(612e) Particles Formulation Using PGSSTM Process

PGSS^TM micronization and formulation process: Conventional well-known processes for particle-size re-distribution of solid materials in pharmaceutical industry are crushing and grinding, air micronization, sublimation, and recrystallization from solution. Applying supercritical fluids may overcome the drawbacks of conventional processes. For production of particles with micron and submicron size, several methods using supercritical fluids like RESS and GASR, GASP, SAS/PCA/SEDS, SAA, UNICARB?, VAMP?, PGSS^TM are studied. Powders and composites with special characteristics can be produced. In details PGSS^TM (Particles from Gas Saturated Solutions) process co invented by author of this manuscript (USP 6,056,791) for the formation and formulation of fine particles will be presented. In this process melts, solutions, emulsion or suspensions are intensively mixed with compressed gas ? most frequently the gas is carbon dioxide. In PGSS? process the substance or the mixture of substances to be powderized must be converted into a spray-able form by liquefaction/dissolution. This can be achieved by melting or/and dissolving of the substance or mixture of substances in a liquid solvent, or by dispersing solids or liquids in a melt or solution, and saturation of the melt/solution/dispersion with the gas. Thus, viscosity and surface tension is lowered to such extent that low and high viscous fluids can be sprayed in a nozzle forming fine droplets. Then the gas-containing solution is rapidly expanded in an expansion unit and the gas is evaporated. Due to the Joule-Thomson effect and/or the evaporation and the volume-expansion of the gas effects, the solution cools down below the solidification temperature of the solute the supersaturation is extremely high. In this way, fine particles are obtained, where the morphology, particle size, particle size distribution and crystallinity (various polymorphs) can be adjusted with operating process parameters. The formed powder is separated and fractionated from the gas stream by a cyclone and electro-filter. When the liquefaction is achieved by melting, the knowledge of the Pressure (P)-Temperature (T) trace of the Solid-Liquid-Vapor (S-L-V) equilibrium gives information on the pressure needed to melt the substance to be micronized and form a liquid phase at a given temperature, and to calculate its composition. When the supercritical fluid has a relatively high solubility in the molten heavy component, the S-L-V curve can have a negative dP/dT slope. The second type of three-phase S-L-V curve shows a temperature minimum. In the third type, where the S-L-V curve has a positive dP/dT slope, the supercritical fluid is only slightly soluble in the molten heavy component, and therefore the increase of hydrostatic pressure will raise the melting temperature and a new type of three-phase curve with a temperature minimum and maximum may occur. In general, for substances for which the liquefaction is achieved by melting, a system with a negative dP/dT slope and/or with a temperature-minimum in the S-L-V curve could be processed by PGSS?. For other system for example PGSS^TM drying of solutions or suspension the mass of gas necessary for evaporation of solvent is very important. The PGSS? process was tested in the pilot- and technical size on various classes of substances. Up to the present time the application of the PGSS? process has been investigated for polymers, waxes and resins, natural products, fats and fat derivatives, pharmaceuticals, synthetic and natural antioxidants, surface-active compounds, UV-stabilizers, composites of the mentioned substances, etc. The highly compressible fluids which have been used were carbon dioxide, propane, butane, dimethyl ether, freons, nitrogen, alcohols, esters, ethers, ketones and mixtures of above-mentioned gasses and solvents. The powders produced show narrow particle-size distributions, and have improved properties compared to the conventional produced powders. The material structure of the substance to be micronized (crystalline-amorphous, pure or composite), the process parameters (pre-expansion pressure, temperature, gas to substance ratio(GSR), viscosity of melt/solution/dispersion) of the PGSS? process and geometry of the process equipment influences particle size, particles size distribution, bulk density, the morphology (particle shape) and ratios crystalline/amorphous of the processed substances. PGSS^TM process enables also the production of solid composite particles with up to 50% by weight of liquids. Based on the process parameters the solids can have an open or closed structure.

Micronization of pharmaceuticals by PGSS^TM process: In details micronization and formulation of pharmaceuticals - practically water-insoluble calcium antagonists (dihydropyridine calcium-channel blockers) will be presented in details. The active ingredient (AI) was processed by the PGSS^TM process, with the aim to increase dissolution rate and enhance bio availability. Using the PGSS? process, pure AI was micronized at various pressures in the range from 100 to 200 bar and at temperatures 165, 175 and 185°C. The mean particle-size of the starting AI was 50 µm, and it was decreased to 15-30µm, depending on the experiments process conditions. The resulting particle size distribution was also function of the process conditions. With increasing pre-expansion pressure the mean particle-size was reduced and, as a result, the dissolution rate was found to be higher for samples prepared at higher pre-expansion pressures. The shape of the micronized particles was irregular and, according to scanning electron microscopy pictures, it was assumed that the particles were porous. With particle-size reduction and therefore increased specific surface area (external and internal) the dissolution rate increased to some extent, but the anticipated effective surface area was probably reduced by the drug's hydrophobicity and agglomeration of the particles during and after micronization. From studies on formation of fine particles of several other pharmaceutical substances it is evident that the reduction of particle size in many cases does not increase the solubility. In some cases it could even decrease the dissolution rate due to reduced wet ability of small particles. These effects could be overcomed by formation of composites that enhances dissolution rate and therefore bio availability. In order to avoid agglomeration of micronized particles, and thermal degradation of AI at high temperatures (175 and 185°C), the hydrophilic polymer was added to AI to reduce its melting point. It was found that eutectic mixture for system polymer/AI is at mass ratio 80:20 at temperature 58°C. Micronization at pre-expansion temperatures between 50 and 70°C was possible and fine powdered co-precipitates of AI/polymer were obtained. The dissolution rate of formed composite powder was much higher as that for pure micronized AI.

Conclusion: The removal of solvent from a product is a problem of conventional co-precipitation or co-evaporation techniques where large amounts of organic solvents are needed and in which complete removal is often a long and difficult process. With the PGSS? process, micronized drug or micronized drug/carrier can be obtained in single step without organic solvent. Through the choice of the appropriate combination of supercritical solvent and operating conditions for a particular compound, PGSS? can eliminate some of the disadvantages of traditional methods of particle-size redistribution in material processing. Solids formation by PGSS? therefore shows potential for the production of crystalline and amorphous powders with a narrow and controllable size-distribution, thin films, and mixtures of amorphous materials. Due to the low processing costs PGSS? can be used not only for highly valuable, but also for commodity products. One goal of RESS/CSS, the anti-solvent processes such GAS/SAS, and the PGSS? process, is to obtain submicron- or micron-sized particles. Although several features concerning RESS and GAS-processes scale-up are not yet very well known, it is probable that these processes are, or may be, used for producing relatively small amounts of high-value-added substances. Restrictions arising from the difficult product- and gas-recovery in the RESS and GASR, GASP, SAS/PCA/SEDS processes are avoided by the PGSS? process. The PGSS? process has several advantages, which favor its use for large-scale applications. This process has promise for the processing of low melting, highly viscous, waxy, and sticky compounds, even if the obtained particles are not of submicron size. The process already runs in plants with a capacity of some hundred kilograms per hour. New possibilities for generation of particles and composites based on PGSS? processes are: ? microfoam particles, ? powderization of reactive compounds and immiscible substances, ? powderous liquids, ? powderous emulsions.

The specific properties of dense gasses allow obtaining fine dispersed solids, especially of substances with low melting point temperatures, high viscosity and very waxy or sticky properties. Economic evaluation of the process shows that these compounds cannot be efficiently and economically processed by conventional mechanical processes and there is a big advantage of the use of super critical fluids.