MXPA98007095A - Methods and apparatus for the precipitation of particles and coatings that use antidisolvents almost criticos and supercriti - Google Patents

Abstract

The present invention relates to: An improved method and apparatus (110) for particle precipitation and coating when using near critical or supercritical fluid conditions is described. A fluid dispersion (128) having a continuous phase dispersant and at least one precipitable substance therein is contacted with a supercritical fluid antisolvent (SCF) (126) to generate sonic waves of the high frequency antisolvent focused , which break the dispersion into extremely small drops. The improved mass transfer rates between the drops and the anti-solvent, cause the precipitation of very small particles of the order of 0.1-10 microns. In the coating processes, a turbulent fluidized flow of core particles is created by using the SCF antisolvent in an enclosed zone. The core particles are brought into contact therein at near critical or supercritical conditions by the fluid dispersion containing a dispersant and together with a precipitable substance. The anti-solvent exhausts the dispersant and the substance is precipitated on the fluidized particles

Description

METHODS AND APPARATUS FOR PRECIPITATION OF PARTICLES AND COATINGS THAT USE ANTIDISOLVENTS ALMOST CRITICAL AND SUPERCRITICS Field of the Invention The present invention relates to a method and apparatus for the precipitation of extremely small particles, wherein a dispersion of fluid containing a substance to be precipitated is contacted with a supercritical fluid antisolvent (SCF), such as carbon dioxide, under conditions of almost critical or supercritical temperature and pressure to maximize the formation of small particles. The invention provides spraying or sprinkling techniques wherein the mass transfer rate at the interface is aximized between the small droplets of the dispersion and the anti-solvent to generate precipitated particles having an average diameter of about 0.1-10 μm. The invention also includes supercritical fluid coating techniques, wherein the fluidized core particles are coated with precipitated particles in an SCF anti-solvent precipitation chamber (supercritical fluid).

Description of prior art A variety of industries have experienced a long-felt need for micronization and REF. 28344 nano ization of particles. The need for an apparatus or method capable of producing submicroscopic and nano-sized particles is particularly pronounced in the field of pharmaceutical products. Conventional techniques for particle size reduction in the present suffer from many disadvantages. These conventional methods involve either mechanical disintegration (breaking, grinding and crushing) or recrystallization of the solute particles from liquid solutions. The limitations of mechanical disintegration for particle size reduction are the sensitivity to shock associated with thermal, solid degradation, due to the generation of heat during mechanical disintegration, lack of fragility of some solids (for example, most polymers) and chemical degradation due to exposure to the atmosphere. Conventional recrystallization of solutes from liquid solutions takes advantage of the dependence of the solubility of a compound at the temperature and / or composition of the mixture. By changing the temperature or adding antisolvents to selectively remove the solvent in which the solid is solubilized, the desired material can be precipitated or crystallized from the solution to form particles. Crystallization either by evaporation of solvent or solvent extraction of a solute usually requires the use of toxic organic antisolvents, surfactants and oils and produces wet particles which require further drying to separate the traces of the adsorbed solvent residues. Freeze drying tends to produce particles with a wide size distribution that require additional drying. Spray drying usually requires the evaporation of the solvent in a bed of hot fluidized air. High temperatures can degrade sensitive medicines and polymers. An onodispersed particle size distribution with crystalline structure and consistent crystalline properties is also difficult to obtain, using the techniques indicated above. In the last decade, processes have emerged for the production of microscopic and submicroscopic particles, which use either a supercritical fluid (ie, a fluid whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Pc)), or compressed fluids in the liquid state. A characteristic of a substance at a temperature higher than its critical temperature is that it can not be condensed independently of the pressure exerted. It is well known that at near-critical temperatures, large variations in density properties and fluid transport, from gas-like to liquid-like, can result from relatively moderate pressure changes in a range around the critical pressure (0.9-1.5 Pc). While the liquids are almost incompressible and have low diffusivity, the gases have a higher diffusivity and a lower solvent power. Supercritical fluids can be made to have an optimal combination of these properties. The high compressibility of supercritical fluids (which implies that large changes in fluid density can be effected by relatively small changes in pressure, which makes the solvent power highly controllable) together with its liquid-like solvent power and properties of transport better than liquid (higher diffusivity, lower viscosity and lower surface tension compared to liquids) provide a means to control mass transfer (mixing) between the solvent containing the solutes (such as a drug or polymer, or both) and the supercritical fluid. Two processes that use supercritical fluids for particle formation are: (1) Rapid expansion of supercritical solutions (REES) (Tom JW Debenedetti, PG, 1991, The Formation of Bioerodible Polymeric Microspheres and Microparticles by Rapid Expansion of Supercritical Solutions. BioTechnol, Prog. 7: 403-411), and (2) Recrystallization of gas anti-solvent (GAS) (Gallagher, PM, Coffey, MP, Kru onis, VJ, and Klasutis, N., 1989, Gas Antisolvent Recrystallization: New Process to Recrystallize Compounds in Soluble and Supercritical Fluids, Am. Chem. Sypm. Ser. No. 406; U.S. Patent No. 5,360,478 issued to Krukonis et al .; U.S. Patent No. 5,389,263 issued to Gallagher et al.). See also PCT Publication WO 95/01221 and U.S. Patent No. 5,043,280 which disclose additional SCF particle formation techniques. In the RESS process, a solute (from which the particles are formed) is first solubilized in supercritical C02 to form a solution. Then, the solution is sprayed by means of a nozzle to a gaseous medium of lower pressure. The expansion of the solution through this nozzle at supersonic speeds causes rapid depressurization of the solution. This rapid expansion and reduction in C02 density and solvent power leads to supersaturation of the solution and subsequent recrystallization of virtually contaminant-free particles. However, the RESS process is not suitable for the formation of particles from polar compounds, because such compounds, in which the drugs are included, exhibit little solubility in the supercritical C02. Co-solvents (eg, methanol) can be added to C02 to improve the solubility of polar compounds; however, this affects the purity of the product and the otherwise environmentally benign nature of the RESS process. The RESS process also suffers from scaling and operation problems associated with nozzle plugging, due to the accumulation of particles in the nozzle and the freezing of C02 caused by the Joule-Thompson effect that accompanies the large pressure drop . The relatively low solubilities of the pharmaceutical compounds in the unmodified carbon dioxide are exploited in the second process, wherein the solute of interest (usually a drug, polymer or both) is dissolved in a conventional solvent to form a solution. The behavior of the preferred ternary phase is such that the solute is virtually insoluble in the dense carbon dioxide, while the solvent is completely miscible with the dense carbon dioxide at the recrystallization temperature and pressure. The solute is recrystallized from the solution in one or two ways. In the first method, a batch of the solution is expanded several times by mixing with dense carbon dioxide in a vessel. Because the solvent expanded into carbon dioxide has a lower solvent strength than the pure solvent, the mixture is supersaturated to force the solute to precipitate or crystallize as microparticles.

