(373g) Acid Effects on Electrostatic Interactions of Ionomer-Coated Nanoparticles: Colloidal Stability and Aggregation

Ristroph, K. D., Princeton University
Issah, L., Princeton University
Ott, J. A., Princeton University
Datta, S. S., Princeton University
Prud’homme, R. K., Princeton University
Processing poorly-soluble drugs into amorphous nanoparticle formulations with high specific surface area is an attractive method for boosting dissolution kinetics. We previously used Flash NanoPrecipitation (FNP) in combination with spray drying to formulate low-cost nanoparticles of the antimalarial lumefantrine and process them into a dry powder for facile shipping and storage. We found that the low solids concentration of particles in suspension immediately downstream of FNP resulted in prohibitively long spray drying times.

In this work, we have developed a method of concentrating the nanoparticles prior to spray drying by taking advantage of their anionic surface chemistry. The particles are stabilized by a layer of hydroxypropyl methylcellulose acetate succinate (HPMCAS), an amphiphilic anionic polymer commonly used as a pharmaceutical excipient. When acid is added to the nanoparticle suspension and the pH dropped to 2, the succinyl groups on HPMCAS are protonated; the electrostatic repulsion between particles that provides colloidal stability is mitigated; and the particles flocculate. We find that the flocculation is reversible; that is, subsequently increasing the system’s pH results regenerates the original nanoparticles. The floccs may be easily separated from the bulk, redispersed at a significantly higher solids concentration, and then further processed.

The governing rules for nanoparticle flocculation, solids recovery, and redispersion are explored. We demonstrate the effects that major process variables such as pH and organic solvent content have on the particle flocculation and re-dispersion events, particularly settling time and extent of flocculation. A series of fluorescent nanoparticles are prepared and the flocculation and redispersion events are imaged in real time using confocal microscopy to quantify settling time, flocc size, and flocc fractal dimension as a function of the variables above. We demonstrate that when most of the residual organic solvent is removed, the flocculation follows diffusion-limited aggregation and the fractal dimension of the resulting floccs falls within predicted limits. This technique, which takes advantage of the ionomer nanoparticle coating and its sensitivity to pH, is an important step in improving nanoparticle processing at scale and translating our combined particle formulation and drying process to the industrial scale.