Investigation of the Effect of Operational Variables in the Production of Indomethacin Nanoparticles by Confined Impinging Jets

Document Type : Research Article


Department of Chemical Engineering, Faculty of Engineering, University of Guilan, P.O. Box 41635-3756 Rasht, I.R. IRAN


The great challenge of many drug candidates in the pharmaceuticals industry is their low bioavailability due to the poor solubility and low dissolution rate in the different solvent, especially in water. Reduce drug particle size to nano size including a method that is effective in obviation this problem. In this study, the antisolvent precipitation technique with confined two- impinging jets is developed to prepare nanoparticles of Indomethacin to overcome its poor solubility in water.The influence of the operating parameters, such as stirring speed, quenching ratio, drug solution concentration and overallvolumetric flow rate, were also experimentally investigated. The results of Scanning Electron Microscopy (SEM)photomicrographs was revealed that by increasing of stirring speed from without stirrer to 400 and 1200 rpm, the particle size decreased from 215 to 88 nm. In the investigation of the effect of changes of quenching ratio from 1:1.5 to 1:5 and 1:12, it was seen the particle size decreased from 129 to 86 and 80 nm. Increasing of concentration parameter from 10 to 50 mg/mL showed the decrease in particle size from 98 to 77 nm with aggregation. The investigation results of overall volumetric flow rate was showed that as it was increased from 300 to 600 ml/min, the particle size was decreased from 95 to 86 nm. Furthermore, the results of Differential Scanning Calorimetry (DSC) analysis confirmed that the pure metastable srystal of a-form was effectively prepared by the two-impinging jets method and this can dramatically increase its solubility.


Main Subjects

[1] Zhao H., Wang J., Zhang H., Shen Z., Facile Preparation of Danazol Nanoparticles by High-Gravity Anti-solvent Precipitation (HGAP) Method, Chinese Journal of Chemical Engineering, 17: 318-323 (2009).
[3] Wu L., Zhang J., Watanable W., Physical and Chemical Stability of Drug Nanoparticles, Advanced Drug Delivery Reviews, 63: 456-469 (2011).
[5] Wang J.X., Zhang Q.X., Zhou Y., Shao L., Chen J.F., Microfluidic Synthesis of Amorphous Cefuroxime Axetil Nanoparticles with Size-Dependent and Enhanced Dissolution Rate, Chemical Engineering Journal, 162: 844-851 (2010).
[7] صادق زاده نماور، علی؛ صادق مقدس، جعفر، اثر زاویه تزریق در اختلاط جتی، نشریهشیمیومهندسیشیمیایران، (2)30: 53 تا 60 (1390).
[8] Lince F., Marchisio D.L., Barresi A.A., Smart Mixers and Reactors for the Production of Pharmaceutical Nanoparticles: Proof of Concept, Chemical Engineering Research and Design, 87: 543-549 (2009).
[9] Beck C., Dalivi S.V., Dave R.N., Controlled Liquid Antisolvent Precipitation Using a Rapid Mixing Device, Chemical Engineering Science, 56: 5669-5675 (2010).
[10] Akhbarifar S., Shirvani M., Zahedi S., Zahiri M.R., Shamsaii Y., Improving Cyclone Efficiency by Recycle and Jet Impingement Streams, Iranian Journal of Chemistry and Chemical Engineering (IJCCE), 30(2): 119-124 (2011).
[11] Li W., Wei Y., Tu G., Shi Z., Liu H., Wang F., Experimental Study about Mixing Characteristic and Enhancement of T-jet, Chemical Engineering Science, 144: 116-121 (2016).
[12] Mahajan A.J., Kirwan, D.J., Micromixing Effects in a Two-Impinging-Jets Precipitator, AIChE Journal- Fluid Mechanics and Transport Phenomena, 42: 1801-1814 (1996).
[13] Liu W.J., Ma C.Y., Liu J.J., Zhang Y., Wang X.Z., Analytical Technology Aided Optimization and Scale-Up of Impinging Jet Mixer for Reactive Crystallization Process, AIChE Journal, 61: 503-517 (2015).
[14] Lee H.E., Lee M.J., Kim W.S., Jeong M.Y., Cho Y.S., Choi G.J., In-line Monitoring and Interpretation of an Indomethacin Anti-Solvent Crystallization Process by Near-Infrared Spectroscopy (NIRS), International Journal of Pharmaceutics, 420: 274-281 (2011).
[15] Thorson M.R., Goyal S., Gong Y., Zhang G.G.Z., Kenis, P.J.A., Microfluidic Approach to Polymorph Screening Through Antisolvent Crystallization, Cryst. Eng. Comm., 14: 2404-2408 (2012).
[16] Sheng F., Chow P.S., Dong Y., B.H. Tan. R., Preparation of β-carotene Nanoparticles by Antisolvent Precipitation under Power Ultrasound, Journal of Nanoparticle Research, 16: 2772-2781 (1-9) (2014).
[17] Shah S.R., Parikh R.H., Chavda J.R., Sheth N.R., Application of Plackett–Burman Screening Design for Preparing Glibenclamide Nanoparticles for Dissolution Enhancement, Powder Technology, 235: 405-411 (2013).
[18] Zhang H.X., Wang J.X., Shao L., Chen J.F., Microfluidic Fabrication of Monodispersed Pharmaceutical Colloidal Spheres of Atorvastatin Calciumwith Tunable Sizes, Industrial & Engineering Chemistry Research, 49: 4156-4161 (2010).
[19] Zhao H., Wang J.X., Wang Q.A., Chen J.F., Yun J., Controlled liquid Antisolvent Precipitation of Hydrophobic Pharmaceutical Nanoparticles in a Microchannel Reactor, Industrial & Engineering Chemistry Research, 46: 8229-8235 (2007).
[20] Takiyama H., Minamisono T., Osada Y., Matsuoka M., Operation Design for Controlling Polymorphism in the Anti-Solvent Crystallization by Using Ternary Phase Diagram, Chemical Engineering Research and Design, 88: 1242-1247 (2010).
[22] Miller D.A., McConville J.T., Yang W., Williams III R.O., McGinity J.W., Hot-Melt Extrusion for Enhanced Delivery of Drug Particles, Journal of Pharmaceutical Sciences, 96: 361-376 (2007).