|Title of Invention||
A NOVEL PROCESS FOR PRODUCTION OF NANOPARTICLES USING SUBCRITICAL CARBON DIOXIDE
|Abstract||The solid drugs are generally required in the micronized form, in order to enhance drug dissolution rate and bio-activity, provide prolonged action of drug, and eliminate repetitive/excessive dosage. Conventionally these nano/ultra-fine particles are produced by thermal recrystallization, spray drying, recrystallization using solvent evaporation or liquid antisolvent or by supercritical carbon dioxide (SC CO2) processes. These methods suffer from poor particle size control, wide PSD and morphology, requirement of high pressures and specially designed nozzles for spraying. Therefore a new process is developed here for the preparation of nanoparticles with narrow PSD by using CO2 at sub-critical pressure, low temperature and by eliminating the use of nozzle (no spraying of solution) with very fast and easy removal of solvent in order to prevent the subsequent growth and agglomeration of particles.|
|Full Text|| FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See section 10; rule 13)
TITLE OF INVENTION
"A Novel Process for Production of Nanoparticles using Subcritical Carbon Dioxide."
(a) INDIAN INSTITUTE OF TECHNOLOGY Bombay (b) having administrative office at Powai, Mumbai 400076, State of Maharashtra, India and (c) an autonomous educational Institute, and established in India under the Institutes of Technology Act 1961.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
21 OCT 2005
C O M P LATE AFTER PRO V I S IONAL
Field of the Invention
The present invention relates to a novel process of using sub-critical carbon dioxide for preparation of nanoparticles with narrow particle size distribution (PSD).
Background of the Invention
The bioavailability of solid drugs and the efficacy of their delivery systems are often constrained by their size, morphology, and size distribution, as these factors decide their solubilities in the aqueous media of our body fluid systems. Lower the particle size of these solid drugs, higher would be their dissolution rates and their bioavailability in the body fluids. There is a long-felt need for micronized drugs with a narrow particle size distribution (PSD) for utilizing the new drug delivery systems, such as, dry powder inhalers, needle-free injections and controlled release devices, in order to enhance drug dissolution rate and bio-activity, provide prolonged action of drug, and eliminate repetitive/excessive dosage. Ultra-fine particles are also required in the areas of explosives, catalysts, specialty chemicals, high-tech materials, cosmetics, and biochemicals.
Conventionally these nano/ultra-fine particles are produced by thermal recrystallization, spray drying, recrystallization using solvent evaporation or liquid antisolvent, etc. These processes have shortcomings, such as, wide PSD leading to multiple steps (e.g. milling, grinding and sieving which often result in thermal and chemical degradation of products), usage of multiple organic solvents, etc. Further these methods in the prior art have relatively high-energy requirement and suffer from poor control in maintaining particle size, PSD and morphology.
In contrast, nano/ultra-fine particles can be produced by a few recently developed crystallization processes (Jung and Perrut, 2001, the Journal of Supercritical Fluids, Vol.30, p179-219) using supercritical carbon dioxide (SC CO2) in order to overcome some of the above-mentioned shortcomings. This is
accomplished by attaining very rapid, extremely high and uniform supersaturation, (as opposed to a non-uniform, slow and low supersatutation in the case of thermal crystallisation). These techniques use SC C02 either as a solvent for dissolving the solid solute as in the case of Rapid Expansion of Supercritical Solutions (RESS) and Particles from Gas Saturated Solutions (PGSS), or use SC CO2 as an antisolvent in the solution of the solid drug in an organic solvent, as in the case of Gas Antisolvent (GAS), Supercritical Antisolvent (SAS), Precipitation with Compressed Antisolvent (PCA), or Solubility Enhanced Dispersion of Supercritical Solutions (SEDS) processes.
However, these SC CO2 processes also suffer from several drawbacks such as, requirements of (i) very high pressures of the order of 200 to 400 bar for achieving high solubility of solid solute in supercritical fluids (as in the case of RESS or PGSS), as many solids have poor solubility in supercritical fluids at lower (less than 200 bar) pressures, (ii) high pressure CO2 pumps for attaining pressures as high as 120-400 bar, (iii) nozzle devices of micrometer size (of the range of 50-70 urn) for spraying, the nozzle is prone to clogging (iv) accurate control of pressure, temperature, flow rates and concentration and (v) usage of a large amount of SC C02 for removal of solvent by flushing the system .
A recently reported process like(DBLOS)also requires high pressure CO2 pump to generate relatively lower pressures (100 to150 bar) and fine nozzles for spraying the solution (Ventosa et al., 2003, US Patent 20030098517).
