Coaxial electrospraying to produce coated amorphous solid dispersion particles: from polymer solution to fixed dose combinations

During the past decades, the amount of active pharmaceutical ingredients (APIs) with low aqueous solubility and dissolution rate and hence low oral bioavailability has been growing firmly. To address this problem, amorphous solid dispersions (ASDs) can be formulated in which the API is mixed at a molecular level into an inert amorphous polymer. Due to the amorphous nature of these formulations, both solubility and dissolution rate can be improved. Often, hydrophilic polymers are used to obtain an immediate release, however a modified release profile can be advantageous with regard to site specific targeting into the gastrointestinal tract, powders for reconstitution or to obtain more gradual and prolonged supersaturation profiles.

In this PhD project, coaxial electrospraying was used to produce ASD microparticles that are individually coated with an enteric polymer. By using a coaxial nozzle consisting of an inner needle for the core or ASD solution and an outer needle for the coating polymer solution, coated particles can be produced in one step. By applying a high potential difference between nozzle and collector, the fluid leaving the nozzle will deform into a cone-jet, which will then split up in an aerosol of droplets. During the time the droplets travel to the collector, the solvent evaporates quickly and a dry powder of core-shell structured particles can be collected. The general aim of this PhD project was to gain knowledge in the coaxial electrospraying process regarding the manufacturing of coated ASDs and how this is influenced by the different process and formulation parameters in order to predict and modify the API release from the coated particles.

Due to the complex interplay of variables that influence the coaxial electrospraying process, a bottom-up strategy was applied consisting of four consecutive experimental parts. In the first project, a variety of polymer solutions was electrosprayed in a single nozzle setup to map the influence of the different process and formulation parameters on the cone-jet mode or working window of the system. Secondly, ASDs of darunavir were prepared and characterised in terms of solid state and pharmaceutical performance. Moreover, the same ASDs were prepared with spray drying as a bench mark. In the third part, enteric coated ASDs of darunavir were manufactured and the influence of different formulation parameters like the polymer type, concentration and solvent on the API release in acidic medium was investigated. Lastly, fixed dose combinations for cardiovascular treatment were manufactured and studied. The particles consisted of an ASD core with lovastatin and atenolol and an enteric coating layer that also contained acetylsalicylic acid. To conclude, a general discussion relates the findings of the four projects and presents an outlook for future research.