(105e) Influence of Operating Variables on Particle Size and Morphology in High Pressure Carbon Dioxide Antisolvent Process

Chang, A. A. - Presenter, North Carolina State University
Larobina, D. - Presenter, University of Naples

Small particle synthesis using supercritical carbon dioxide as an antisolvent has been of interest in the pharmaceutical, cosmetic, and related industries. We are studying two different precipitation processes using supercritical carbon dioxide as an antisolvent to manipulate particle size and morphology. The first technique is called solution-enhanced dispersion by supercritical fluid or SEDS [1] to precipitate acetaminophen out of ethanol solution. SEDS utilizes a coaxial nozzle design where the liquid solution with the solute of interest is rapidly mixed with supercritical carbon dioxide. The resulting mixture is then sprayed through an external nozzle into a high-pressure capture vessel maintained at constant temperature and pressure. A DOE statistical design study of the system revealed that concentration, solution flow rate, temperature, pressure, and the distance between the inner and outer nozzle (residence time of mixing) affect the particle size and morphology of the drug. These variables were further explored and it was determined that the residence time for the mixing of the two fluids before it is sprayed into the vessel gives the most dramatic effect in controlling particle size. These experiments were supported with an online UV detection method that can indicate the effectiveness of the system variables on particle characteristics by monitoring the amount of the drug that remains in the carbon dioxide + ethanol mixture after it leaves the vessel.

Based on the experience from the SEDS process, another system was tested to improve the control of particle size and shape. In this process, the solution and the antisolvent mix in a low volume tee to initiate nucleation. The precipitated drug then enters a stainless steel residence time tube of different lengths where the particles are allowed to continue nucleation and growth in a controlled environment down the length of the tube. The growth can be slowed down or stopped after the particles exit into the vessel by adding pure carbon dioxide to remove the solvent. However, if the majority of the drug has been consumed during the nucleation and growth process inside the residence time tube before spraying into the vessel, there is no need for the carbon dioxide quenching process. This technique offers an alternative to SEDS for manipulating the final particle size, shape, and uniformity.

1. Hanna, M. and P. York, "Method and Apparatus for the Formation of Particles". World Intellectual Property Organization, 1994. Patent WO95/01121.