Producing In-Situ Nanoparticles of Griseofulvin using Supercritical Antisolvent Methodology

Abstract

Poor aqueous solubility of drug candidates is a major challenge for the pharmaceutical scientists involved in drug development. Particle size reduction to nano scale appears as an effective and versatile option for solubility improvement. Unlike the traditional methods used for the particle size reduction, supercritical fluid (SCF) processing techniques offer advantages ranging from superior particle size control to clean processing. Amongst all of the SCF based techniques, supercritical antisolvent (SAS) processing is of particular interest because most pharmaceuticals, including the model drug for this study-griseofulvin, are insoluble in supercritical carbon dioxide (scCO2), and SAS is one of the technique that can effectively process such compounds. Additionally, SAS is the only technique amongst SCF based technologies that has been successfully applied at an industrial scale. There are number of factors in effect during SAS processing. These factors can be grouped into two main categories; formulation related, and process related. In order to design a robust SAS process, it is extremely important to understand the impact of all of these variables on the desirable SAS product attributes, such as particle morphology, particle size, particle size distribution, and % yield of the process. Although several researchers have studied these variables, there is widespread disagreement amongst them. Hence, the goal of the studies shown in this dissertation is to address these gaps in the literature by carrying out a screening design of experiment (DOE), where 7 factors were studied, at 2 levels each, for their impact on particle size, particle size distribution, and process yield. A 2(7-3) fractional factorial design of 16 experiments, plus 3 center point runs, for a total of 19 experiments, was performed. The factors that impacted the particle size the most were the nozzle diameter, temperature, and spray rate of liquid, in the order of decreasing importance. In case of particle size distribution, nozzle diameter, spray rate of liquid, drug concentration, pressure, and polymer concentration played significant roles. The yield was affected by polymer concentration, pressure, and the drug concentration. Additionally, we were able to find optimum processing and formulation variables, which would consistently deliver product of high yield (~90%), small particle size (d50 of ~ 0.4 μm), and narrow particle size distribution. Further, we prepared and compared the physical and physicochemical characteristics of griseofulvin-polymer composite particles produced via three different methods: (1) supercritical antisolvent (SAS) process, (2) spray-drying process, and (3) the conventional solvent evaporation process. The polymers used