August 2010 Keywords: A1. Super saturated solution A1. Crystal morphology A1. Nucleation abstract In pharmaceutical industry, many drugs exhibit poor solubility in biological fluid. Solubility of drugs affects on the rate of dissolution and bioavailability in biological fluids. The bioavailability of drugs can be enhanced by decreasing the drug particle size. In this study, sulindac was micronized via rapid expansion of supercritical solution (RESS) where CO2 was used as a solvent. The experiments were conducted to investigate the effect of the extraction pressure and temperature (140–230 bar and 40–60 1C), collection distance (1–10 cm), effective nozzle diameter (450–1700 mm) and nozzle length (2–15 mm) on the size and morphology of the sulindac particles. The size and morphology of the precipitated particles were monitored by scanning electron microscopy (SEM). The particle size of intact sulindac particles was about 33.03 mm, while the average particle size of the micronized sulindac particles was between 0.76 and 8.02 mm based on different experimental conditions. Additionally, the different morphology of the micronized particles was observed like needle, rectangular, quasi spherical and irregular form while the morphology of the intact particles of sulindac was rectangular and irregular. & 2010 Elsevier B.V. All rights reserved. 1. Introduction In the pharmaceutical industry, an even greater number of products are in the form of particulate solids. In addition, several pharmaceutical industries like Separex (France), Fabre (France) or X-Spray (Sweden) are able to manufacture GMP batchs reaching 50 kg. The control of the particles sizes and the polymorphism is well mastered to perform them successfully. Since the mid-1980s, a new method of powder generation has appeared involving crystallization with supercritical fluids. Car- bon dioxide is the most widely used solvent and its innocuity and ‘‘green’’ characteristics make it the best candidate for the pharmaceutical industry. Interest in supercritical fluids and their potential use for process improvements has significantly in- creased in the past decades. These fluids, the properties of which can be tuned by changing the fluid density between those of liquid and gases, have been adopted or are being explored as: (a) alternative solvents for classical separation processes such as extraction, fractionation, adsorption, chromatography, and crys- tallization, or (b) simply as reprocessing fluid as in production of particles, fibers, or foams. Some of the extraction processes such as decaffeination, and some polymerization and foaming pro- cesses have become commercial. Particle formation will most likely be the next major commercial application area that uses supercritical fluids. The particle formation technology that uses supercritical fluids has evolved in many different forms during the last 20 years. A wide variety of organic and inorganic materials have been processed in the form of particles, fibers, films, and foams, employing the supercritical fluids as solvents or as anti-solvents. Supercritical fluids were used as solvents, for example, to crystallize a supercritical fluid-soluble compound [1–7], or as non-solvents to precipitate supercritical fluid-insoluble materials [8,9]. In some cases, these fluids were employed as co-solvents or co-anti-solvents along with an organic liquid solvent to produce particles with a targeted morphology. The versatile operating conditions that are possible with supercritical fluids and their mixtures provide the flexibilities in controlling the size of the particles that span from microns to nanometers. Indeed, the recent advances in these techniques are opening new horizons for the supercritical fluid technology in the area of particle design by extending the utilization domain to nanotechnology-based applications. Different usage of super- critical fluids in particle formation technologies are listed in Table 1. There is no doubt that the basic concept of RESS was first described by the pioneers Hannay and Hogarth [10], y 120 years ago: ‘When the solid is precipitated by suddenly reducing pressure, it is crystalline, and may be brought down as a ‘snow’ in the gas, or on the glass as a ‘frost’, y’! As stated by Krukonis in Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jcrysgro Journal of Crystal Growth 0022-0248/$ - see front matter & 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jcrysgro.2010.07.033 n Corresponding author. Tel.: + 98 711 230 3071; fax: + 98 711 628 7294. E-mail address: esmaeil@shirazu.ac.ir (F. Esmaeilzadeh). Journal of Crystal Growth 312 (2010) 3373–3383