There is a need to develop a process for production of nanoparticles with narrow PSD by (i) using CO2 at sub-critical pressure (ii) lowering of temperature of the solution (in the range of -15 to -55 °C) for attaining extremely low solid solubility in a short time span of the order of 0.5-5.0 min for attaining very rapid, uniform and extremely high supersaturation (iii) not spraying the solution (to eliminate the use of nozzle) (iv) very fast and easy removal of solvent for prevention of subsequent growth and agglomeration of particles.
Summary of the Invention
The main object of the present invention is to use sub-critical carbon dioxide for preparation of nanoparticles of solids soluble in organic solvents.
Another object of the invention is to use low initial pressures such as 25-70 bar and low initial temperatures (such as 8-30°C) of the solution of solids so as to avoid the usage of any equipment for generation of high pressure and high temperature.
Yet another object of the invention is to attain a large temperature reduction of the solution to -15 to -55°C in 0.5 to 5.0 minutes without rejecting heat to an external low temperature sink.
Another object of the invention is to bleed off CO2 for reducing the pressure over the solution to a pressure in the range from 10 to 1 bar.
Yet another object of the invention is to use bleeding off of C02 for achieving a large instantaneous temperature drop of the solution to -15 to -55°C in 0.5 to 5.0 minutes
Another objective of the invention is to achieve uniform mixing of the solution of the dissolved solids due to vigorous boiling of CO2 as a result of reduction of pressure over the solution to 10-1 bar.
Yet another objective of the invention is to avoid the use of depressurization of the solution phase thereby obviating the use of specially designed fine nozzles and thereby clogging problems.
Thus in accordance with the invention the said process comprises:
> Dissolution of a substance in an organic solvent to form a solution
• Pressurization of the solution of the solid substance with CO2 to attain a pressure of 25-70 bar
• Cooling of the solution to 8-30°C while stirring
• Bleeding off CO2 to reduce system pressure to 10-1 bar for achieving a temperature drop of 30-65°C in 0.5-5.0 minutes
• Removal of solvent from the precipitated nanoparticles in 1-30 minutes
• Removal of residual solvent from the nanoparticles by flushing with subcritical CO2
• Collection of nanoparticles for analysis of particle size and PSD.
Detailed Description of the Invention
Provided here is the process for using the subcritical CO2 for the production of nanoparticles. The process involves (i) dissolution of the solid substance in an organic solvent (ii) pressurizing the solution with CO2 to attain a pressure of 25-70 bar while stirring, for which there is an increase in temperature of the solution, (iii) cooling of the solution to 8-30°C and (iv) then bleeding off CO2 over the solution to bring the system pressure down to 10-1 bar within a time span of 0.5 to 5 minutes.
A reduction of approximately 30-65 °C in temperature is achieved in the solution within 0.5 to 5.0 minutes along with vigorous bubbling of CO2 that causes uniform mixing of the solution. This causes extremely high, very rapid and uniform supersaturation in the solution leading to crystallization of the solid to nanoparticles with narrow PSD.
The particles get instantaneously precipitated on the inner walls of the pressure vessel. The solvent is then immediately removed from the pressure vessel through a frit within 1-2 minutes by applying suction and additional flushing the system for 0-30 minutes with subcritical CO2. The nanoparticles are then collected from the inner surface and analyzed for measurement of particle size
and PSD by Zeta meter which uses the method of light scattering for particle size analysis and measures the mean diameter of the particles
The process can be carried out with different solvents such as acetone, methanol, ethanol, dimethyl' sulfoxide, dichloro methane, toluene, ethyl acetate, depending on the solubilities of CO2 and solid in the solvent. The concentration of the solution can vary from dilute to saturated solution of the solid solute in the organic solvent. The solid solute may vary from drug substances to specialty chemicals.
Initial concentration of solution: dilute to saturated
Initial Pressure: 25-70 bar
Initial Temperature: 8-30 °C
Final Pressure: 1-10 bar
Final temperature: -15 to -55 °C
Time for reduction of pressure to 1 atm: 0.5 to 5 minutes.
Time for solvent removal by suction: 1-2 minutes
Time for additional solvent vapor removal by flushing with CO2: 0-30 minutes
Naphthalene is dissolved in toluene at 31 °C to prepare 10 mole % solution of naphthalene in toluene. About 100 ml of solution is taken in a pressure vessel of 1-liter capacity. The solution is pressurized in the vessel with CO2 to attain a pressure of 68.3 bar while stirring. The temperature of the solution rises to 40°C. Within the time span of 1 hour, the temperature of solution is lowered to 30°C while stirring. The pressure in the vessel is reduced to 1 atm within 1 minute by bleeding off the CO2 phase. Reduction of pressure decreases the temperature of the solution to -17°C at 1 atm accompanied with bubbling of CO2. The solution is next removed through a frit from the pressure vessel leaving behind the precipitated particulates and then C02 is passed through the pressure vessel for
about half an hour prior to collection of the particulates. Analysis of the naphthalene sample by zeta meter (which uses the method of light scattering for particle size analysis), measures the mean diameter of the particles to be 783 nm with a narrow PSD (in the range of 689-889 nm) as shown in Table 1 (showing the particle diameter analyzed by Zeta meter in each run).