This process is called recrystallization of gas anti-solvent (GAS) (Gallagher et al., 1989). The second method involves spraying the solution by means of a nozzle to compressed carbon dioxide, as fine droplets. In this process, a solute of interest (usually a drug, polymer or both) that is in solution or is dissolved in a conventional solvent to form a solution, is sprayed, usually by means of conventional spray nozzles, such as an orifice or capillary tube (s), in supercritical C02, which diffuses into the spray droplets to cause solvent expansion. Because the solvent expanded in C02 has a lower solubility capacity than the pure solvent, the mixture can become highly supersaturated and the solute is forced to precipitate or crystallize. This process has been generally referred to as precipitation with compressed anti-solvents (PCA) (Dixon, DJ, Johnston, KP, Bodmeier, RA AIChE J. 1993, 39, 127-139) and employs either liquid or supercritical carbon dioxide as the anti-solvent When a supercritical anti-solvent is used, the spraying or sprinkling process has been called the supercritical anti-solvent process (SAS) (Yeo, S.-D .; Debenedetti, PG; Radosz, M .; Schmidt, H.-W. Macromolecules 1993 , 26, 6207-6210) or aerosol spray extraction system (ASES) Müller, BW; Fischer, W .; Verfahren zur Herstellung einer mindestens einen Wirkstoff und einen Trager umfassenden Zubereitung, German Patent Appl. Do not . DE 3744329 Al 1989). PCT Publication WO 95/01221 teaches the use of a coaxial nozzle for the co-introduction to a supercritical fluid vessel and solutions in countercurrent flow directions. Such nozzles achieve the breaking of the solution by means of the impact of the solution by a fluid of relatively higher speed. The high speed fluid creates high frictional surface forces that cause the solution to disintegrate into droplets. Any high potential energy wave generated by the nozzles described in the prior art is random or disorderly and originates from the impact and frictional effects of the fluid at high velocity on the solution or the secondary impact of multiple droplets of the vehicle. For purposes of clarity, such high energy waves are defined as Type I waves. High frequency sound waves can be generated by various types of transducers such as piezoelectric, magnetostrictive, electromagnetic, pneumatic devices (so-called whistle-like whistles) based on the effect of organ pipe) and other mechanical transducers. The use of sound waves produced by one or more of these devices to generate drops of liquid surfaces or to atomize liquid spray jets has been known for more than half a century (see Ensminger, "Ul trasonics. Fundamentals, Technology, Applications", 2d De., Marcel Dekker, 1988 for numerous examples). One of the first "pneumatic devices" used to generate sound waves used a jet of air that hits a cavity to generate sound waves - the so-called whistle of Hartmann (J. Hartmann, "Construction, Performance and Design of the Acoustic Air -Jet Generator ", Journal of Scientific Instruments, 16, 140-149, 1939). In the Hartmann whistle, a jet of air, with speeds reaching Mach I, is directed to a hollow cavity, the impact at the bottom of the cavity causes a rise in pressure, which in turn causes a backflow of the energizing gas. The moment (or amount of movement) of this backflow of the fluid causes a rarefaction of pressure in the cavity. When the force of the jet exceeds the moment (or amount of movement), the direction of flow is reversed again towards the bottom of the cavity to complete the pressure cycle and propagate a sound wave. The focus of the sound waves generated on the spray jet has been used to atomize liquid spray jets. It should be appreciated that because the smallest practical focal region of a wave is a sphere, of a wavelength of diameter, the focal region of a focused sound wave is relatively large compared to a focused light wave. Whistle-type devices have been used to generate high-intensity sound waves in the air and in liquids. A practical higher frequency for applications that use air is approximately 30 KHz. When using helium or hydrogen, such whistles are capable of generating ultrasonic energy in the air of up to 500 KHz. It is generally recognized in the field that the effectiveness of the device in an application correlates with the frequency (or inversely with the wavelength). The efficiency (ratio of energy radiated to the power fed to the transducer) for such has been reported between <5% to 14%. It is also recognized in the field that the effectiveness of the device does not necessarily correlate with its efficiency. In other words, a low efficiency nozzle can be highly effective in producing desired drop sizes. The whistles to generate sound waves in liquid have also been developed for industrial use. Since the speed of sound is considerably higher in liquids than in gases, jet velocities equal to the speed of sound are impractical in liquids. The whistles of W. Janovsky and R. Pohlmann (Zeitschrift für Angewandte Physik, 1, 222, 1948) operate based on the principle of the edge of the jet, where a high-pressure jet of liquid or liquids is slammed onto the edge of the jet. a thin plate, which is mounted on the displacement nodes. The plate vibrates in flexure in resonance to produce low frequency waves, normally in the order of magnitude of 5000 Hz. Such "liquid whistles" have been used to produce emulsions or dispersions of a dense medium in another dense medium (oil / water, mercury / water, etc.). In many instances, especially in the pharmaceutical industry, it is desirable to coat core particles or medications. In general, such coating has been carried out by employing techniques such as electrolysis, vapor deposition and fluidized bed techniques or air suspension. However, all these methods have several disadvantages, for example, the difficulty of maintaining aseptic conditions, the inability to generate extremely fine particles for coating purposes and control of solvent emission.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides improved near-critical or supercritical fluid processes for the precipitation of extremely small particles having average diameters (inferred from SEM photographs) of the order of about 0.1-10 μm and more preferably up to about 0.6. μm. The methods of the invention find particular utility as methods for particle micronization and nanopartization, particularly in the field of pharmaceutical products. However, the methods of the invention can also be used in other fields, such as those related to food, chemicals, polymers, pesticides, explosives, coatings and catalysts, where benefits are obtained from a decrease in the sizes of particles and the concomitant increases in the surface areas of the particles. Broadly speaking, the methods of the invention involve the precipitation of extremely small particles, which can be recovered as particles or deposited on core particles to form composite products. However, in all cases, the methods of the invention involve contacting a fluid dispersion (e.g., a gas or liquid solution or suspension) that includes a continuous phase dispersant with at least one substance (per example, a medicament such as a drug) dispersed in the dispersant with an antisolvent at almost critical or supercritical conditions for the antisolvent, to cause the antisolvent to deplete the dispersant and precipitate the substance as extremely small particles. Conditions are established during the contacting step to improve the mass transfer rate between the anti-solvent and the dispersant, such that nucleation of particles and precipitation occur rapidly. In most cases, the fluid dispersions of the invention would be in the form of liquid solutions, that is, the dispersant is a solvent and the substance to be precipitated is a solute dissolved in the solvent. In addition, the dispersants should comprise at least about 50% by weight (and more preferably, at least about 90% by weight) of the total dispersions. The conditions set during the contacting step of the dispersion / antisolvent are usually in the range of about 0.7-1.4 Tc and about 0.2-7 Pc of the antisolvent; more preferably, these ranges are about 1-1.2 Tc and about 0.9-2 Pc of the anti-solvent. Preferably, the conditions during the contact are maintained in such a way that the dispersant and the anti-solvent are essentially completely miscible in all proportions thereof. The anti-solvents used in the invention are usually selected from the group consisting of carbon dioxide, propane, butane, isobutane, nitrous oxide, sulfur hexafluoride and trifluoromethane; carbon dioxide is the most preferred antisolvent for reasons of cost and ease of processing . In all cases, the anti-solvent must be substantially miscible with the dispersant, while the substance or drug to be precipitated must be substantially insoluble in the anti-solvent, ie the substance or medicament, at the contact conditions of the dispersion. selected anti-solvent, should not be more than about 5% by weight soluble in the anti-solvent and preferably is essentially completely insoluble. In a preferred aspect of the invention, improved spraying or spraying processes are provided for the precipitation of extremely small particles. For example, special nozzles can be used to create sprays of extremely fine droplets of fluid dispersions to a precipitation zone containing antisolvent. In using such equipment, the methods of the invention involve passing the fluid dispersion through a first passage and a first passage exit to the precipitation zone containing the anti-solvent and maintained at the near critical or supercritical conditions defined above. pressure temperature for the anti-solvent. Simultaneously, an energizing gas stream is passed along the second passage and through a second outlet of the passage close to the first outlet of the fluid dispersion. The passage of such an energizing gas stream through the second outlet generates high frequency waves of the energizing gas adjacent to the first outlet of the passage, in order to break the fluid dispersion into extremely small drops. This causes the antisolvent in the precipitation zone to deplete the dispersant and quickly precipitate small particles of the substance. The preferred process of the invention involves the deliberate generation of high energy sound waves (type II waves) in addition to and substantially independent of any common frictional and impact forces of the prior art nozzles (type I waves). Type II sound waves can be generated in the energizing gas stream or in the dispersion itself. In the first situation, specialized nozzles are used as described hereinafter and in a later one, the starting dispersion can be sprayed onto a sonication surface coupled to a transducer (e.g., piezoelectric, magnetostrictive or electromagnetic) and the particles resulting in contact with the turbulent SCF fluid.

In preferred forms, the "specialized nozzle is of the type marketed by Sonimist of Farmingdale, NY as Model 600-1.This nozzle includes an elongated body having a central tube which serves as the primary spray nozzle for the dispersions of the invention. The nozzle structure also includes a secondary passage in relation to the central tube for the passage of the energizing gas along the length of the central tube and out of the outlet of the nozzle The secondary passage for the energizing gas it is configured to present a converging section defining a restricted throat, with a diverging section downstream of the throat and leading to the outlet of the nozzle, In addition, the diverging portion of the secondary passage is equipped with an annular resonator cavity, radially expanded. , to reflect the sound waves.The output end of the central tube is located downstream of the a restricted throat. The use of nozzles of this type serves to generate and focus the preferred high frequency sonic waves of energizing gas, which has been shown to maximize the production of extremely small dispersion droplets in the precipitation zone, to thereby drive the precipitation of the very small particles of the invention. The frequency of the generated waves of energizing gas can fluctuate anywhere from 0.5 KHz to 300 KHz and more preferably from about 10-100 KHz. It is believed that the inherent kinetic energy of the energizing gas stream is converted to acoustic energy by virtue of the passage of the energizing gas stream through the restricted throat, the resonator cavity and the outlet of the nozzle. In general, at least about 1% (more preferably about 2-14%) of the kinetic energy of the energizing gas stream is converted to acoustic energy. In preferred forms, the energizing gas is the same as the selected anti-solvent and in most cases carbon dioxide is used as the anti-solvent and the energizing gas. However, more broadly, the energizing gas may be selected from the group consisting of air, oxygen, nitrogen, helium, carbon dioxide, propane, butane, isobutane, trifluoromethane, nitrous oxide, sulfur hexafluoride, and mixtures thereof. When it is desired to coat core particles with a desired substance, a fluid dispersion of the type described is sprayed into an enclosed precipitation zone containing an amount of antisolvent at near critical or supercritical conditions for the anti-solvent. Simultaneously, a turbulent fluidized flow of the core particles is created within the precipitation zone; by passing a fluidizing gas stream comprising the selected anti-solvent to the precipitation zone. Conditions are maintained in the zone such that the antisolvent rapidly exhausts the dispersant and precipitates the substance as small particles on the fluidized core particles. Although the specialized nozzle arrangement described above can be used in the coating methods of the invention, such is not generally required. That is, in coating applications, the coating particles may commonly be relatively larger without impairing the usefulness of the final product; thus, conventional capillary nozzles and the like can be used to obtain a good effect in such coating processes. In one form, the fluidized flow of core particles is established by passing the fluidizing gas stream in a direction which is substantially countercurrent to the spray direction of the fluid dispersion to the precipitation zone. However, where modified Wurster coating devices are employed, the fluidizing gas stream is directed co-current in relation to the spray direction of the fluid expression. It is important that at least part of the fluidizing gas stream be composed of the solvent, particularly where the flow of the countercurrent fluidizing current is used. However, in any case, the fluidizing gas stream should normally have an antisolvent concentration therein of at least about 70% by weight and more preferably, the fluidizing gas stream consists essentially of antisolvent. A wide variety of core particles can be used in the invention, but in general these should have a maximum dimension of up to about 15 mm and more preferably up to about 1 mm. Core particles such as glass beads or sugar can be used and in pharmaceutical applications, it is contemplated that discrete solid or medicament tablets or other dosage forms can be coated. The final coated products can range in microscopic size to several millimeters. In the case of medicaments, depending on the application, the final coatings would normally have a thickness of about 0.1 μm to 2 mm (more preferably about l-500 μm) and the coating would be about 1-30% (more preferably about 5-15%) by weight of the final coated product.

