Dissolution rate enhancement of sulfamethoxazole using the gas anti-solvent (GAS) process Sasiwimon Phothipanyakun a , Siwaporn Suttikornchai a,b , Manop Charoenchaitrakool a,b, ⁎ a Center of Excellence on Petrochemical and Materials Technology, Department of Chemical Engineering, Faculty of Engineering, Kasetsart University, Bangkok 10900, Thailand b Center for Advanced Studies in Nanotechnology and Its Applications in Chemical, Food and Agricultural Industries, Kasetsart University, Bangkok 10900, Thailand abstract article info Article history: Received 20 July 2013 Received in revised form 11 September 2013 Accepted 11 October 2013 Available online 19 October 2013 Keywords: GAS process Sulfamethoxazole PVP Composite materials The aim of this work was to improve the dissolution rate of a poorly water-soluble antibiotic drug, sulfamethoxazole (SMX), by precipitation and co-precipitation with poly(vinylpyrrolidone) (PVP) using the gas anti-solvent (GAS) process. In the precipitation study, the effects of solvent type (acetone, methanol and ethanol), temperature (35, 40, and 45 °C) and percent drug saturation (25, 50 and 75%) on the particle size were investigated using the Box-Behnken design of experiment. It was found that an increase in temperature resulted in a reduction in particle size. Moreover, smaller precipitates were produced when using ethanol as a solvent. An increase in percent saturation of the drug in acetone yielded larger particle size. It was also found that after passing through a 200 mesh sieve the precipitates obtained from the GAS process exhibited a higher dissolution rate than the micronized starting material. In the co-precipitation study, it was found that when using a mass ratio of drug and PVP polymer of 1:1, at 50% drug saturation in methanol and 35 °C, the highest % drug content (50.0%) was achieved. The dissolution rate of the prepared composites was found to be 10 times greater than that of the GAS precipitates. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Sulfamethoxazole (SMX) is an effective antibiotic drug used for treating a variety of bacterial infections esp., urinary tract infection. According to the Biopharmaceutical Classification System (BCS), SMX is classified as class IV drug. It has low solubility in aqueous solution, low dissolution rate and low permeability in the gastrointestinal tract. It is suggested that sufficient amount of water intake is needed when administrating this drug in order to prevent crystals forming in the urine. Moreover, lower doses should be used for persons with advanced kidney disease. In order to minimize the drug dosage required but still maintain the drug effectiveness, it is necessary to enhance the dissolution rate of this drug. Various techniques such as micronization or co-precipitation with a hydrophilic polymer are commonly employed to improve the dissolution rate of poorly water-soluble drugs [1–8]. Chang et al. [9] demonstrated that SMX was successfully micronized using the batch and continuous supercritical anti-solvent (SAS) processes. The mean particle sizes for the unprocessed SMX and the precipitates obtained from the batch and continuous SAS processes were 41.7, 41.2 and 5.1 μm, respectively. It was found that the micronized SMX exhibited a higher dissolution rate than the unprocessed drug and 95% of the drug was dissolved after 10 min. With the addition of 10 wt.% of hydrophilic polymer hydroxypropylcelluouse (HPC) in the co-precipitation study, the obtained composites exhibited a significantly higher dissolution rate than the micronized SAS precipitates. To date, however, there is no report on the precipitation of SMX and production of SMX and poly(vinylpyrrolidone) (PVP) composites using the gas anti-solvent (GAS) process. In this study, the feasibility to micronize the SMX and produce SMX-PVP composites using the GAS technique was investigated. In the precipitation of SMX study, the effects of solvent type (acetone, methanol and ethanol), temperature (35, 40, and 45 °C) and percent drug saturation (25, 50 and 75%) on the particle size were investigated. A design of experiment combined with response surface methodology analysis is employed in this work in order to understand the simultaneous effects of various parameters on the particle size and the interaction between parameters. For a three- level-three-factor design, the Box–Behnken design offers some advantage in requiring a fewer number of experiments compared to other designs such as a factorial design or central composite design [10]. In the co-precipitation study, the effect of drug to polymer ratio (1:1, 1:2 and 1:3) and percent drug saturation (50 and 75%) on the drug content were investigated, while the operating temperature was kept constant at 35 °C or 45 °C. Methanol was selected as a solvent in the co-precipitation study due to its ability to dissolve both drug and polymer reasonably well compared to acetone or ethanol. Powder Technology 250 (2013) 84–90 ⁎ Corresponding author at: Center of Excellence on Petrochemical and Materials Technology, Department of Chemical Engineering, Faculty of Engineering, Kasetsart University, Bangkok 10900, Thailand. Tel.: +66 2 797 0999x1216; fax: +66 2 561 4621. E-mail address: manop.c@ku.ac.th (M. Charoenchaitrakool). 0032-5910/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.powtec.2013.10.019 Contents lists available at ScienceDirect Powder Technology journal homepage: www.elsevier.com/locate/powtec