Run Effective Particle Diameter
Std. Error 17.4
Phenanthrene is dissolved in toluene at 30 °C to prepare 3 mole % solution of phenanthrene in toluene. About 100 ml of solution is taken in a pressure vessel of 1-liter capacity. The solution is pressurized with CO2 to attain a pressure of 64.8 bar while stirring. The temperature of solution rises to 41.5 °C. The temperature of solution is then lowered to 16 °C while maintaining the stirring. The pressure above the solution is reduced to 1 bar within 2 minutes by bleeding off the CO2 phase. Reduction of pressure decreases the temperature of the
solution to -48.2 °C. Immediately solution is removed through a frit from the pressure vessel and then CO2 is flushed through the pressure vessel for about half an hour prior to the collection of the precipitated particulates. Analysis of phenanthrene powder using zeta meter shows the mean diameter of the particles to be 892 nm with a narrow PSD (in the range of 742-1196 nm) as shown in Table 2.
Run Effective Particle
Std. Error 38.5
Naphthalene is dissolved in toluene at 8°C to prepare 10 mole % solution of naphthalene in toluene. About 100 ml of solution is taken in a pressure vessel of 1-liter capacity. The solution is pressurized with CO2 to attain a pressure of 66.7 bar. The temperature of solution rises to 29°C. The temperature of solution is lowered to 8°C while stirring. The pressure in the vessel is reduced to 1 atm. within 14 minute by opening the valve at the CO2 outlet. Reduction of pressure decreases the temperature of the solution to -51°C at 1 atm. The solution is
immediately removed through a frit from the pressure vessel and then CO2 is flushed through it for about half an hour prior to collection of the particulates. Analysis by zeta meter shows the particles of naphthalene to be of the mean diameter of 1524 nm with a narrow PSD (in the range of 1961-3407 nm) as shown in Table 3.
Run Effective Particle Diameter (nm)
1 2 3 1961.5 2251.5 3407.2
Std. Error 667.5
The novel process described in the invention does not require additional equipment to pressurize CO2 as the process is carried out at sub-critical pressures of the order of 25-70 bar. The temperature of the process is governed by the change in pressure. The reduction in pressure results in liberation of CO2 and corresponding change in temperature. Thus, separate temperature control is not required. Uniform and large reduction of 30-65°C in temperature of the solution is observed from the initial temperature (8-30°C) within 0.5-5.0 min, (as compared to processes mentioned in the prior art) without the usage of any external low temperature sink, high temperature heating source, high pressure liquid C02 pumps /compressors, and fine expansion nozzles. Thus the extremely high and rapid supersaturation is attained due to instantaneous and drastic lowering of temperature merely by bleeding off CO2.
1) A process for preparation of nanoparticles using sub-critical carbon dioxide
from substances soluble in organic solvents comprising the steps of:
i) Dissolution of the substance in organic solvent;
ii) Pressurization of the solution with carbon dioxide (C02) in a pressure
vessel; iii) Cooling the solution;
iv) Bleeding off C02 to reduce the system pressure;
v) Removal of solvent from the precipitate;
vi) Removal of residual solvent from the precipitate by flushing with
2) A process for preparation of nanoparticles using sub-critical carbon dioxide as claimed in claim 1 wherein the solution is pressurized with carbon dioxide to 25 to 80 bar.
3) A process for preparation of nanoparticles using sub-critical carbon dioxide as claimed in claims 1-2 wherein the solution is cooled to 8°C to 30 °C .
4) A process for preparation of nanoparticles using sub-critical carbon dioxide as
claimed in claims 1-3 wherein C02 is bled off from the pressure vessel in 0.5-5 minutes to reduce the pressure to 10 to 1 bar.
5) A process for preparation of nanoparticles using sub-critcal carbon dioxide as
claimed in claims 1-4 wherein solvent from the precipitated nanoparticles is removed in 1 to 30 minutes.
6) A process for preparation of nanoparticles using sub-critcal carbon dioxide as
claimed in claims 1-5 wherein dissolution of solid substance is carried out in
organic solvents such as acetone, methanol, ethanol, dimethyl sulfoxide,
dichloro methane, toluene, ethyl acetate, depending on the solubilities of CO2 and solid in the solvent.
|Indian Patent Application Number||544/MUM/2004|
|PG Journal Number||13/2008|
|Date of Filing||11-May-2004|
|Name of Patentee||INDIAN INSTITUTE OF TECHNOLOGY, BOMBAY|
|Applicant Address||POWAI MUMBAI 400 076|
|PCT International Classification Number||B82B 3/00|
|PCT International Application Number||N/A|
|PCT International Filing date|