In another aspect of the invention, a process is provided for the preparation and administration to a patient of a particulate medicament, without the need to transfer the medicament between containers, that is, the dispersion / anti-solvent precipitation is carried out in a end-use container, which is subsequently sealed and allows the withdrawal of medication doses from the container of use. In general, this method involves the lyophobic precipitation of drugs, which can be carried out in a batch or semi-batch mode. In preferred forms, the following general steps are carried out: (a) the medicament is dissolved in an organic solvent to form a solution or suspension; (b) the solution or suspension is filtered sterile; (c) the solution or suspension is either dosed to the end-use container before being contacted with the supercritical fluid (batch mode) or continuously as a spray, with contact with the supercritical fluid (semi-batch mode); (d) the suspension or solution of the medicament in the container is brought into contact with the supercritical fluid, at a predetermined concentration of the supercritical fluid, the mixed expanded liquid is no longer a solvent for the medicament and the precipitation of particles is effected; (e) the use container is purged with supercritical fluid until the organic solvent is completely exhausted from the system; and (f) the finished solid particulate medicament is aseptically sealed in the container of use. After this, when it is desired to use the medicament, a liquid carrier can be placed in the container of use to form a mixture, which can then be administered by injection or the like.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic view of the apparatus for recrystallization of conventional SAS from organic solutions. Figure 2 is a schematic representation of an apparatus useful in the practice of the invention. Figure 3 is a schematic cross-sectional view of the nozzle used in the practice of the invention. Figure 4 is a micrograph of SEM (amplification at 10,000X) of micronized hydrocortisone by recrystallization from a 5 mg / ml solution of DMSO, using the conventional SAS process with a 100 μm capillary nozzle. Figure 5 is a SEM micrograph of micronized hydrocortisone by recrystallization from a 30 mg / ml solution of DMSO, using the conventional SAS process with a 100 μm capillary nozzle. Figure 6 is a GC-FID analysis of recrystallized hydrocortisone from a 30 mg / ml solution of DMSO using the conventional SAS process with a 100 μm capillary nozzle. Figures 7a and 7b are a pair of micrographs of SEM (amplification at 5,000X and 9,900X respectively) of nanocounted hydrocortisone by recrystallization of a 30 mg / ml solution of DMSO using the nozzle of the present invention (compressed C02 is used) as the energizing gas and as anti-solvent). Figure 8 is a micrograph of SEM (amplification at 3,000X) of micronized hydrocortisone by recrystallization of a 30 mg / ml solution of DMSO, when using the nozzle of the present invention (He (helium) is used that the energizing gas and compressed C02 is used as an anti-solvent). Figures 9a and 9b are a pair of micrographs of SEM (amplification at 500X, and 1000X respectively) of polylactic-glycolic acid polymer (RG503H) micronized by recrystallization of a 10 mg / ml solution of ethyl acetate when using the process of conventional SAS with a capillary nozzle of 100 μm.

Figure 10 is a micrograph of. SEM (amplification at 1,000X) of micronized RG503H by recrystallization from a 10 mg / ml ethyl acetate solution using the nozzle of the present invention (compressed C02 is used as the energizer and as an anti-solvent). FIGS. 11a and 11b are a pair of micrographs of SEM (amplification at 1,000X and 10, OOOX respectively) of nanosized ibuprofen by recrystallization of a 30 mg / ml solution of DMSO, using the nozzle of the present invention (used C02 compressed as the energizing gas and as an anti-solvent). Figure 12 is a SEM micrograph (amplification at 1,000X) of micronized camptothecin by recrystallization from a 5 mg / ml solution of DMSO, when using the nozzle of the present invention (compressed C02 is used as the energizing gas and as an anti-solvent). Figures 13a and 13b are a pair of micrographs of SEM (amplification at 2, OOOX and 15, OOOX, respectively) of nanomated camptothecin by recrystallization from a 5 mg / ml solution of DMSO, using the nozzle of the present invention (FIG. compressed C02 is used as an energizing gas and as an anti-solvent); Figure 14 is a schematic view of a modified precipitation vessel, specifically adapted for coating core particles in the overall apparatus of Figure 1; Figure 15 is a SEM photograph of an uncoated nomparell sugar bead used in example 5; Figure 16 is a photograph of SEM of a nomparell sugar bead coated with final RG503H; Figure 17 is a photograph of SEM of a glass bead coated with RG503H; Figure 18 is a photograph of SEM of a nomparell sugar bead coated with RG503H produced according to example 7; Figure 19 is a photograph of SEM of a nomparell sugar bead coated with RG503H produced according to example 7; Figure 20 is a SEM photograph of a glass bead coated with hydrocortisone produced according to example 8; Figure 21 is a schematic representation of an apparatus useful in the aspects of lyophobic precipitation of the present invention; Figure 22a is a differential scanning calorimetric thermography of unprocessed phenytoin; and Figure 22b is a differential scanning calorimetric thermography of phenytoin processed by lyophobic precipitation according to example 10.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples summarize techniques, compositions and system parameters, also as test results, which demonstrate various aspects of the present invention. Examples 1-4 relate mainly to the micronization and particle nanonization aspects of the invention, while examples 5-8 relate to particle coating; the remaining examples illustrate the production of finished products by lyophobic precipitation. It will be understood, however, that these examples are presented by way of illustration only and that nothing in them should be taken as limiting the overall scope of the invention.

