Plastic and nonmetallic article shaping or treating: processes – Formation of solid particulate material directly from molten... – Coated particles
Reexamination Certificate
2001-05-16
2003-09-16
Theisen, Mary Lynn (Department: 1732)
Plastic and nonmetallic article shaping or treating: processes
Formation of solid particulate material directly from molten...
Coated particles
C264S009000
Reexamination Certificate
active
06620351
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The current invention relates to a method for the production of micron or nanometer size particles by precipitation, wherein a dispersion containing the substance of interest is contacted with a supercritical fluid antisolvent under near or supercritical conditions in order to maximize micro or nanoparticle formation. The invention also provides techniques to control the particle size, particle size distribution and particle morphology. The invention also includes supercritical fluid coating or composite material particle formation, wherein encapsulation of one substance by another substance or coprecipitation of more than one substance in the form of micro or nanoparticles are achieved in the supercritical fluid antisolvent.
2. Background and Prior Art
Nanoparticles are of considerable importance in numerous technological applications. Nanoparticles of materials in fact exhibit properties significantly different from those of the same material with larger sizes. Some nanostructured materials with novel properties include: fullerenes, zeolites, organic crystals, non-linear optical material, high temperature superconductors, molecular magnetic materials, starburst dendrimers, piezoelectric materials, shape changing alloys and pharmaceuticals. The novel properties of these nanostructured materials can be exploited and numerous potential applications can be developed by using them in different industries. One such industry where the need for nanoparticles is particularly pronounced is the pharmaceutical industry where nanoparticles of different pharmaceutical materials are used for designing ‘drug delivery systems’ for controlled release and targeting.
Several techniques have been used in the past for the manufacture of nanoparticles but these techniques suffer from some inherent limitations. Some of the conventional techniques include: Spray drying, which is one of the well-known techniques for particle formation and can be used to produce particles of 5 &mgr;m or less in size. The major disadvantage of this technique is that it requires high temperature in order to evaporate the solvent in use, and this makes it unsuitable for treating biological and pharmaceutical substances. Furthermore, the final product yield may be low in case of small-scale applications. Milling can be used to produce particles in the 10-50 &mgr;m range, but the particles produced by this method have a broad size distribution. Fluid energy grinding can produce particles in the 1-10 &mgr;m range but this process involves the use of high-velocity compressed air, which leads to electrostatically charged powders. In addition, particle size reduction by this process tends to be more efficient for hard and brittle materials such as salt and minerals, but much less so for soft powders, such as pharmaceuticals and other biological substances. Lyophilization produces particles in the desired range, but with a broad distribution. A main disadvantage of this process is that it employs the use of organic solvents that may be unsuitable for pharmaceutical substances. In addition, control of particle size can also be difficult, and a secondary drying step is required to remove residual solvents. In the case of precipitation of protein particles, not all proteins can be lyophilized to stable products, and the process must be tailored to each protein.
Thus, none of these methods are entirely satisfactory, and it is therefore important to explore alternative methods that will produce particles from 5 &mgr;m down to as low as 10 nm.
Particle Technology Based on Supercritical Fluids
One of the first uses of supercritical fluids in particle formation was proposed by Krukonis et al. in 1984 for processing a wide variety of difficult-to-handle solids. Since then, several experimental studies have been conducted to develop methods for particle formation using this technology. The two primary methods utilizing supercritical fluid technology for particle processing include Supercritical Antisolvent (SAS) Precipitation technique and the Rapid Expansion of Supercritical Solutions (RESS) technique. For many years now, these techniques have been successfully used to produce microparticles of various compounds including difficult to handle explosives (Gallagher et al., 1989), lysozyme, trypsin (Winter et al, 1993), insulin (Yeo et al., 1993; Winter et al, 1993), prednisolone acetate (U.S. Pat. No. 5,803,966), polystyrene (Dixon et al., 1993), HYAFF-11 polymers (Benedetti et al., 1997), different steroids (Larson and King, 1985), and numerous other organic substances. Other areas of application of supercritical fluids include formation of solvent free, drug loaded polymer micro-spheres for controlled drug release of therapeutic agents (Tom et al., 1992; Mueller and Fischer, 1989), production of ultra-fine and chemically pure ceramic precursors (Matson et al., 1985 a,b, 1987 a,b; Peterson et al. 1985), formation of intimate mixtures of ceramic precursors (Matson et al., 1987a), and for formulation of crystalline powders of labile pharmaceutical drugs. Dixon and coworkers (1993) used the supercritical CO
2
antisolvent process to make polystyrene particles ranging from 0.1 to 20 &mgr;m by spraying polymer/toluene solutions into CO
2
of varying densities. A major advantage of supercritical fluid precipitation process is that they can generate particles having a narrow size distribution unlike other conventional processes that provide a wide size distribution. Further the particles formed by supercritical fluid precipitation process are free of organic solvents and the formation of powdered blends, thin films and micro-encapsulation of materials is straightforward.
The Working of the RESS Technique
In the RESS process, the solid of interest is first solubilized in supercritical CO
2
and then sprayed through a nozzle into a low-pressure gaseous medium. Rapid expansion of the solution on being passed through the nozzle causes a reduction in CO
2
density and also a reduction in the solvent power of supercritical CO
2
and this subsequently leads to the recrystallization of the solid in the form of fine particles.
RESS provides a useful tool for controlling the size and morphology of the precipitated powders. The influence of operating conditions on the process has been studied by several investigators, sometimes with different and conflicting results (Larson and King, 1985; Mohamed et al., 1989; Peterson et al., 1985). When RESS is carried out in the usual mode, solvent free particles are obtained which makes the technique advantageous for processing pharmaceutical substances. No surfactants or nucleating media are required to trigger the nucleation and the solvent is removed by a simple mechanical separation.
One of the main constraints in the development of the RESS process however is supercritical fluid solvent capacity. For example, carbon dioxide, which is the preferred solvent in many applications, has a low solubility towards polar substances. Different supercritical fluids can be chosen in case of such a problem: a second solvent (cosolvent) can be added to enhance the CO
2
solvent capacity, but these solvents remains within the precipitated product as impurities. In general, polymers possess low solubility in supercritical fluids, including CO
2
(with or without cosolvents), and for such materials other processing methods are more suitable.
The Working of the SAS Process
In the SAS process, the supercritical fluid is used as the antisolvent. First the solid of interest is dissolved in a suitable organic solvent. Then this solution is introduced into the supercritical fluid using a nozzle. The supercritical fluid dissolves the solvent, precipitating the solid out as fine particles.
The volumetric expansion of the liquid when in contact with the SCF plays a key role in the process. For example, experiments conducted by Yeo et al. (1993a,b) for dimethylsulfoxide (DMSO)-CO
2
system at two temperatures, shows that CO
2
produces a remarkably high volumetric expansion of DMSO (as hig
Chattopadhyay Pratibhash
Gupta Ram B.
Auburn University
Paul Beck & Associates
Theisen Mary Lynn
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