ARR - Annual Report
Executive Summary
In this research work, nucleation and growth phenomena of organic nanoparticles from solution are investigated using an experimental approach. In particular, the effects of solution supersaturation and polymeric additives on submicron crystallization are studied. The ultimate goal is to gain fundamental understanding of the combination of process variables that will consistently produce submicron crystals during an antisolvent precipitation process.
Antisolvent precipitation experiments were carried out using naproxen, a poorly watersoluble drug, as an organic model compound. Naproxen solution in ethanol and water (antisolvent) were rapidly and homogeneously mixed in a static Y-mixer to generate high levels of supersaturation. The degree of supersaturation was varied by changing the flow rates of the solute and antisolvent streams respectively. Particle size distribution of naproxen particles obtained from the precipitation experiments were measured offline using dynamic light scattering technique. Preliminary results showed that the particle size ranged between 100−5500 nm. On increasing the initial supersaturation from 16 to 100, the z-average particle size decreased from 2100±1900 nm to 330±190 nm. This experimental result is in line with the classical nucleation theory, according to which primary homogeneous nucleation rates increase with the supersaturation levels, thereby resulting in smaller particles. On the other hand, the median particle size (d50) obtained in this supersaturation range was found to vary between 50−300 nm and did not show a clear trend with the changes in supersaturation. As observed under SEM, the primary naproxen particles obtained under the higher supersaturation conditions were mostly spherical in shape and were in reasonable agreement with the z-average particle size. The crystalline nature of these particles were confirmed using powder X-ray diffraction and from high resolution TEM images.
Executive Summary
Our goals for the past year have focused on developing and refining an experiment to directly and quantitatively measure thermal rupture forces in a depletion system. Keeping in mind that we want to relate these force measurements to the macroscopic rheology of the gels, we have conducted these experiments using a new model system that will enable us to measure the rupture forces, observe the microstructure using confocal microscopy, and also measure the rheology of the gels. This work is being performed in close collaboration with Professor Michael Solomon, University of Michigan.
Executive Summary
In this research work, nucleation and growth phenomena of organic crystals from solution were investigated experimentally, with an objective to produce a dispersion of submicron particles. Specifically, the effects of solute concentration and polymeric additives on the precipitation kinetics of naproxen (organic model compound) were studied. The ultimate goal is to gain fundamental understanding of the combination of process variables that will consistently produce submicron crystals during an antisolvent precipitation process.
Naproxen solution and antisolvent (deionized water with trace amounts of polymeric additives dissolved) were rapidly and homogenously premixed in a Y-micromixer using two syringe pumps. The degree of supersaturation was varied by changing the solute concentration in ethanol. The outlet stream from the Y-mixer was directly fed into a glass vial and the solution turbidity monitored online using the Avantium Crystalline system. The rate of desupersaturation during precipitation process was determined by offline measurement of solute concentration using UV-Vis spectroscopy. Initial results show that in the presence of HPMC K86 polymer additive, induction period for nucleation of naproxen crystals increased significantly as compared to the pure system. On the other hand, in the presence of PVP K10 polymer additive, the induction time apparently decreased. In line with this trend, the rate of desupersaturation in the presence of HPMC decreased significantly as compared to the pure system. These kinetic data correlate well with the effectiveness of the polymeric additives in controlling particle size of naproxen crystals in the submicron range. From the experimentally determined induction periods for crystal nucleation as a function of supersaturation, the nucleation mechanism (viz., primary homogeneous and heterogeneous) controlling the precipitation process was determined.
Future work will focus on unraveling the mechanisms underpinning the effects of polymer additives on stabilization of colloidal crystal dispersion using both experimental techniques and molecular modeling.