Micronization and particle nanopartization Experimental equipment and procedures for examples 1-4 Figure 1 shows a schematic view of the apparatus 10 used for the recrystallization of particles from organic solvents, by using the process of Conventional SAS The experimental unit 10 allows SAS experiments to be carried out either in a batch or semi-continuous mode at pressures up to 351.5 Kg / cm2 (5,000 psi) and temperatures up to 70 ° C. The mixing of the solvent and the anti-solvent occurs at two different sites 12, 14 within the unit. Unit 10 provides versatility in adjusting operating parameters. Unit 10 was integrated around a 65 ml high pressure Jerguson gauge display cell 16 (Burlington, MA). Cell 16 was equipped with a sapphire window that allowed the visualization of the expansion and crystallization process. Cell 16 was housed in a heated, isothermal transparent acrylic water bath 18. This water bath 18 is used to maintain cell 16 at a desired temperature (20-70 ° C). When the bath temperature is stable to a desired value, C02 is pumped through the orifice 20 on the upper side of cell 16 with an ISCO syringe pump 22 (Lincoln, EN) 260D at a constant speed (typically 5 ml / minute of liquid C02) until the pressure in cell 16 reaches a desired level (105.4 Kg / cm2 (1, 500 psi)). When the temperature and pressure in cell 16 are stabilized, the organic solution (DMSO or ethyl acetate solution of medicament and / or polymer) is dosed from the upper central hole 24 of cell 16 through a tube 26 of stainless steel capillary nozzle, 0.1587 cm (1/16") outside diameter, internal diameter 100 μm, when using a mini pump 28 Milton Roy 396-89 (Riviera Beach, FL). Minimum flow rate of the 2.5 ml / minute solution to consistently obtain a jet spray Both fluids were pre-heated to operating temperature by passing them through heat exchangers 30, 32 housed together with cell 16 in the water bath 18. Fresh C02 currents and the organic solution are mixed at site 14, which is downstream from tip 33 of the nozzle at the top of cell 16. It is seen that an area is formed turbid approximate 1 cm long in this area, which indicates the intimate mixing of the fluids and the formation of particles. The depletion of the solvent from the spray droplets causes the drug and / or polymer dissolved in the organic solvent to undergo nucleation. The resulting particles descend to the cell. Alternatively, the streams can be pre-mixed before reaching the tip 33 of the nozzle when using the bidirectional valve 34. The particles descending through the cell 16 either adhere to the walls of the cell or accumulate on a rod of glass 36 of 15.24 cm (6 inches) long. Particles larger than 0.5 μm leaving the chamber of the display cell are retained in a 0.5 μm stainless steel frit housed in the T-shaped fitting in the lower central hole 38. A thermocouple inserted through this accessory is used to check the temperature of the cell. The spent mixture of medicament and / or C0 polymer and organic solution flows through a heated microdosing valve assembly 40, controlled by a stepper motor. After expansion at a subcritical pressure (usually close to atmospheric pressure), the mixture is separated into an organic liquid phase and a C02 gas phase. The phase separation is carried out in the instant vaporization vessel 42; the organic solution flows through a microdosing valve 44 and is collected in a container 46. Then, the solution is analyzed in terms of the drug and polymer content. The C02 is vented through a second micro-dosing valve 48, a rotator 51 and an electronic mass flow meter 50. Normally, the solution is pumped for 15 minutes in order to produce a statistically representative sample of the medicament and / or polymer microparticles. Following this, the flow of the organic solution is stopped while continuing the C02 flow for another 1.5 hours in order to wash any remaining organic phase in the cell and dry the collected particles. It is found that the C02 flows at 105.4 Kg / cm2 (1,500 psi), during 1.5 hours it is suitable to wash the organic solvent present in the cell and to dry the particles. Following the drying period, the pressure is reduced to atmospheric level at a rate of 3.5 Kg / cm2 (50 psi / minute). The particle samples are collected from the cell window, the porous frit and the glass tube and analyzed by scanning electron microscopy (SEM) to estimate particle size and morphology. An exact control of the pressure is essential in the region close to the highly compressible critic. The fluctuations of pressure in this region have a great effect on the level of expansion of the organic solution and thus on the level of supersaturation and consequently, on the crystal growth and the crystal size distribution. The control of the pressure in cell 16, together with the verification of temperature, pressure and flow rate is carried out when using the Data Acquisition and Control System Camile® (Midland, MI) 2500. "A stepper motor of 100 steps / revolution, which operates at 200 half steps / revolution, is used to operate the heated micro-dosing valve 54. The pressure control is obtained by using a HC-11 microprocessor that interprets the output or result of the Camile PID control and It acts as a stepper motor controller.The programming elements allow the microprocessor to search for a window where the valve will be put into operation to provide pressure control within the transducer accuracy (± 0.7 Kg / cm2 (10 psi) Fig. 2 schematically shows an apparatus 110 according to the present invention.The apparatus 110 is identical to the apparatus 10, with the exception that the display cell which gives rise to vice as a crystallization chamber is replaced with a larger stainless steel container (450 ml), which can accommodate the nozzle. Here again, the crystallization chamber is housed in an isothermal water bath and the pressure is controlled as previously described with respect to the conventional SAS process (Figure 1) . In apparatus 110, an organic solvent such as dimethyl sulfoxide (DMSO), in which solutes such as medicament, polymer, and / or excipient materials are solubilized, is also sprayed as a fine mist to a chamber containing an anti-solvent almost critical or supercritical. In more detail, the apparatus 110 of the present invention includes an isobaric and isobaric recrystallization chamber 120, a spray nozzle 124, a supercritical (se) or near critical (C02) source 126, a source 127 of compressed gas which serves to energize the nozzle 124, a solution 128 of medicament and excipient and collection vessel 156 for the organic solvent and a C02 output collector 130. The drug and excipient solution is withdrawn from vessel 140 through line 142 via pump 144 and discharged via line 146 to chamber 120 through line 146 as shown in figure 2. The nozzle 124 is attached to the end of line 146 inside chamber 120. The energizing gas for the nozzle, consisting of He, N2, 0, air, C02, other supercritical fluids or a mixture thereof, of the source 127 , is admitted through line 150 to the chamber 120, as shown in figure 2. The almost critical or supercritical fluid (anti-solvent) is admitted from the source 126. Alternatively, if the energizing gas is supercritical (or almost critical), the source 127 can also be used to admit the supercritical fluid to the chamber 120; then, the source 126 may either be used or not to admit a supercritical fluid in the same composition as in the source 124 or a supercritical fluid of different composition. This latter alternative can be used either to increase or decrease the concentration gradients between the antisolvent phase and the buffer zone. The solute-depleted organic solvent and solvent-loaded C02 are separated from the chamber 120 via the outlet 122 via the line 152 and the metering valve 154 to the instant vaporization vessel 156, in which the C02 is allowed to flow. Separate from the liquid organic solvent. C02 is allowed to vent from vessel 156 through vent line 158. Figure 3 is a schematic view of a nozzle (Sonimist, Farmingdle, NY, Model 600-1) employed in apparatus 110. This nozzle N it is of the convergent-divergent type and includes a central capillary-type T-tube having an outlet 0. The nozzle N also includes a surrounding P-passage having an I input for the energizing gas. The passage P includes a converging section C having a restricted throat TH and a diverging section downstream D. The section D includes a radially expanded annular resonating cavity CV. It will be noted that the outlet 0 of the tube T is positioned downstream of the throat TH. The nozzle N is energized by compressed gas (conventionally a light gas such as air, He, 02 or N2 and in the present invention, preferably by means of the use of anti-solvent gas). A sonic field (Type II waves) is created in the throat TH of the nozzle N as the gas and energization accelerates and reaches the speed of sound or at a higher speed. These high-frequency waves collide at the entrance of a CV resonant cavity and the latter serves to produce high-frequency waves of the energizing gas, to produce a cutting effect that breaks up the liquid jet comprising the solute-laden solvent into drops extremely little . In the device of figure 3, the generated sonic waves are focused on the spray of the dispersion in order to facilitate the improved atomization of the spray. For precipitation to occur, the droplet dispersant must be transferred to the anti-solvent phase surrounding the droplets. In addition to improving atomization, the concomitant increase in the surface area of mass transfer produced by sonic waves improves the rate of mass transfer between the droplets forms and the surrounding fluid medium, to increase by this, the speed of precipitation of solids. When sprayed into the ambient air, with a back pressure of 1.4-7.0 Kg / cm2 (20-100 pounds per square inch gauge) of the energizing gas, the Sonimist nozzle produces a spray of evenly dispersed, fine droplets having diameters in the 0.1-50 μm range depending on the operating conditions. Average droplet diameters of 1-10 μm are obtained when water is sprayed into the ambient atmosphere. If the interphase mass transfer does not significantly interfere with the atomization process, it is expected that the droplet sizes are even smaller when sprayed into a higher pressure gaseous environment or when organic solvents with a lower surface tension are used and viscosity lower than water. When this nozzle is used, the flow velocity of the energizing gas must be such that sonic velocities are obtained by the energizing gas in the throat of the nozzle. While in the conventional use of this nozzle, a pressure differential of 2 atmospheres between the energizing gas and the ambient atmosphere is sufficient to obtain this sonic velocity, this pressure differential is not sufficient when operating at almost critical conditions or supercritical The following equation is used to estimate whether a discharge velocity is subsonic (Perry and Chilton, 1973, Chemical Engineer's Handbook, 5th De., McGraw Hill, Chap.5): P2P0 >; [2 / (k + l)] k / k-1 where P0 is the pressure of the energizing gas, P2 is the outlet pressure of the nozzle and k is the ratio of thermal capacities at constant pressure and constant volume of the gas (that is, Cp- / Cv). For example, for a pressure of 105.4 Kg / cm2 (1.5000 pounds per square inch gauge) at the outlet of the nozzle and an energizing gas pressure (C02) of 421.8 Kg / cm2 (6,000 pounds per square inch gauge) , P2 / PQ = 105.4 / 421.8 (1,500 / 6,000) = 0.25; Cp / Cv at 105.4 Kg / cm + 2 (1,500 pounds per square inch gauge) = 4.81; and [2 / (k + 1)] k / k_1 = 0. 26. From here P2P0 < [2 / (k + 1)] k k_1 and the speed can be sonic. While the above example illustrates conditions under which sonic velocities can be estimated, such high speeds may not be required for all applications. For example, it has been found that using a chamber pressure of 87.9 Kg / cm2 (1,250 pounds per square inch gauge) and an energizing gas pressure of 130.0 Kg / cm2 (1,850 pounds per square inch gauge) provides sufficient energy to substantially reduce the particle size. An order of magnitude reduction in particle size when compared to the results obtained by conventional SAS recrystallization), is also observed when a pressure differential of only 7.0 Kg / cm2 (100 psig) is used between the maintained chamber at 105.4 Kg / cm2 (1,500 psi) and the energizing gas (C02). Thus, the nozzle illustrated in Figure 3 can be used in a wide range of operating conditions in order to substantially reduce the particle size and increase the surface area. Broadly speaking the energizing gas should be fed to the N nozzle at a pressure of approximately 77.3-421.8 Kg / cm2 (110-6000 pounds per square inch gauge) more preferably of approximately 105.45-175.7 Kg / cm2 (1,500-2,500 psig) ) and at a temperature such that after expansion, the energizing gas reaches the desired temperature of the recrystallization chamber. The frequency of the anti-solvent waves created at the outlet of the nozzle should be at least about 0.5 KHz and more preferably about 10-100 KHz. In addition, the invention can be practiced without the use of the nozzle illustrated in Figure 3. The invention can be practiced with any nozzle that provides a means to utilize a gaseous stream (or near critical or supercritical fluid). as an energizing means for atomizing the solution sprayed into smaller droplets and / or to create turbulence around the spray droplets, which increases the mass transfer rates between the anti-solvent droplet phases. Convergent-divergent nozzles can be used, as well as converging nozzles in the present invention.

Examples 1-4 Comparison of the particles produced by the process SAS conventional and the process of the present invention In these examples, the recrystallization of hydrocortisone, poly (D, L-lactide-glycolide) copolymer is studied (RG503H), ibuprofen and camptothecin. The recrystallization of hydrocortisone and RG503H is carried out by using the conventional SAS process also as the process of the present invention. Hydrocortisone is a common anti-inflammatory agent and ibuprofen is an agent for common pain relief. They are purchased from Sigma Chemical Co. , St. Louis, MO, and are used without further purification. Camptothecin is an anticancer drug with a very low solubility in water; the reduction in its particle size or an increase in its surface area of the particle can substantially increase its rate of dissolution and render it therapeutically more useful. RG503H is purchased from Henley, Montvale, N.J. It contains a 1: 1 molar ratio of lactide and glycolide and has an inherent chloroform viscosity of 0.3. The RG503H is approved by the FDA for administration to humans. It is non-toxic, non-reactive with tissues, biodegrades to non-toxic products and is particularly appropriate for surgical sutures. PLGA copolymers have been the subject of intense studies of micronization and microencapsulation. Certified grade DMSO and ethyl acetate (purity 99.9%, Fisher Scientific, Farilawn, N.J.), dry base C02 (purity 99.8%, Genex, Kansas City) are used without further purification. The particles are collected on a double-sided carbon tape applied to an aluminum SEM tab that is placed in the crystallization chamber before each experiment. The particles that are deposited on the walls of the cells are also collected for analysis. The morphology of the particles is determined by SEM (Hitachi, Model S-570). The particle size is also estimated by SEM. The SEM samples are coated by spraying with Au / Pd alloy. The hydrocortisone particles are redissolved in ethyl acetate and analyzed by GC-FID for trace DMSO contamination. The effluent solutions recovered in the flash vessel are also analyzed for hydrocortisone content. The results of repeated conventional SAS recrystallization experiments are compared in Table 1. The particle size for the mustache particles refers to their thickness or width. The data in Table 1 demonstrate that the average particle size for all the solutes studied, in which HYAFF-7 (in ethyl ester of hyaluronic acid) is included, is reproducible, which indicates that the SAS spray technique is a controllable and reproducible recrystallization technique.

Table 1. Reproducibility of the morphology and particle size formed by the conventional SAS recrystallization method, as estimated from SEM micrographs. P = 105.4 Kg / cm2 (1,500 pounds / square inch gauge); Flow rate of C02 = 5 ml / minute; Solution flow rate = 2.5 ml / min: Internal diameter of the capillary nozzle = 100 μm.

