Thermodynamic Modeling of the Gas-Antisolvent (GAS) Process for Precipitation of Finasteride

Document Type : Research Paper


Department of Chemical Engineering, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran


Experimental study of the effect of gas antisolvent (GAS) system conditions on the particle size distribution of finasteride (FNS) requires a thermodynamic model for the volume expansion process. In this study, the phase behavior of the binary system including carbon dioxide and  Dimethyl sulfoxide, and a ternary system comprising carbon dioxide, dimethyl sulfoxide, and Finasteride was studied. The Peng-Robinson equation of state was employed for the evaluation of the fluid phases and a fugacity expression to represent the solid phase. By developing an accurate predictive model, the GAS operating conditions can be optimized to produce particles with no need for a large number of experiments. First, the critical properties of the FNS were evaluated by the group contribution methods. The method of Marrero and Gani was also selected to predict the normal boiling point, critical temperature, and critical pressure. The correlation of Edmister was chosen for the prediction of the acentric factor. The lowest pressures for the ternary system at 308, 318, 328, and 338 K were 7.49, 8.13, 8.51, and 9.03 MPa, respectively. The precipitation of the dissolved finasteride happened at these operating pressures.


[1] Zodge A, Kőrösi M, Madarász J, Szilágyi IM, Varga E, Székely E. Gas antisolvent fractionation: a new approach for the optical resolution of 4-chloromandelic acid. Periodica Polytechnica Chemical Engineering. 2019 Mar 18;63(2):303-11.
[2] Mihalovits M, Horváth A, Lőrincz L, Székely E, Kemény S. Model Building on selectivity of gas antisolvent fractionation method using the solubility parameter. Periodica Polytechnica Chemical Engineering. 2019 Mar 19;63(2):294-302.
[3] Pessoa AS, Aguiar GP, Oliveira JV, Bortoluzzi AJ, Paulino A, Lanza M. Precipitation of resveratrol-isoniazid and resveratrol-nicotinamide cocrystals by gas antisolvent. The Journal of Supercritical Fluids. 2019 Mar 1;145:93-102.
[4] Gil-Ramírez A, Rodriguez-Meizoso I. Purification of Natural Products by Selective Precipitation Using Supercritical/Gas Antisolvent Techniques (SAS/GAS). Separation & Purification Reviews. 2019 May 23:1-21.
[5] Esfandiari N. Production of micro and nano particles of pharmaceutical by supercritical carbon dioxide. The Journal of Supercritical Fluids. 2015 May 1;100:129-41.
[6] Reverchon E, Adami R. Nanomaterials and supercritical fluids. The Journal of supercritical fluids. 2006 Feb 1;37(1):1-22..
[7] Sodeifian G, Sajadian SA. Solubility measurement and preparation of nanoparticles of an anticancer drug (Letrozole) using rapid expansion of supercritical solutions with solid cosolvent (RESS-SC). The Journal of Supercritical Fluids. 2018 Mar 1;133:239-52.
[8] Bahrami M, Ranjbarian S. Production of micro-and nano-composite particles by supercritical carbon dioxide. The Journal of supercritical fluids. 2007 Mar 1;40(2):263-83.
[9] Sodeifian G, Sajadian SA, Ardestani NS, Razmimanesh F. Production of Loratadine drug nanoparticles using ultrasonic-assisted Rapid expansion of supercritical solution into aqueous solution (US-RESSAS). The Journal of Supercritical Fluids. 2019 May 1;147:241-53.
[10] Sodeifian G, Sajadian SA. Utilization of ultrasonic-assisted RESOLV (US-RESOLV) with polymeric stabilizers for production of amiodarone hydrochloride nanoparticles: Optimization of the process parameters. Chemical Engineering Research and Design. 2019 Feb 1;142:268-84.
[11] Fahim TK, Zaidul IS, Bakar MA, Salim UM, Awang MB, Sahena F, Jalal KC, Sharif KM, Sohrab MH. Particle formation and micronization using non-conventional techniques-review. Chemical Engineering and Processing: Process Intensification. 2014 Dec 1;86:47-52.
[12] Sodeifian G, Sajadian SA, Honarvar B. Mathematical modelling for extraction of oil from Dracocephalum kotschyi seeds in supercritical carbon dioxide. Natural product research. 2018 Apr 3;32(7):795-803.
[13] Kim S, Lee SJ, Seo B, Lee YW, Lee JM. Optimal Design of a Gas Antisolvent Recrystallization Process of Cyclotetramethylenetetranitramine (HMX) with Particle Size Distribution Model. Industrial & Engineering Chemistry Research. 2015 Nov 11;54(44):11087-96.
