Accelerated dissolution testing conditions of long-acting injectable suspensions: an exploration of dissolution rate and particle behaviour through in vitro imaging and in silico methods.

Long-acting injectables (LAIs) bring patient benefits of more steady drug plasma concentrations and increased compliance. Developing LAI dissolution/release testing methods, including accelerated methods, is challenging due to a lack of understanding of in vivo processes and in vitro parameters affecting release. This work aimed to explore the impact of simple changes in surfactant concentration and flow rate on accelerated LAI in vitro dissolution tests and to examine how these changes affect the effective exposed surface area and relative particle-fluid velocity using particle motion simulation and in vitro imaging studies. Dissolution tests were conducted in the USP IV dissolution apparatus, at 4, 8, 16 mL/min in water with SLS concentrations of 0.005 to 0.55 % (w/v) and in phosphate buffered saline without surfactant. The particle motion behaviour during in vitro and in silico tests was observed through shadowgraph imaging (SGI) and in silico dissolution-based particle motion simulations, respectively. Flow rate and in particular surfactant concentration, and their interaction, significantly impacted the early dissolution rate. There was a notable relationship between particle behaviour and dissolution rate; when 40 to 60 % of drug was dissolved, particles were no longer detected by SGI and were accumulated at either the top or bottom of the cell. This likely decreased the effective surface area, reducing the impact of flow rate and lower SLS concentrations, leading to dissolution profiles converging. In silico simulations suggested the particle detection timeframe can be predicted given appropriate particle size inputs. Exploitation of such particle behaviour-dissolution rate relationships could assist in developing discriminating accelerated test methods.