Example 1 Comparison of hydrocortisone recrystallization results from DMSO solutions Hydrocortisone particles produced by using the conventional sas process Figure 4 shows the SEM micrograph of recrystallized hydrocortisone particles from a 5 mg / ml DMSO solution when using the 100 μm capillary nozzle (P = 105.4 Kg / cm2 (1,500 pounds per square inch gauge)); T = 35 ° C; Flow rate of C02 = 5 ml / minute; flow rate of the solution = 2.5 ml / minute). The particles are agglomerated, almost spherical and fluctuate in size from 0.5-1 μm. "Recrystallization of hydrocortisone from a 30 mg / ml DMSO solution produces mustache-shaped particles of 1 μm thickness, long, (up to 1 mm), shown in figure 5 (P = 105.4 Kg / cm2 (1,500 pounds per square inch gauge); T = 35 ° C; Flow rate of C02 = 5 ml / minute; flow rate of the solution = 2.5 ml / minute; internal diameter of capillarity = 100 um). Note that the amplification level at the top of the micrograph (b) is five times higher when compared to the lower micrograph. Higher nucleation rates must result at this higher concentration which should lead to the formation of smaller particles (Gallagher et al., 1989); however, the increase in viscosity at higher solute concentrations and the premature onset of nucleation and recrystallization before secondary atomization prevent the atomization process to result in the formation of elongated mustache-like particles.

- Certainly, the increase in particle size with an increase in solute concentration is observed for all recrystallized solutes when using the process of Conventional SAS The size of the particles is quite reproducible. For three runs under these same conditions (30 mg / ml), the particle thickness is closely distributed and is of the order of 1 μm. The amount of DMSO in the hydrocortisone particles was less than the detection limit of GC-FID (= 10 ppm) (Figure 6). It is evident that the particles are virtually solvent-free.

Hydrocortisone particles produced using the present invention in which compressed C02 is used as the energizing gas and as an anti-solvent. For a nozzle outlet pressure of 105.4 Kg / cm2 (1,500 pounds per square inch gauge) and a temperature of 35 ° C, calculations indicate that a pressurization energy of approximately 421.8 Kg / cm2 (6,000 pounds per square inch gauge) at 55 ° C is necessary to obtain sonic velocities at the outlet of the nozzle. The C02 must be pumped at a speed in such a way that a back pressure of 316.3 Kg / cm2 is established (4,500 pounds per square inch gauge). An experiment that uses a back pressure of 7.03 Kg / cm2 (100 pounds per square inch gauge) (that is, a C02 feed pressure of 112.5 Kg / cm2 (1,600 pounds per square inch gauge) and 105.4 Kg / cm2 (1,500 pounds per square inch gauge) at the outlet of the nozzle , corresponding to a flow rate of C02 of 25 ml / minute), produces hydrocortisone particles consisting of almost spherical and whisker-shaped particles of 0.5-1 μm in size of approximately 1 μm and 10 μm long. These results suggest that the production of smaller particles can be obtained by using C02 at still subsonic speeds to energize the nozzle. From here, while near-sonic, sonic and supersonic compressed gas speeds are preferred for nanoparticle production, even the lower compressed gas flow rates can significantly reduce particle size when compared to the conventional SAS process where the anti-solvent phase is almost stagnant. Figures 7a and 7b show a pair of SEM micrographs of recrystallized hydrocortisone particles of a 30 mg / ml solution of DMSO using the nozzle of Figure 3, and C02 as the energizing gas. In the recrystallization chamber, P = 87.9 Kg / cm2 (1,250 psig); T = 35 ° C; and the flow rate of the solution 2.5 ml / minute. During the period when the solution was pumped (approximately 1 minute) the pressure of C02 on line 50 (figure 2) is equal to 130.0 Kg / cm2 (1,850 psig), to thereby provide a back pressure of 42.2 kg / cm2 (600 psi). The temperature of C02 at source 24 (figure 2) was brought to 50 ° C, so that after expansion from 130.0 kg / cm2 (1,850 psig) to 87.9 kg / cm2 (1,250 psig), the temperature decreases to almost 35 ° C, the temperature in the crystallization chamber. This back pressure is translated to a flow rate of C02 of 90 ml / minute during the atomization phase. It is observed that the particles are discrete, almost spherical and appear closely distributed around 500 nanometers (nm). Almost all particles are less than 600 nm. These results are in contrast to the long fibers 1 μm wide and almost 1 mm long previously observed (figure 5) when using the 100 μm capillary nozzle. From here, a significant decrease in the average particle size is observed with the use of the present invention.

Hydrocortisone particles produced by using the present invention in which He (helium) is used as an energizing gas and compressed co2 is used as an anti-solvent The DMSO solution of 30 mg / ml hydrocortisone is also recrystallized by using He (helium) at 112.5 Kg / cm2 (1,600 psig) as the energizing gas and C02 105.4 Kg / cm2 (1,500 psig), at 35 ° C, as an anti-solvent. Figure 8 shows that it is possible to use a light gas to energize the nozzle. Although these conditions are not optimal, the process still produces particles that are relatively small. Some particles appear to be even less than 1 μm. The benefits of using He (helium) as opposed to C02 as an energizing gas are not evident from Figure 8; however, it is anticipated that as the concentration of the solute and the viscosity of the solution increase, it may be necessary to introduce a gaseous buffer such as helium to prevent premature nucleation. When a light gas is used to energize the nozzle, the flow velocity of the supercritical fluid relative to that of the light gas must be high enough to provide sufficient anti-solvent power for the gaseous mixture of supercritical / light fluid. The use of C02 as both antisolvent and energizing gas, when possible, is advantageous with respect to the use of a light gas as an energizing gas, because: (a) the chances of contamination are reduced, (b) the anti-solvent power of C02 is not decreased, (c) the required flow rates of C02 are lower and (d) solvent recovery is efficient.

Example 2 Comparison of the recrystallization results of R503H particles produced using the conventional SAS process The RG503H is recrystallized from solutions of DMSO and ethyl acetate at a pressure of 105.4 Kg / cm2 (1,500 psig) and a temperature of 35 ° C when using a 100 μm capillary nozzle. Net RG503H particles, as supplied by the supplier, are relatively large agglomerated precipitates (> 50 μm). Table 2 illustrates the effect of the concentration of RG503H on the size and morphology of recrystallized RG503H from the solution. RG503H in DMSO recrystallizes as tubules at low concentrations, as a mixture of flakes and tubules at medium concentrations and as precipitates of large amorphous material at higher concentrations. The premixing of C02 with the DMSO solution before expansion, helps to improve mass transfer efficiency, has little effect on the size and morphology of the particles, but causes the formation of bubbles on the surface of the flakes. The formation of relatively large agglomerated particles at increased concentrations of the polymer parallels that of Dixon, D.J., Johnston, K.P. and Bodmeier, R.A., 1993, Polymeric materials formed by precipitation with a compressed antisolvent. Amer. Inst. Chem. Eng. J. 39: 127-139; Randolph et al. (1993); and Bodmeier, R., H. Wang, D.J. Dixon, S. Mawson, and K. P. Johnston, 1995, Polymeric microspheres prepared by spraying into compressed carbon dioxide. Pharm. Res. 12: 1211-1217. As in the previous example, these results also demonstrate the increased difficulty of atomization and micronization of particles in the increased concentration of the polymer due to an increase in the viscosity of the solution and a premature mass transfer between the solution and the C02. This observation is further corroborated in Figures 9a and 9b, which shows that a reduction in the viscosity and / or surface tension of the solution by means of a change of solvent, that is DMSO (1.9 cp and 41 dynes / cm) to ethyl acetate (0.46 cp and 24 dynes / cm) leads to the formation of discrete microspheres (in figures 9a and 9b, the sprayed solution is 10 mg / ml of RG503H in ethyl acetate, P = 105.4 Kg / cm2 (1,500 psi), T = 35 ° C, flow rate of C02 = 5 ml / minute, solution flow rate = 2.5 ml / minute, capillary diameter = 100 μm). The inability to obtain submicroscopic particles of average size less than 0.6 μm when using the conventional SAS process is attributed to the limitations of mass transfer. These are overcome in the present invention as explained above and as demonstrated in the following example.

Table 2. Micronization of RG503H by conventional SAS recrystallization. P = 105.4 Kg / cm2 (1,500 psig); T = 35 ° C; flow rate of C02 = 5 ml / min; flow rate of the solution = 2.5 ml / min; internal capillary diameter = 100 μm; the solvent consists of DMSO except for run 6. Run # Form Part size. [RG503H] (mieras) 1 mustache 15 0.5 2 whiskers / leaflets 15/50 2.0 3 whiskers / leaflets 25 / > 100 2.0 4 flakes 100 10.0 5 amorphous > 500 100.0 6 hollow microspheres < 50 10.0 * 7 flakes with bubbles > 500 10.0? * • V. 1 rl i .o n 1 \; -Qi-i t- pí P. < -5 to rpi-; i t H P p t i l n. • Pre-- mP 7r, l aHn HP I solvent and C02.

RG503H particles produced when using the present invention, in which CO? compressed as an energizing gas and as an anti-solvent Figure 10 shows an SEM micrograph of recrystallized RG503H particles from a 10 mg / ml solution of ethyl acetate. These particles are compared with the particles shown in Figures 9a and 9b, which are obtained by using the conventional SAS process.

Both experiments are carried out at identical conditions of pressure, temperature and flow velocity of the solution (105.4 Kg / cm2 (1,500 pounds per square inch gauge)), 35 ° C and 2.5 ml / minute, respectively) within the crystallization chamber, except that the particles shown in Figure 10 were obtained using the present invention, which compressed C02 is used as the energizing gas. The feed pressure of C02 was 112.5 Kg / cm2 (1,600 psig). Similar to the particles shown in Figures 9a and 9b, the particles of RG503H of Figure 10 are also almost spherical; however, the particles obtained using the present invention are more discrete and are of an order of magnitude smaller than the particles of Figures 9a and 9b. Similar to the results obtained in the previous example, the particle diameter is again distributed narrowly around 1 μm. Thus, the present invention produces smaller particles than the conventional process with less agglomeration, a property that is desirable, especially in the pharmaceutical industry.

EXAMPLE 3 Recrystallization of ibuprofen from a DMSO solution using the present invention in which compressed C02 is used as the energizing gas and as an anti-solvent FIGS. 11 and 11b show a pair of SEM micrographs of recrystallized ibuprofen particles from a solution of 30 mg / ml of DMSO under the same operating conditions as in example 2. Once again, the particles appear to be discrete, the particle sizes are small and, except for a fraction of microscopically sized particles, most of the particles are smaller and in the range of 0.6 μm or smaller.

