Giuseppe Caputo

Pilot scale micronization of amoxicillin by supercritical antisolvent precipitation

The supercritical antisolvent precipitation (SAS) process has been frequently applied to pharmaceutical compounds, due to its potential capacity to control particle size (PS) and distribution and the simple separation and recovery of the solvent and of the antisolvent. However until now, the SAS process has been performed prevalently in laboratory scale apparatus; therefore, process limitations that are significant on the large scale, have not been studied yet. These limitations may even lead to the failure of translating the process to commercial dimensions. Herein we report the results of SAS precipitation of Amoxicillin from N -methylpyrrolidone performed in a semi-continuous pilot plant equipped with a 5 dm 3 precipitator, operated at 40 8C and 150 bar. Non coalescing spherical microparticles were obtained with mode diameters ranging from 0.3 to 1.2 mm depending on the concentration of Amoxicillin in the liquid solution. The effect of the scale enlargement and of the kind of injection device on the powder size and morphology has been investigated and a comparison with laboratory scale results is also presented. The change of nozzle arrangement and diameter from the laboratory to the pilot scale does not affect significantly the PS and distribution of Amoxicillin. # 2002 Elsevier Science B.V. All rights reserved.

Synthesis of titanium hydroxide nanoparticles in supercritical carbon dioxide on the pilot scale

Abstract Titanium tetra-isopropoxide (TTIP) hydrolysis in supercritical carbon dioxide (SC-CO 2 ) was performed using a continuous pilot plant with an internal volume of 5 dm 3 , operated at mild pressure conditions (8–14 MPa) and in the temperature range 40–60xa0°C. Preliminary to reaction experiments, some tests on TTIP solubility in SC-CO 2 were performed. TTIP solubility varies from 1.5 to 3.0% (w/w) in the range 40–60xa0°C and for pressures between 10 and 15 MPa. Titanium hydroxide nanospheres with a diameter ranging from about 70 to 110 nm and surface areas larger than 300 m 2 g −1 were obtained. The influence of the process temperature and pressure on particle morphology, particle size and surface area was studied.

Production of cromolyn sodium microparticles for aerosol delivery by supercritical assisted atomization.

The purpose of this study was to produce cromolyn sodium (CS) micrometric particles with controlled particle size (PS) and PS distribution (PSD) suitable for aerosol delivery, using a supercritical fluids-based process. CS was micronized using the supercritical assisted atomization (SAA) technique at different solute concentrations in water and different precipitation temperatures. Two techniques were used to measure PS and PSD of produced particles: scanning electron microscopy image analysis and laser scattering analysis. The 2 techniques were compared to provide a complete description of the powder obtained. High-performance liquid chromatography analysis was used to verify the absence of degradation of CS after micronization; differential scanning calorimetry, thermogravimetric analysis (TGA), and X-ray analysis were performed to study the effect of operative conditions on the crystalline structure and on the water content of SAA micronized particles. The CS particles obtained were spherical, with a volumetric percentage of particles with a diameter ranging between 1 and 5 µm of 50% to 66%. The precipitation temperature had no significant effect on PSD, but high drying temperatures led to product degradation. Increasing the concentration of CS in water solution produced an increase in PS of the micronized particles. TGA showed that the micronized CS had a different hydration state than the untreated CS did. The micronized product was stable after 12 months of storage, and no modifications in structure, morphology, or crystallinity were detected. In conclusion, SAA is an efficient technique for micronization of CS, and stable spherical amorphous particles suitable for aerosol delivery can be produced.

Supercritical Assisted Atomization: Polyvinylpyrrolidone as Carrier for Drugs with Poor Solubility in Water

Supercritical assisted atomization (SAA) is an efficient technique to produce microparticles and composite microspheres formed by polymers and pharmaceutical compounds. In this work polyvinylpyrrolidone (PVP) was proposed as carrier for pharmaceutical compounds that show a poor solubility in water medium. Indeed, this polymer is hydrosoluble and can be generally used to enhance the dissolution rate of hydrophobic compounds when finely dispersed in it. However, it is difficult to obtain coprecipitates with a uniform dispersion of the active molecule using other micronization techniques. The experiments were performed using ethanol as solvent; SAA plant was operated at 40°C and 76 bar in the saturator and 70°C and 1.6 bar in the precipitator. Three different dexamethasone/polymer weight ratios were selected: 1/2, 1/4, and 1/8. Produced composite particles showed a regular, spherical shape and a mean diameter ranging from about 0.8 to 1u2009μm, depending on the polymer/drug weight ratio. Dissolution analysis demonstrated that microparticles containing a lower drug amount show a higher dissolution rate.

Gamma radiation induced polymerization of vinyl monomers in dense CO2

Abstract The dispersion polymerization of methyl methacrylate in dense carbon dioxide, initiated by γ-rays, utilizing different polysiloxanes as polymeric stabilizers, was investigated. The progress of the reaction, as a function of the irradiation dose, was also studied and the occurrence of a gel effect has been detected. For comparison, the dispersion polymerization has been carried out in supercritical conditions ( T =65°C and 38xa0MPa) in the presence of 2,2′-azobis(isobutyronitrile) (AIBN) as initiator. High molecular weight polymer (M w > 1000 kg/mol) with narrow molecular weight distribution has been obtained both with γ-rays and AIBN. The electron scanning micrographs show that regular spherical particles (average diameter ca. 2.5xa0μm) with narrow particle size distribution have been obtained through the dispersion polymerization mechanism in CO 2 .

Fixed Bed Adsorption of Drugs on Silica Aerogel from Supercritical Carbon Dioxide Solutions

Supercritical adsorption coupled with the high adsorption capacity of silica aerogel allows the preparation of a new kind of delivery systems of poor water soluble drugs. In order to overcome drawbacks of conventional techniques where the use of liquid solvents can cause the fracture of aerogel porous structure, in this work a new adsorption process of drugs from a supercritical mixture is proposed. Adsorption takes place from a fluid solution of the drug in supercritical CO2 and ethanol as cosolvent. A fixed bed adsorption plant has been developed to allow fast mixing of fluid phase and effective contact in the adsorption column. The use of ethanol as cosolvent allows to overcome the limitation of supercritical adsorption due to low solubility of many drugs in supercritical CO2. Adsorption isotherms were measured for one-model substance, nimesulide, at 40°C, and breakthrough curve was experimentally obtained. The drug loading of the drug into silica aerogel was up to 9u2009wt%. The drug composite was characterized using scanning electron microscopy, and release kinetics of the adsorbed drug were also evaluated by in vitro dissolution tests. The dissolution of nimesulide from loaded aerogel is much faster than dissolution of crystalline nimesulide. Around 80% of nimesulide dissolves from the aerogel within 6 minutes, whereas dissolving 80% of the crystalline drug takes about 90u2009min.

Advances and Perspectives of Supercritical Fluid Technology

1 Dipartimento di Ingegneria Industriale, Universita di Salerno, Salerno, 84084 Fisciano, Italy 2 Departamento de Ingenieŕia Quimica, Universidad de Castilla-La Mancha, 13004 Ciudad Real, Spain 3 Department of Agricultural, Food & Nutritional Sciences, University of Alberta, Edmonton, AB, Canada T6G 2P5 4Dipartimento di Ingegneria Chimica, Gestionale, Informatica, Meccanica, Universita di Palermo, 90128 Palermo, Italy