Submicron Crystallization: Building Colloidal Crystal Dispersion from Solution

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Sendhil Poornachary, Jin Wang Kwek, Ann Chow, Reginald Tan
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Particle Formation
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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.