EXAMPLE 4 Recrystallization of camptothecin from a DMSO solution using the present invention, in which compressed C02 is used as the energizing gas and as an anti-solvent. Camptothecin, as supplied by the supplier, appears as amorphous particles with fluctuating diameters. 1-10 μm. Figure 12 is an SEM micrograph of recrystallized camptothecin particles from a 5 mg / ml solution of DMSO under the same operating conditions as in Example 2, (ie, P = 105.4 Kg / cm2 (1,500 psig), 35 ° C, with a back pressure of C02 of approximately 7.0 Kg / cm2 (100 psig)). The particles are almost spherical and discrete. Although they are relatively large in size (5-20 μm), these particles appear to be porous. The relatively high surface area of these particles must increase their rate of dissolution and bioavailability. Figures 13a and 13b show a pair of SEM micrographs of recrystallized camptothecin particles from a 5 mg / ml solution of DMSO under the same operating conditions as in Example 1, Figures 7 and 8 (ie, P = 87.9 Kg / cm2 (1,250 psig); T 35 ° C; with a C02 back pressure of 42.2 Kg / cm2 (600 psig). Due to the expansion and higher speeds of the compressed gas (from 130.0 Kg / cm2 (1,850 psig) to 87.9 Kg / cm2 (1.20 psig) compared to 112.5 Kg / cm2 (1,600 psig) at 105.4 Kg / cm2 (1,500 psig) in the previous experiment), smaller particles are formed. As seen in Figure 13b, the particles are not agglomerated with the average diameter in the 0.5 μm range. Here, again, as in example 1, where favorable operating conditions are used, nanoparticles are produced.

Alternative modalities Note that in an alternative process, the chamber contains liquid C02 or other liquid antisolvent as opposed to supercritical C02 or another solvent in its supercritical form. In this case, the volume above the liquid phase (ie, the vapor phase) contains most of the light gas or anti-solvent which energizes the nozzle of the present invention, and the recrystallization is carried out either in the liquid phase (when a light gas is used to energize the spray nozzle) or in both phases (when an anti-solvent is used to energize the spray nozzle). In the case where the anti-solvent itself is used to energize the nozzle, the operating conditions are such that the gas 'Energization in its almost critical or supercritical state will almost reach the conditions in the recrystallization chamber after expansion through the nozzle. This alternative process is attractive for applications where the containment of the recrystallized particles in the crystallization chamber is difficult due to entrainment in the supercritical phase. The lower buoyancy of liquids compared to supercritical fluids can minimize the losses of microscopic or small nanosized particles.

OTHER APPLICATIONS FOR THE METHOD AND APPARATUS OF THE INVENTION DESCRIBED IN THE PRESENT This invention finds application in areas where the reduction in particle size to less than 1 μm is desirable for the purpose of increasing the surface area, the rate of dissolution , reactivity or bioavailability. The disclosed invention also finds application in areas where recrystallization of microparticles or nanoparticles from organic solutions is desirable. These applications can find use in the production of food, electronic equipment, explosives, pharmaceuticals or intermediates (micronization, nanonization, coating, microencapsulation, lyophilization or coprecipitation), catalysts (micronization and nanonization to increase the surface area of active sites and supports ), explosives (improved reactivity, coating (finer coatings), polymers (micronization and nanonization), pesticides (micronization, nanonization and microencapsulation) and other chemical compounds (micronization, nanonization and microencapsulation) .The anti-solvents useful in the application of this invention include, but are not limited to, C02, propane, butane, isobutane, CHF3, SF6, and N20.Organic solvents may be from either the class of aromatic hydrocarbons, alcohols, esters, ethers, ketones, amines, or hydrocarbons. nitrated or chlorinated, preferred solvents inc They contain acetone, ethanol, methanol, dichloromethane, ethyl acetate and DMSO.

Conclusion The method and apparatus of the present invention overcomes the disadvantages associated with conventional SAS processes in several ways. The high-speed front wave and / or turbulence established at the outlet of the nozzle by the energizing gas breaks the solution leaving the nozzle to a fine spray of drops. The mass transfer rate between the spray droplets and the surrounding anti-solvent phases is essentially proportional to the surface area of the spray droplets and the concentration gradients of the anti-solvent and the solute. The use of the nozzle of the present invention provides a means to improve mass transfer rates by means of an increase in spray surface area and interphase concentration gradients. One effect of creating small droplets is to increase the specific surface area of the droplets, which in turn increases the rate of mass transfer. Also, in contrast to the nozzle electrically energized, which produces a relatively low velocity spray, the compressed energizing gas passes to the atomized droplets as it enters the supercritical antisolvent at high velocity and thereby creates a turbulence, which prevents the accumulation of spent solvent in the vicinity of atomized spray. An increase in the concentration gradients between the droplet phase and the anti-solvent phase provides an increased driving force for an interface mass transfer.

Other advantages of the nozzle energized by compressed gas of the present invention with respect to other nozzles is its use for the recrystallization of solutes from organic solutions or suspensions are: 1. The relatively large size of the line through which the Solution flows through the nozzle in comparison to either capillary or microscopic orifice nozzles that allow for higher solution performance and reduce the likelihood of nozzle clogging. 2. The same fluid can be used to energize the spray nozzle as well as an anti-solvent. 3. The high velocity of the energizing gas stream imparts a high velocity to the spray droplets and consequently reduces the tendency of the droplet coalescence which can lead to the formation of larger particles. 4. The high gas velocity or energizing current of the supercritical fluid provides a buffer zone at the tip of the nozzle that is either a gas or a low density supercritical fluid. If the gas has little or no anti-solvent power, the buffer zone at the tip of the nozzle serves to retard recrystallization until secondary atomization of the spray has been obtained. This case is more attractive when highly viscous or concentrated solutions are used (almost saturated or supersaturated). If the energizing gas is itself an anti-solvent of supercritical fluid, the buffer zone is a highly turbulent zone of almost pure anti-solvent. to maximize by this the mass transfer rates between the drops and the anti-solvent, while minimizing the speed of coalescence of the drops. This case is more attractive when drugs or polymers of solutions with low concentrations of solute are recrystallized. The use of a compressed gas with intermediate anti-solvent power (that is, a mixture of light gas and anti-solvent) provides a means for controlling the interface mass transfer rates and therefore means for controlling the particle size. The teachings of all references cited herein and those cited in provisional patent application Serial No. 60 / 012,593 (identified above) and all references cited therein, are incorporated herein by reference.

Particle Coating In Examples 5-8, the coating of model core materials (1.5 mm nomparell sugar beads and 2 mm glass beads) is investigated with either a drug (hydrocortisone) or a polymer (poly (D)). , L-lactide-glycolide, RG503H) Hydrocortisone is purchased from Sigma Chemical Co., St. Louis, MO and used without further purification The polymer is purchased from Henley Co. Montvale, NJ and contains a molar ratio of 1. 1: from lacuro to glycolide and has an inherent viscosity in chloroform of 0.3 cps RG503H is approved by the FDA for administration to humans, is non-toxic, non-reactive with tissues, biodegrades to non-toxic products and is Suitable for surgical sutures Certified grade ethyl acetate and DMSO (99.9% purity, Fisher Scientific, Fairlaw, NJ), dry base C02 (99.8% purity, Genex, Kansas City) are used without further purification Recrystallized microparticles recollected ectan on glass beads or on nomparell sugar pearls. The particles that are deposited on the walls of the cells are also collected for analysis. The morphology of the particles and the uniformity of the coating are evaluated by SEM (Hitachi, Model S-570). The particle size is also estimated by SEM. The SEM samples are coated by spraying with gold / palladium alloy. Fig. 14 is a schematic view of a modified display cell used in the apparatus of Fig. 1 in the coating experiments. Specifically, the apparatus of Figure 1 was employed, except that the modified display cell 16a was used in place of cell 16. Cell 16a in the experiments was equipped with an internal glass tube 36a of 16 cm long, of 8 ml, instead of the rod 36 of figure 1, a line 20a of extension C02 leading from the orifice 20 to the bottom of the tube 36a and the capillary nozzle tube 26a extends down to a point adjacent to the open end of the tube 36a . In use, the 16 ml long 8 ml glass tube 36a is first charged with nomparell sugar beads or glass beads and then adjusted to the bottom of the display cell, as shown in figure 14. When the bath temperature is stable to a desired value, C02 is pumped through line 20a at a constant speed (typically 5 ml / minute of liquid C02) until the pressure in the cell reaches a desired level (105.45). Kg / cm2 (1,500 psi)). When the temperature and pressure in the cell are stabilized, the organic solution (solution of DMSO or ethyl acetate of the medicament and / or polymer) is dosed through the capillary tube 26a. The organic mixture and C02 are preheated to the operating temperature by passing them through heat exchangers housed together with the cell in the adjacent water bath (see Figure 1). In order to establish the countercurrent flow and fluidize the beads, as described C02 is introduced to the bottom of the tube through the line 20a of the hole while the organic solution of the coating material is sprayed from about 5.2 cm (2 inches) from the top. It is found that a minimum solution flow rate of 2.5 ml / min is necessary to consistently obtain a jet spray. Freshly prepared C02 and the organic solution are thus mixed inside the glass tube. The expansion of the solution causes the drug and / or polymer dissolved in the organic solvent to undergo nucleation and the particles to crystallize and descend through the tube. The recrystallized particles adhere either to the walls of the glass tube or are deposited on the beads. Any particle escaping the retention inside the chamber of the display cell is retained on the steel frit housed in the T-shaped fitting in the lower central hole 38 (Figure 1). A thermocouple inserted through this accessory is used to check the temperature of the cell, the mixture of C02 and depleted organic solution of medicament / polymer flows through the heated, micro-controlled valve assembly 40, controlled by motor. After expansion at a subcritical pressure (usually close to atmospheric pressure), the mixture is separated into an organic liquid phase and a gas phase of C02. The phase separation is carried out in the flash vessel 42; the organic solution flows through the microdosing valve 44 and is collected in the container 46. Then the solution is analyzed in terms of the drug and polymer content. The C02 is vented through a second micro-dosing valve 48, the rotameter 59 and a flowmeter 50 of electronic mass (all as shown in Figure 1). After the flow of the organic solution is stopped, the flow of C02 is continued for another 1-1 / 2 hours in order to wash any organic solvent remaining in the cell and to dry the collected particles. It is found that the C02 flowing at 105.4 Kg / cm2 (1,500 psig) for 1-1 / 2 hours (approximately seven times the volume of the display cell) is suitable for washing the organic solvent present in the cell and for drying of the particles. It is observed that no recrystallized particle can be recovered when the drying periods are less than one hour. In this case, the particles adhering to the walls of the tube are redissolved in the organic solvent during the reduction of the pressure as the organic solvent condenses from the C02 phase. Clearly, an increase in the flow rate of C02 will reduce the drying time required; The flow rate of C02 can also be set high enough, so that the coating process can be put into operation continuously while maintaining the steady state concentration of the solvent in the coating chamber at a level sufficiently low that the mixture is always supercritical and no condensation of the solvent is carried out in the coating chamber. Following the drying period, the pressure is reduced to the atmospheric level at a rate of 3.5 Kg / cm2 (50 psig / min). The coated beads are discharged from the glass tube and analyzed by scanning electron microscopy (SEM).

