Reduction of submicron particle agglomeration via melt foaming in solid crystalline suspension

Particle size reduction of poorly water-soluble drug crystals down to the submicron region (0.1–1 µm) is a focus strategy to increase bioavailability. In this context, solid crystalline suspensions (SCS) manufactured in an adapted wet milling process have been introduced as a promising formulation technique. However, for such particle size, agglomeration due to the prevailing attractive interactions poses a major limitation to product quality. As a countermeasure, steric and electrostatic stabilizers have been extensively used in conventional wet grinding applications to introduce kinetic stability to primary particles. In this study the formulation of SCS, containing Xylitol and Griseofulvin, is optimized using the surfactant sodium dodecyl sulfate (SDS).

The stabilizer did not impact suspension stability during grinding, as a constant apparent grinding limit (d₅₀=0.35-0.40 µm) was observed over a wide range of concentrations. Nevertheless, redispersion of primary particles from the solidified SCS in water was enhanced at concentrations of 1 wt.% and above. This behavior of the optimized formulation positively impacted the dissolution kinetics of the Griseofulvin particles compared to the binary system. Different imaging techniques revealed the morphology of the solidified Xylitol matrix and the particle location inside it. At 1 wt.% SDS a porous matrix was obtained, which is caused by a foaming process during grinding. Further investigations indicated the importance of this foam regarding the improved particle redispersion, rather than an electrostatic stabilization. A mechanism, which is inspired by particle stabilized foams and emulsions, is proposed.

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Philip da Igreja, Daniel Klump, Jens Bartsch & Markus Thommes (2022) Reduction of submicron particle agglomeration via melt foaming in solid crystalline suspension, Journal of Dispersion Science and Technology, DOI: 10.1080/01932691.2022.2146707