Slurry media milling is an important unit operation in various industries for the fine and ultra-fine grinding of minerals, paints, inks, pigments, micro-organisms, food and agricultural products and pharmaceuticals. In these mills, the feed particles are reduced in size between a large number of small grinding media which are usually sand, plastic beads, glass, steel or ceramic beads. As a result of the internally agitated, very small, grinding media and the liquid medium (aqueous, non-aqueous or a mixture thereof, finer particles of submicron or nanosize particles dispersion product can be produced, which has not been previously done by conventional mills.
Supercritical fluid (SCF) processing technology has many applications in food, nutraceutical and chemical industries and is now emerging as an alternative technology in the pharmaceutical industry with applications ranging from particle formation, micro-encapsulation, coating, extraction, and purification. Carbon dioxide is the most widely used SCF for pharmaceutical applications even though other hydrocarbon gases such as ethane, propane, butane and ethylene, water, nitrous oxide ammonia and trifluoromethane have been reported for other applications. Three types of SCF processes have been disclosed. They are:
1) rapid expansion of supercritical solutions (RESS) process,
2) antisolvents process, and
3) particles from gas-saturated solution (PGSS) process.
The RESS process is limited for SCF soluble compounds because it involves dissolving the compounds in the SCF and the subsequent formation of particles by rapid expansion through a nozzle. Most drug compounds have very low solubility in SCF especially supercritical CO2.
The antisolvent process uses the SCF as an antisolvent to precipitate particles from predissolved solvent solution with the sample principle of antisolvent crystallization process. The method developed by University of Bradford in U.S. Pat. No. 5,108,109 combines the antisolvent and nozzle expansion to control particle formation. The limitation of the antisolvent process is a soluble solvent has to be used for a given compound.
Weidner (U.S. Pat. No. 6,056,791) discloses a process to dissolve CO2 in liquid or melted drugs or polymers to form a gas-saturated solution followed by depressurization to form particles. Some apparent disadvantages with this process are that the elevated temperature required to melt the compounds could degrade the compound, and that the high viscosity of melts could limit the particle size of product.
U.S. Pat. No. 5,854,311 discloses the use of 10 to 40 μm particles in powder coating applications. The process disclosed was run at no more than 30 psig.
U.S. Pat. No. 5,500,331 discloses the comminution of materials with small particle milling material. U.S. Pat. No. 5,145,684 discloses surface modified drug nanoparticles. The technology disclosed in these patents relates to a milled slurry, but not dry flowable nanoparticles, as a liquid media is used in the process.
Hock S. Tan and Suresh Borsadia, Particle Formation Using Supercritical Fluids: Pharmaceutical Applications, Exp.Opin. Ther. Patents (2001)11(5), Asley Publications Ltd. reviews a number of process concepts using supercritical fluid (SCF) processing methods for controlled particle formation. However the article does not describe grinding milling equipment using SCF to generate dry flowable sized micro particles.
The present invention, a high pressure media milling (HPMM) process, combines a slurry media mill with supercritical fluid (SCF) technology or with volatile gases as a milling medium to produce micron and nanosize particles in a dry free flowing powder form without a limitation of solubility and without the requirement of organic solvents or high temperature. The volatile gas may also include those cooled to a liquid state, such as liquid CO2. The process has applications for use with a broad range of materials including heat sensitive bioactive materials and environmental sensitive electronic materials.
USPTO Backgrounds
USPTO Backgrounds