Equipment and experimental procedures for examples 5-8 Example 5 Coating of nomparell sugar beads and glass beads with RG503H nomparell sugar beads and glass beads 1. 5 mm and 2 mm in diameter respectively, are first charged to an 8 ml glass tube 16 cm long. Then, the tube is equipped at the bottom of the display cell (figure 14) and the cell is brought to operating pressure with C02. Then, a 10 mg / ml solution of ethyl acetate of RG503H is pumped into the glass tube for 5 minutes. In order to establish the countercurrent flow and fluidize the beads, the C02 is introduced into the bottom in tube while the suspension is introduced from 5.1 cm (2 inches) above. The capillary nozzle internal diameter, temperature, pressure, solution flow rate and C02 velocity were 100 μm, 35 ° C, 105.4 kg / cm2 (1,500 psig), 2.5 cc / min and 5 ml / minute of liquid C02 cooled respectively. Figure 15 is a micrograph of an uncoated nomparell bead. Figures 16 and 17 show micrographs of a resulting coated nomparell bead and glass beads respectively. The nomparell bead is almost uniformly coated with a layer of the majority of RG503H microspheres. The coating on the glass bead is less uniform possibly due to its larger size which reduces its mobility within the glass tube. The recrystallized microspheres (Figure 16) are of similar size (approximately 10 μm) to those obtained in runs at identical conditions with the same solution in the absence of the beads (see Table 1). In this experiment, restricting the expansion to a level within the glass tube and reducing the efficiency of the atomization process by pumping the solution into a relatively small volume glass tube causes the solution to expand as a pseudo-liquid phase instead of a micro-droplet phase. Thus, the recrystallized polymer microparticles were not entrained in the SCF, and were able to coat the beads. As evidence of this observation, there is the fact that after the separation of the glass tube from the display cell, only the lower half of the tube visibly contains polymer particles. The upper half, which was not reached by the solution after expansion, appears polymer-free. The operation under conditions of higher flow rates of C02 (25 cc / minute, as liquid) to improve the efficiency of the atomization stage eliminates the formation of the expanded liquid phase, but few coatings are deposited on the beads due to the entrainment of the recrystallized polymeric microparticles by the high-speed SCF to the display cell, outside the glass tube, thereby reducing their likelihood of contacting the beads. The entrainment of microparticles away from the region where the core material is confined can be avoided by eliminating the use of the glass tube and loading the core particles throughout the display cell. Alternatively, the use of a modified cell approaching a Wurster coating apparatus would provide suitable conditions for the distribution of the anti-solvent, solution or suspension, and substrate within the coating chamber.

EXAMPLE 6 Effects of concentration on coating nomparell sugar beads with RG503H In this study, a 35 mg / ml solution of RG503H in ethyl acetate is recrystallized under the same conditions as in example 6. Figure 18 is a SEM micrograph of a nomparell coated bead. The coating is less uniform than on the coated beads as described in example 5 using a 10 mg / ml ethyl acetate solution of RG503H. 'The increase in concentration seems to increase the size of the recrystallized particles and reduce the uniformity of the coating. The increase in the size of the recrystallized microparticles also observed in the absence of the beads.

EXAMPLE 7 Effects of temperature on the coating of nomparell sugar beads with RG503H Figure 19 shows a SEM micrograph of nomparell sugar beads coated with recrystallized RG503H under the same conditions as in example 6, except that the cell temperature display was maintained at 40 ° C. Under these conditions, it is seen that the polymer is deposited on the sugar beads as a continuous film. Thus, a small increase in temperature (from 35 ° C to 40 ° C) may be sufficient to change the texture of the coating layer. The agglomeration of the beads can be avoided by improving the conditions under which fluidization is carried out. Alternatively, the use of a modified cell that approximates a Wurster coating apparatus would provide appropriate conditions for the distribution of the anti-solvent, the solution or suspension and the substrate within the coating chamber.

EXAMPLE 8 Coating of Glass Beads with Hydrocortisone Figure 20 shows a micrograph of a glass bead collected from a run wherein a suspension of hydrocortisone in ethyl acetate was sprayed on C02 when using the capillary nozzle. This suspension is prepared by filtering a 10 mg / ml suspension of hydrocortisone in ethyl acetate filtered through a 2 μm porosity paper. The 16 ml long 8 ml glass tube is first loaded with 1 gram of glass beads of approximately 2 mm diameter and then adjusted to the bottom of the display cell. The temperature, pressure, flow velocity of the solution and operating flow rate of C02 were 35 ° C, 105.4 Kg / cm2 (1,500 psig), 2.5 ml / min of liquid C02 respectively. The suspension was pumped for five minutes. As illustrated in Figure 20, the beads can be coated almost uniformly with a thin film of hydrocortisone. The formation of a film, as opposed to microparticles, was expected since the studies of those of the researchers referred to previously, indicate that an implement at the saturation level of the organic solution with concentration leads to the formation of amorphous particles with agglomerate to form films and porous structures.

Alternative Modes Due to its environmentally benign nature compared to alternative organic solvent based coating processes and its greater potential for forming thin film coatings, the present coating process provides an attractive alternative to the electrostatic coating spray technique. dust. The present process also provides an alternative to the Wurster coating technique. Alternatively, the core materials can be poured to a conveyor belt disposed in a high pressure C02 chamber, while a solution or suspension is sprayed continuously onto the core materials. Another alternative is to use this process to coat objects larger than drug tablets or pesticide granules. Because recrystallization can occur almost as soon as the spray leaves the nozzle in the SAS process, a technique can be employed whereby a nozzle bars the surface of the object and the microparticles quickly deposit on the surface on the surface. which nozzle sprays the solution. This process can be particularly useful for efficiently painting large surfaces. Another alternative is to cover a large object by simply expanding the spray of the solution onto a chamber containing the object without necessarily sweeping the surface of the object. Adhesives or plasticizers should alternatively be added to the organic solution to facilitate adhesion of the recrystallized particles to the surface of the substrate or to improve the physical properties of the coating. Excipients such as colorants may also be added to the organic solution to improve the aesthetic or functional properties of the coating.

Other applications for the coating method and apparatus This invention finds application in all areas where the coating of particles by recrystallization of the cover material of an organic phase is desirable. These applications may find use, but are not ted to, the coating of: pharmaceutical tablets; granules, pellets or capsules; pesticides; fertilizers; catalysts; seeds; you go out; circuit boards; wires, containers and covers. Anti-solvents useful in the application of this invention include, but are not ted to, C02, propane, butane, isobutane, CHF3, SF6 and N20. The organic solvents can be either of the class of aromatic hydrocarbons, alcohols, esters, ethers, ketones, amines or nitrated or chlorinated hydrocarbons. Preferred solvents include acetone, methanol, ethanol, propanol, isopropanol, dichloromethane, ethyl acetate and DMSO. Combinations of these solvents can also be used. Coating materials useful for this application include sugars, polymers such as poly-lactide glycolide (PLGA) copolymers, PLA, PGA, polyvinylpyrrolidine, polyethylene glycols and methacrylic acid ester. The largest group of film-forming resins are cellulose ethers, especially hydroxypropylmethylcellulose. Other cellulose ethers include hydroxypropylcellulose, methylhydroxypropylcellulose, methylcellulose and ethylcellulose. Plasticizers may also be added to the coating solution or suspension if the properties of the controversial coating are not appropriate. These plasticizers are used to modify the properties of the coating material by means of a reduction in its glass transition temperature. This can result in a coating that is less brittle, softer and more resistant to mechanical stress. Plasticizers can also decrease the permeability of the film to moisture and improve the stability of the product. Common plasticizers include, but are not ted to, phthalate esters, castor oils, acetylated monoglycerides, triacetin, glycerin, propylene glycol, and polyethylene glycols. Dyes such as dyes and pigments, including iron oxides and titanium dioxide, can also be added to improve the aesthetic appearance or physical properties of the coating.

Lipophobic precipitation In examples 9-12, the lyophobic precipitation of drugs (hydrocortisone), phenytoin, ibuprofen) is investigated in containers. Hydrocortisone, phenytoin and ibuprofen are purchased from Sigma Chemical Co. , St. Louis, MO and are used without further purification. Acetone certified grade, DMSO (99.9% purity, Fisher Scientific, Farilawn, NJ) and dry C02 (99.8% purity, Air Products, Lenexa) are used. The apparatus of Figure 1 was employed in Example 9, except that the display cell 16 was modified, it was equipped with a 15 cm long glass tube sealed at one end with a 4 μm frit. The tube resembles a specialized container for the purposes of these experiments. For examples 10, 11 and 12, the apparatus of figure 1 was employed, except that the display cell 16 was replaced by the 95 ml display cell 16b of figure 21. Cell 16b was equipped with two lines of carbon dioxide input Ci and C2, each, has a corresponding valve Vi and V2 interposed therebetween; the valves were in turn coupled to a common source of C02 as shown in figure 21. The display cell 16b was also equipped in these examples with borosilicate tubes Tu of 12 x 75 mm which resemble containers of use final. As illustrated in Figure 21, the line Ci of C02 extends downwardly from the interior of the tube Tu below the level of the liquid therein.