[14] Kim SJ, Lee BM, Lee BC, Kim HS, Kim H, Lee YW. Recrystallization of cyclotetramethylenetetranitramine (HMX) using gas anti-solvent (GAS) process. The Journal of Supercritical Fluids. 2011 Nov 1;59:108-16.
[15] Foster NR, Kurniawansyah F, Tandya A, Delgado C, Mammucari R. Particle processing by dense gas antisolvent precipitation: ARISE scale-up. Chemical Engineering Journal. 2017 Jan 15;308:535-43.
[16] Jafari D, Yarnezhad I, Nowee SM, Baghban SH. Gas-antisolvent (GAS) crystallization of aspirin using supercritical carbon dioxide: experimental study and characterization. Industrial & Engineering Chemistry Research. 2015 Apr 15;54(14):3685-96.
[17] Park SJ, Yeo SD. Recrystallization of caffeine using gas antisolvent process. The Journal of Supercritical Fluids. 2008 Nov 1;47(1):85-92.
[18] Wichianphong N, Charoenchaitrakool M. Application of Box–Behnken design for processing of mefenamic acid–paracetamol cocrystals using gas anti-solvent (GAS) process. Journal of CO2 Utilization. 2018 Jul 1;26:212-20.
[19] Ulker Z, Erkey C. An advantageous technique to load drugs into aerogels: Gas antisolvent crystallization inside the pores. The Journal of Supercritical Fluids. 2017 Feb 1;120:310-9.
[20] Dittanet P, Phothipanyakun S, Charoenchaitrakool M. Co-precipitation of mefenamic acid− polyvinylpyrrolidone K30 composites using Gas Anti-Solvent. Journal of the Taiwan Institute of Chemical Engineers. 2016 Jun 1;63:17-24.
[21] Lőrincz L, Bánsághi G, Zsemberi M, de Simón Brezmes S, Szilágyi IM, Madarász J, Sohajda T, Székely E. Diastereomeric salt precipitation based resolution of ibuprofen by gas antisolvent method. The Journal of Supercritical Fluids. 2016 Dec 1;118:48-53.
[22] Esfandiari N, Ghoreishi SM. Kinetic Modeling of the Gas Antisolvent Process for Synthesis of 5‐Fluorouracil Nanoparticles. Chemical Engineering & Technology. 2014 Jan;37(1):73-80.
[23] Esfandiari N, Ghoreishi SM. Kinetics modeling of ampicillin nanoparticles synthesis via supercritical gas antisolvent process. The Journal of Supercritical Fluids. 2013 Sep 1;81:119-27.
[24] Esfandiari N, Ghoreishi SM. Synthesis of 5-fluorouracil nanoparticles via supercritical gas antisolvent process. The Journal of Supercritical Fluids. 2013 Dec 1;84:205-10.
[25] Jafari D, Nowee SM, Noie SH. A kinetic modeling of particle formation by gas antisolvent process: Precipitation of aspirin. Journal of Dispersion Science and Technology. 2017 May 4;38(5):677-85.
[26] Chen K, Zhang X, Pan J, Zhang W, Yin W. Gas antisolvent precipitation of Ginkgo ginkgolides with supercritical CO2. Powder technology. 2005 Apr 29;152(1-3):127-32.
[27] Bakhbakhi Y, Charpentier PA, Rohani S. Experimental study of the GAS process for producing microparticles of beclomethasone-17, 21-dipropionate suitable for pulmonary delivery. International journal of pharmaceutics. 2006 Feb 17;309(1-2):71-80.
[28] Esfandiari N, Ghoreishi SM. Ampicillin Nanoparticles Production via Supercritical CO2 Gas Antisolvent Process. AAPS PharmSciTech. 2015 Dec 1;16(6):1263-9.
[29] Mukhopadhyay M. Partial molar volume reduction of solvent for solute crystallization using carbon dioxide as antisolvent. The Journal of supercritical fluids. 2003 Apr 1;25(3):213-23.
[30] Kordikowski A, Schenk AP, Van Nielen RM, Peters CJ. Volume expansions and vapor-liquid equilibria of binary mixtures of a variety of polar solvents and certain near-critical solvents. The Journal of Supercritical Fluids. 1995 Sep 1;8(3):205-16.
[31] Esfandiari N, Ghoreishi SM. Optimal thermodynamic conditions for ternary system (CO2, DMSO, ampicillin) in supercritical CO2 antisolvent process. Journal of the Taiwan Institute of Chemical Engineers. 2015 May 1;50:31-6.
