Valentina Prosapio

Control of Powders Morphology in the Supercritical Antisolvent Technique Using Solvent Mixtures.

The supercritical antisolvent process (SAS) has been frequently used to obtain microparticles and nanoparticles. The fluid dynamics of the process related to the study of the liquid jet in contact with supercritical carbon dioxide (scCO2) is characterized by a one-phase mixing at supercritical conditions and a two-phase mixing at subcritical conditions. The transition between the two kinds of mixing can be measured in terms of amplitude of the corresponding pressure range; some organic solvents, like dimethylsulfoxide (DMSO) are characterized by a wide pressure range, other solvents, like acetone (AC), by a narrow pressure range. Generally, microparticles are precipitated by atomization, droplets formation and drying in the transition range, whereas nanoparticles are precipitated in correspondence of completely developed supercritical conditions. Mixing a wide-transition solvent, like DMSO, to a narrow-transition solvent, like acetone, the pressure range of the transition from one-phase mixing to two-phase mixing and, accordingly, the morphology of the precipitates will change. In this work, two model compounds were SAS processed from DMSO/AC mixtures: cellulose acetate, which is slightly soluble in DMSO and freely soluble in acetone with the aim of obtaining microparticles and polyvinylpyrrolidone (PVP) that is slightly soluble in acetone and freely soluble in DMSO in order to obtain nanoparticles. In the case of cellulose acetate, well-defined microparticles with a mean diameter of 0.42 μm were obtained, whereas, for PVP, nanoparticles with a mean diameter of 114 nm were precipitated, demonstrating that this SAS strategy is successful.

Supercritical Antisolvent Process: PVP/Nimesulide Coprecipitates

Nimesulide (NIM) is an anti-inflammatory drug, widely used in the treatment of acute pain associated with different diseases. A major limitation in its usage is due to its reduced solubility in water; therefore, large doses are required to reach the therapeutic level, with consequent undesired effects on patient’s health. In order to improve NIM dissolution rate, a possible solution is represented by its micronization. Traditional micronization techniques show several drawbacks: lack of control over the particle morphology and particle size distribution, large solvent residues and use of high temperatures. An alternative to conventional techniques is represented by supercritical carbon dioxide (scCO2) based processes. In particular, nanoparticles and microparticles of different kind of materials were successfully obtained by supercritical antisolvent (SAS) precipitation. However, when processed using SAS, nimesulide precipitated in form of large crystals or it is completely extracted by the mixture solvent/antisolvent. A solution to this problem can be the production of drug-polymer composite microspheres, using a water soluble polymer in which the drug is entrapped. In this work, NIM coprecipitation with polyvinylpyrrolidone (PVP) is proposed on pilot scale. The effects of polymer/drug ratio, concentration, pressure and temperature were investigated to identify successful operating conditions for SAS coprecipitation. Microparticles with a mean diameter ranging between 1.6 and 4.1 µm were successfully produced. Drug release analyses revealed that NIM dissolution rate from PVP/NIM microparticles was 2.5 times faster with respect to unprocessed drug. The possible precipitation mechanisms involved in the process were discussed.

Analysis of Mechanisms for PVP-Active-Agent Formulation as in Supercritical Antisolvent Spray Process

Supercritical antisolvent technology can precipitate polyvinylpyrrolidone (PVP) particles and crystallize paracetamol (PCM) crystals first separately and then together in the form of a solid dispersion. Supercritical carbon dioxide (scCO2) is used as an antisolvent. For PVP particle generation, ethanol, acetone, and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 and 5 wt%, the operation pressure between 10 and 30 MPa, and the composition of ethanol/acetone solvent mixtures between 100 and 0 wt% of ethanol at a constant temperature of 313 K. An increase in the content of the “poor” solvent acetone in the initial solution leads to a significant decrease in mean particle size. Fully amorphous PVP powder always precipitates for all the parameters investigated.