Supercritical Antisolvent Process: PVP/Nimesulide Coprecipitates

Abstract

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.