Example 9 Batch precipitation of hydrocortisone from a 200 mg / ml solution of DMSO is undertaken. An aliquot of 1 cc of solution is pumped into the fritted glass tube positioned inside the display cell 16. The pressure and temperature are maintained at 110.7 Kg / cm2 (1, 575 psig) and 31 ° C. Twelve standard liters of C02 are introduced from the lower end of the tube and through the frit to expand the solvent and recrystallize the drug. Following this expansion period, 300 standard C02 liters are introduced from the upper end of the glass tube to "push" the expanded solution out of the tube through the glass frit and to dry the particles for one hour. This method is attractive because it provides a means to rapidly expand the solution and recrystallize the medicament, while preventing the solution from expanding on the upper rim of the glass tube (or dispensing vessel).

Example 10 1 ml of a 24.1 mg / ml solution of pheitone in acetone is transferred to the borosilicate tube. The tube is placed in the display cell 16b of Figure 21. Line Ci extends through the phenytoin solution to the bottom of the borosilicate tube Tu. The cell is rapidly pressurized to a pressure of 56.2 Kg / cm2 (800 psig) with C02 at 40 ° C through line C2. It is noted that the introduction of C02 via line Ci must be slow enough to prevent forced ejection of the solution. Therefore, the initial pressurization can be carried out more quickly by using line C2. Following the initial pressurization, valve V2 is closed and C02 is introduced through line Ci at 20 g / minute for 9 minutes. The solution expands and it is observed that the medicine is precipitated. When the expanded solution reaches the top of the borosilicate tube, the flow rate of C02 on the Ci line is decreased to 4.5 grams / minute to minimize the loss of drug as the expanding solvent overflows to the top of the tube test. After 8 minutes, the pressure inside cell 16b reaches 91.4 Kg / cm2 (1,300 psig). The introduction of total C02 by bubbling through the Cx line is 200 g. Then, the cell is depressurized and the borosilicate tube containing the product is recovered.

The precipitated phenytoin (Figure 22b) is compared to the starting material (Figure 22a) by Differential Scanning Calorimetry (DSC) and is found to exhibit consistent enthalpic transitions with the starting material.

Example 11 1 ml of a 30 mg / ml solution of ibuprofen in DMSO is transferred to the borosilicate tube. The tube is placed in the display cell 16b of Figure 21. Line Ci extends through the ibuprofen solution to the bottom of the borosilicate tube. The cell is rapidly pressurized to 43.6 Kg / cm2 (620 psig) with C02 at 40 ° C through line C2. The valve V2 on the line C2 is closed and then C02 is introduced through the line C? ° flow rate fluctuating between 9 and 36 grams / minute. The solution expands and it is observed that the drug precipitates. When the expanded solution reaches the top of the silicate tube, the flow rate of C02 on the Ci line is decreased to 0.9 g / min for 12 minutes. It is observed that no solvent remains in the test tube. The precipitate is observed on the walls of the tube. This is an introduction of total C02 by bubbling through the Ci line of 125 grams. Then, the flow increases in the Cx line at 18 g / min, for 1.5 minutes. The cell is depressurized and the tube containing the product is recovered.

Example 12 1 ml of a 12.6 mg / ml solution of phenytoin in acetone is transferred to the borosilicate Tu tube. The tube is placed in the display cell of Figure 21. The display cell 16b is placed in a solid state ultrasonic bath (Fisher Scientific). The cell is rapidly pressurized to 63.3 Kg / cm2 (900 psig) with C02 at 40 ° C through line C2. The ultrasonic bath is energized to produce ultrasonic energy at 43 KHz. After one hour, the solution had expanded to three times its initial volume and it is observed that the drug precipitates. After depressurization, the precipitated drug is redissolved in acetone. To continue with the processing, as described or by direct sonication of the drug solution container, would ultimately result in the isolation of the solid medicament. It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (17)

1. Claims 1. A process for the precipitation of small particles, characterized in that it comprises the steps of: providing a fluid dispersion including a continuous phase dispersant with at least one substance to be precipitated dispersed in the dispersant; and contacting the dispersion with an anti-solvent in a precipitation zone at near critical or supercritical conditions for the solvent and causing the substance to precipitate and form small particles, the anti-solvent, is miscible with the dispersant, the substance is substantially insoluble in the In an solvent, the contacting step comprises the steps of: passing the fluid dispersion through a first passage and a first passage exit to the precipitation zone containing the antisolvent; passing an energizing gas stream along a second passage and through a second outlet of the passage close to the first outlet, the passage of the energizing gas stream through the second outlet generates high frequency sonic waves of the energizing gas adjacent to the first outlet of the passage, to break the fluid dispersion into extremely small drops; and causing the antisolvent within the precipitation zone to deplete the dispersant and precipitate - the small particles of the substance.
2. 2. The process according to claim 1, characterized in that the dispersion consists of a solution, the dispersant is a solvent and the substance is a solute dissolved in the solvent.
3. 3. The process in accordance with the claim 1, characterized in that the conditions during the contacting step are about 0.7-1.4 T and about 0.2-7 Pc of the antisolvent. 4. The process according to claim 1, characterized in that the dispersant and the anti-solvent are essentially completely miscible in all proportions thereof. 5. The process according to claim 1, characterized in that the dispersant comprises at least about 50% by weight of the dispersion. 6. The process according to claim 1, characterized in that the energizing gas is the same as in the antisolvent. The process according to claim 1, characterized in that the antisolvent is selected from the group consisting of carbon dioxide, propane, butane, isobutane, nitrous oxide, sulfur hexafluoride and trifluoromethane. The process according to claim 1, characterized in that it includes the step of generating high frequency waves of energizing gas at a frequency of at least about 0.5 KHz. 9. The process according to claim 1, characterized in that it includes the step of causing the depletion of the dispersant and the precipitation of particles, to obtain particles having an average diameter of approximately 0.1-10 μm. 10. A process for coating core particles with a desired substance, the process is characterized in that it comprises the steps of: spraying a fluid dispersion to an enclosed precipitation zone containing an amount of anti-solvent at near critical or supercritical conditions for the anti-solvent, the fluid dispersion includes a continuous phase dispersant with the desired substance dispersed therein, the antisolvent is miscible with the dispersant and the substance is substantially insoluble in the antisolvent; creating a turbulent fluidized flow of the core particles within the precipitation zone, by placing a quantity of the core particles within the precipitation zone and passing a stream of fluidizing gas comprising the anti-solvent to the precipitation zone; and causing the antisolvent to deplete the dispersant and precipitate the substance on the fluidized core particles. 11. The process according to "claim 10, characterized in that the conditions during the contacting step are about 0.7-1.
4. 4 Tc and about 0.2-7 Pc of the anti-solvent. The process according to claim 10, characterized in that the spraying step comprises the steps of passing the fluid dispersion through a first passage and a first passage exit to the precipitation zone and passing a gas stream of energization along a second passage and through a second outlet of the passage, close to the first outlet, the passage of the energizing gas stream through the second outlet generates high frequency waves of the energizing gas, adjacent at the first exit of the passage to break the fluid dispersion into extremely small drops. 13. A process for preparing and administering a medication to a patient, characterized in that it comprises the steps of: providing a container for use for the medication; contacting, within the use container, a fluid dispersion including a. dispersant with the drug dispersed therein and a solvent at near critical or supercritical conditions for the anti-solvent and causing the anti-solvent to precipitate the drug from the dispersion as small particles; separating the antisolvent from the container of use and sealing the container of use with the medicament particles therein; and extracting at least one dose of the medication from the use container and administering the dose to the patient. 14. An improved process for the production of particles, the process comprises the step of spraying a solution that includes at least one solvent and at least one solute through a nozzle to an anti-solvent, the improvement is characterized in that it comprises the steps of: generating atomized drops of the solution; and contacting the droplets with the anti-solvent to produce particles having an average diameter of 0.6 μm or less. 15. An improved process for the production of particles, the process comprises the step of spraying a solution that includes at least one solvent and at least one solute through a nozzle to an anti-solvent, the improvement is characterized in that it comprises: combining the solution with a compressed fluid to produce a solution; passing the mixture through a nozzle to produce atomized drops of the mixture; and contacting the drops with the anti-solvent to produce the particles. 16. An improved process for the production of particles, the process comprises the step of spraying a solution that includes at least one solvent and at least one solute through the nozzle to an anti-solvent, the improvement is characterized in that it comprises: the solution with a compressed fluid to produce a mixture; passing the mixture through a nozzle to establish a wave front at the outlet of the nozzle, the wave front produces atomized drops; and contacting the drops with the anti-solvent to produce the particles. 17. A method for producing particles, the method is characterized in that it comprises the steps of: providing a solution that includes at least one diluent and at least one solute; provide an anti-solvent; provide a compressed fluid; provide a nozzle to atomize the solution, the nozzle has; a first inlet for receiving the solution, a second inlet for receiving the compressed fluid, an outlet, and means configured to receive and combine the solution and the compressed fluid of the first and second inlets respectively; introducing the solution and the compressed fluid to the first and second inlets of the nozzle, respectively, to produce a mixture; eject the mixture through the outlet of the nozzle to produce atomized drops; contacting the drops with the compressed fluid outside the outlet of the nozzle, to cause depletion of the solvent of the drops; and contacting the drops with the antisolvent to cause additional solvent exhaustion of the droplets to produce the particles.