Carrier particle design for stabilization and isolation of drug nanoparticles.

Nanoparticles of poorly water-soluble drugs were prepared in suspension via antisolvent precipitation in order to improve their dissolution behaviour. Insoluble, surface-functionalized, micron-range, clay carrier particles were employed for the dual purpose of stabilizing the nanoparticles in suspended state, and facilitating their unhindered isolation to solid state; often a challenging step in nanoparticle production. The carrier particles, which were functionalized with an optimal level of cationic polymer (protamine), attracted negatively-charged nanoparticles to their surface as a uniform and segregated nanoparticle layer, at drug loadings up to 9% w/w. By using carrier particles to stabilise the nanoparticles on their surface, the traditionally used solubilised nanosuspension stabilisers could be eliminated, thus avoiding time-consuming stabiliser screening tests. The carrier particle system facilitated stabilisation of nanoparticles in suspension, isolation of nanoparticles to the solid state via filtration, and preservation of fast nanoparticle-induced dissolution rates of the dried nanoparticle-carrier composites, indicating preservation of their high surface area during drying. The process was validated with two poorly water-soluble BCS Class II drugs, fenofibrate and mefenamic acid, both of which demonstrated negative surface charge in aqueous suspension.

Effect of the Charge Regulation Behavior of Polyelectrolytes on Their Nonequilibrium Complexation with Oppositely Charged Surfactants.

The nonequilibrium features of oppositely charged macromolecule/surfactant mixtures have been the subject of intensive research recently. Although the nature and extent of polyion charge crucially affect the development of trapped states in these systems, their role in the nonequilibrium association is still poorly understood. In the present study, the impact of mixing on the complexation of hexadecyltrimethylammonium bromide (CTAB) with sodium poly[(vinyl alcohol)-co-(vinyl sulfate)] (PVAS) and poly(acrylic acid) (PAA) samples of similar charge densities has been compared using a variety of experimental methods. The results indicate largely different nonequilibrium behavior depending on the polyions. In the case of the weak polyacid PAA, the binding of CTAB increases its ionization degree, which leads to enhanced equilibrium two-phase concentration range, where kinetically arrested states can be observed upon rapid mixing of the solution components. In contrast, the charge density of the double-hydrophilic PVAS copolymer is fixed, and in addition to the binding of CTAB onto its vinyl sulfate groups, the surfactant molecules also bind onto the vinyl alcohol segments of the copolymer. These factors result in reduced precipitation concentration range and diminishing nonequilibrium effects with decreasing polyion charge density. Our study clearly demonstrates that the charge regulation behavior of various polyelectrolytes can be successfully used to tune the nonequilibrium characteristics of macromolecule/surfactant association.

Impact of Polyelectrolyte Chemistry on the Thermodynamic Stability of Oppositely Charged Macromolecule/Surfactant Mixtures.

The complexation between hexadecyl- and dodecyltrimethylammonium bromides (CTAB and DTAB) with sodium poly[(vinyl alcohol)-co-(vinyl sulfate)] (PVAS) copolymer of low charge density has been investigated using pyrene fluorescence spectroscopy, electrophoretic mobility, turbidity, and dynamic light scattering measurements. The results indicate that the binding of the cationic surfactant occurs in three steps. At low surfactant concentrations, the cationic amphiphile binds to the vinyl sulfate groups. Above charge neutralization, surfactant binding may occur on the surface of the hydrophobic vinyl sulfate/CnTAB nanoassemblies. At even higher concentrations, the surfactant binds on the nonionic vinyl alcohol units of the polyion which reswells the PVAS/CnTAB complexes and makes them highly soluble in water. In earlier studies on oppositely charged ionic surfactants and homopolyelectrolytes the impact of mixing protocols was found remarkable, especially at surfactant excess, where these systems can be trapped in the charge stabilized colloidal dispersion state. In contrast, in the case of PVAS/CnTAB mixtures the effect of mixing is less pronounced and diminishes with increasing ionic strength or decreasing alkyl chain length of the surfactant. These findings are rationalized by taking into account the different binding mechanism of surfactants on oppositely charged homopolyelectrolytes and double hydrophilic copolymers.