J. of Supercritical Fluids 101 (2015) 17–23 Contents lists available at ScienceDirect The Journal of Supercritical Fluids j our na l ho me page: www.elsevier.com/locate/supflu Solid-state property modification and dissolution rate enhancement of tolfenamic acid by supercritical antisolvent process Hung-Hsin Chen a , Chie-Shaan Su a,∗ , Jun-Jen Liu b , Ming-Thau Sheu c,∗∗ a Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan b School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan c School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan a r t i c l e i n f o Article history: Received 6 October 2014 Received in revised form 25 February 2015 Accepted 25 February 2015 Available online 4 March 2015 Keywords: Recrystallization Supercritical antisolvent Carbon dioxide Tolfenamic acid a b s t r a c t In this study, the supercritical antisolvent (SAS) process is applied to crystallization of an active pharma- ceutical ingredient, tolfenamic acid, using carbon dioxide as the antisolvent. Six operating parameters in the SAS process including solvent system, operating temperature, operating pressure, solution concentra- tion, solution flow rate and nozzle diameter are studied. The effects of operating parameters on solid-state properties of the processed tolfenamic acid including crystal habit, mean particle size and polymorphic form are compared and discussed. The crystal habit of original tolfenamic acid crystals is irregular shape with Form I polymorph. The mean particle size of original powders is about 30 m. After recrystalliza- tion using SAS process, two polymorphic forms of tolfenamic acid with different crystal habits and mean particle sizes are obtained. Form I tolfenamic acid shows a needle-like crystal habit with mean particle size of about 20 m; while Form II tolfenamic acid shows a rod-like crystal habit with mean particle size of around 10 m. In addition, the dissolution profiles of original and recrystallized tolfenamic acids are also studied and compared. Experimental results show that the recrystallized Form II tolfenamic acid crystals has an enhanced dissolution rate compared with the original sample, demonstrating that the SAS technology is an efficient process for controlling and modifying the solid-state properties of tolfenamic acid and also produces microparticles with enhanced dissolution behavior. © 2015 Elsevier B.V. All rights reserved. 1. Introduction The solid-state properties of active pharmaceutical ingredients (API) such as particle size, crystal habit and polymorphic form have been shown to play critical roles in pharmaceutical industry for controlling the dissolution rate, developing suitable administra- tion routes, and designing the appropriate dosage form [1–3]. In conventional API manufacturing process, the solid-state properties of API are frequently controlled by the crystallization process and mechanical milling. However, this conventional route has several disadvantages including residual solvent contamination, batch- to-batch variation and surface property destruction. Thus, in the literature, alternative processes have been designed and developed. Examples of such processes are supercritical fluid crystallization ∗ Corresponding author. Tel.: +886 227712171. ∗∗ Corresponding author. Tel.: +886 227361661. E-mail addresses: cssu@ntut.edu.tw (C.-S. Su), mingsheu@tmu.edu.tw (M.-T. Sheu). technology, ultrasonic crystallization process and ionic liquid crys- tallization method [4–9]. Supercritical fluid technology has been widely applied in differ- ent fields including extraction, chromatography, chemical reaction and material processing [10,11]. Among these applications, the use of supercritical fluids for the recrystallization of pharmaceu- tical compounds has been investigated by an increasing number of research groups because of its numerous advantages [12,13]. Depending on the solubility of API in supercritical fluid, differ- ent supercritical fluid particle formation techniques have been developed, classified and reviewed. These techniques include rapid expansion of supercritical solution (RESS), supercritical antisolvent (SAS), supercritical assisted atomization (SAA) and particle from gas saturated solution (PGSS) [14], among which SAS and RESS pro- cesses are more widely used. In the RESS process, supercritical fluid is used as the solvent while in the SAS process, supercritical fluid is recognized as the antisolvent. The SAS process is most commonly applied to processing phar- maceutical compounds. For example, Rossmann et al. [15] used the SAS process to manipulate the size, crystal habit and polymorphic form of acetaminophen. The polymorph of acetaminophen crystals http://dx.doi.org/10.1016/j.supflu.2015.02.031 0896-8446/© 2015 Elsevier B.V. All rights reserved.