[32] Kloc AP, Grilla E, Capeletto CA, Papadaki M, Corazza ML. Phase equilibrium measurements and thermodynamic modeling of {CO2+ diethyl succinate+ cosolvent} systems. Fluid Phase Equilibria. 2019 Dec 15;502:112285.
[33] Su CS, Tang M, Chen YP. Recrystallization of pharmaceuticals using the batch supercritical anti-solvent process. Chemical Engineering and Processing: Process Intensification. 2009 Jan 1;48(1):92-100.
[34] Almeida HM, Marques HM. Physicochemical characterization of finasteride: PEG 6000 and finasteride: Kollidon K25 solid dispersions, and finasteride: β-cyclodextrin inclusion complexes. Journal of Inclusion Phenomena and Macrocyclic Chemistry. 2011 Aug 1;70(3-4):397-406.
[35] Ahmed TA, Al-Abd AM. Effect of finasteride particle size reduction on its pharmacokinetic, tissue distribution and cellular permeation. Drug Delivery. 2018 Jan 1;25(1):555-63.
[36] Yamini Y, Kalantarian P, Hojjati M, Esrafily A, Moradi M, Vatanara A, Harrian I. Solubilities of flutamide, dutasteride, and finasteride as antiandrogenic agents, in supercritical carbon dioxide: Measurement and correlation. Journal of Chemical & Engineering Data. 2010 Feb 11;55(2):1056-9.
[37] Shariati A, Peters CJ. Measurements and modeling of the phase behavior of ternary systems of interest for the GAS process: I. The system carbon dioxide+ 1-propanol+ salicylic acid. The Journal of supercritical fluids. 2002 Aug 1;23(3):195-208.
[38] Bakhbakhi Y, Rohani S, Charpentier PA. Micronization of phenanthrene using the gas antisolvent process. 1. Experimental study and use of FTIR. Industrial & engineering chemistry research. 2005 Sep 14;44(19):7337-44.
[39] De la Fuente Badilla JC, Peters CJ, de Swaan Arons J. Volume expansion in relation to the gas–antisolvent process. The Journal of Supercritical Fluids. 2000 Feb 29;17(1):13-23.
[40] Juan C, Shariati A, Peters CJ. On the selection of optimum thermodynamic conditions for the GAS process. The Journal of supercritical fluids. 2004 Dec 1;32(1-3):55-61.
[41] Peng DY, Robinson DB. A new two-constant equation of state. Industrial & Engineering Chemistry Fundamentals. 1976 Feb;15(1):59-64.
[42] Sodeifian G, Sajadian SA, Ardestani NS. Evaluation of the response surface and hybrid artificial neural network-genetic algorithm methodologies to determine extraction yield of Ferulago angulata through supercritical fluid. Journal of the Taiwan Institute of Chemical Engineers. 2016 Mar 1;60:165-73.
[43] Sodeifian G, Sajadian SA, Ardestani NS. Optimization of essential oil extraction from Launaea acanthodes Boiss: Utilization of supercritical carbon dioxide and cosolvent. The Journal of Supercritical Fluids. 2016 Oct 1;116:46-56..
[44] Wager TD, Nichols TE. Optimization of experimental design in fMRI: a general framework using a genetic algorithm. Neuroimage. 2003 Feb 1;18(2):293-309.
[45] Smit B, Karaborni S, Siepmann JI. Computer simulations of vapor–liquid phase equilibria of n‐alkanes. The Journal of chemical physics. 1995 Feb 1;102(5):2126-40.
[46] Reid RC, Prausnitz JM, Poling BE. The properties of gases and liquids.
[47] Marrero J, Gani R. Group-contribution based estimation of pure component properties. Fluid Phase Equilibria. 2001 Jul 1;183:183-208.
[48] Esfandiari N, Estimation of Thermodynamic Properties of Ampicillin and Paclitaxel via Group Contribution, The 9th International Chemical Engineering Congress & Exhibition, Shiraz, Iran, 26-28 December, 2015.
[49] Sajeesh S, Sharma CP. Interpolymer complex microparticles based on polymethacrylic acid-chitosan for oral insulin delivery. Journal of applied polymer science. 2006;99(2):506-12.
[50] Mukhopadhyay M, Dalvi SV. Partial molar volume fraction of solvent in binary (CO2–solvent) solution for solid solubility predictions. The Journal of supercritical fluids. 2004 May 1;29(3):221-30.