PRODUCTION OF NANO PARTICLES USING SUPERCRITICAL CO2 By Satya Chaitanya Class 702 - Modules in nano pharmaceuticals Dr.Rajesh Dave
What is Super Critical Fluid? • A fluid is compressed beyond its Pc and heated beyond its Tc. Why we choose CO2: • nonflammable, nontoxic, Low dielectric constant, inexpensive, mild Tc. Solubility • Non polar or light molecules easily dissolve in CO2. • Heavy molecules have a very poor solubility.
Three important factors that govern drug solubility • vapor pressure. f (T) • CO2 interaction. • Density of CO2. f (P,T). The solubility can be correlated by using the equation An empirical expression for density is given below
The most studied SF-based micronization techniques are • Rapid Expansion of Supercritical Solutions (RESS) • Supercritical Anti Solvent precipitation (SAS) • Supercritical fluids Assisted Atomization (SAA) • Particles generation from Gas Saturated Solutions (PGSS) • Supercritical Carbon dioxide Assisted Nebulization (CAN-BD) with a Bubble Dryer.
RESS with solid co-solvent for nano particle formation RESS-SC RESS-SC is a modification of RESS process and overcomes the limitations of RESS. Setup is divided into 3 parts Pre extraction chamber (section I). Extraction chamber (section II). Expansion chamber (section III).
The choice of a proper SC is the key for successful RESS-SC. • Requirements for the selection of the SC are • Good solubility in supercritical CO2. • Solid at nozzle exit condition (5–30 °C). • Good vapor pressure for easy removal by sublimation. • Nonreactive with drugs or CO2. • Inexpensive.
Magnified view of the RESS nozzle. (B) Schematic of RESS–SC process. Circles-drug particles, Stars-SC particles.
SAS with Enhanced Mass transfer (SAS-EM) process for nanoparticle formation I, inline filter; U, ultrasonic processor; P, pump for drug solution; R, precipitation chamber; SCF pump, supply of supercritical CO2; G, pressure gauge; C, heating coil with temperature controller.
At higher power supply to the ultrasound transducer, narrower and shorter needle shaped crystals were obtained. size of the precipitated GF nanoparticles Volume of long needle shaped GF crystals obtained versus power supply to the ultrasound transducer, for power 75 W.
SEM micrographs showing the change in the morphologies of GF particles obtained from experiments conducted at different values of power supply using DCM as solvent. (a) No power supply, (b) 60 W power supply, (c) 90 W power supply, (d) 120 W power supply, (e) 150 W power supply, (f) 180 W power supply. Magnification is ×1000
Two atomization processes take place • Primary droplets at the outlet of the injector (pneumatic atomization) are further divided in • Secondary droplets due to SC-CO2 expansion from the inside of the primary ones (decompressive atomization). Pneumatic atomization Decompressive atomization Amorphous or crystalline particles have been produced, depending on the process temperatures and the chemical characteristics of the solid solute.
Experiments were performed varying HMR1031 concentration (50 to 150 mg/ml) in the methanol solution. SEM observations revealed that SAA micronized particles are spherical whereas the jet-milled particles are irregular in shape. Particles from SAA Particles from Jet-mill
PSDs of the SAA micronized drug were measured by laser diffraction. • curves of HMR1031 produced by SAA from HMR1031 concentrations
Griseofulvin nano particles • The particles obtained are spherical and noncoalescing.
CAN-BD Process(Carbon Dioxide Assisted Nebulization with a bubble Dryer)Schematic of Bubble Dryer
References • Thakur R, Gupta RB. Rapid expansion of supercritical solution with solid cosolvent (RESS-SC) process: formation of griseofulvin nanoparticles. Ind Eng Chem Res 2005. In press. • Chattopadhyay P, Gupta RB. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer. Int J Pharm 2001; 228(1–2):19–31. • Production of griseofulvin nanoparticles using supercritical CO2 anti solvent with enhanced mass transfer * Pratibhash cattopadhyay, Ram B. Gupta AL 36839 -5127, USA Received 19 February 2001; received in revised form 3 July 2001; accepted 5 July 2001. • Supercritical Assisted Atomization: A Novel Technology for Microparticles Preparation of an Asthma-controlling Drug *Giovanna Della Porta, Carlo De Vittori, and Ernesto Reverchon
Other references • Coffey MP, Krukonis VJ. Supercritical Fluid Nucleation. An Improved Ultrafine Particle Formation Process. Phasex Corp.Final Report to NSF, 1988, Contr. ISI 8660823. • Pathak P, Meziani MJ, Desai T, Sun Y-P. Nanosizing drug particles in supercritical fluid processing. J Am Chem Soc 2004;126:10,842. • Turk M, Hils P, Helfgen B, Schaber K, Martin H-J, Wahl MA.Micronization of pharmaceutical substances by the rapidexpansion of supercritical solutions (RESS): a promisingmethod to improve the bioavailability of poorly soluble pharmaceutical agent. J Supercrit Fluids 2002; 22:75. • 20. Mohamed RS, Halverson DS, Debenedetti PG, Prud’homme RK.Solids formation after the expansion of supercritical mixtures.In: Johnston KP, Penninger JML, eds. Supercritical Fluid Science and Technology. Washington, DC: ACS Symposium Series 406, 1989:355–378.