Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Biomedical and Pharmaceutical Sciences

First Advisor

Serpil M. Kislalioglu


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 were Kollidon® VA64, HPMCAS-LF, and Eudragit® EPO. Particle properties were analyzed using scanning electron microscopy, powder X-ray powder (PXRD), differential scanning calorimetry (DSC), and Fourier transform infra red (FTIR). Particle size and particle size distribution measurements were made using Malvern laser diffractometer. The dissolution behavior of pure API and solid dispersions were compared. Amorphous solid dispersions of spherical shapes were obtained, independent of the type of polymer used, when spray drying process was used. FTIR spectra indicated the formation of hydrogen bonding between the drug and polymers, during spray drying process. Whereas, the drug remained in its crystalline form when the processing method was SAS or conventional solvent evaporation, and there was no hydrogen bonding for these formulations. The griseofulvin particles used as unprocessed starting material had a mean diameter of approximately 12 μm with a size distribution range between 5-20 μm. With the spray drying or SAS process, and using any of the three hydrophilic polymers, in-situ nanoparticles with the mean particle size of 0.3 to 0.5 μm were obtained. These nanoparticles were associated with improved dissolution performance compared with unprocessed crystalline griseofulvin.

In conclusion the physicochemical properties and dissolution of crystalline griseofulvin could be improved by physical modification such as particle size reduction using SAS process, and generation of amorphous state using spray-drying process.



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