Microstructure-driven opacity of semi-permeable membranes in push-pull osmotic tablets and its impact on...

Push-pull osmotic pump tablets provide controlled, zero-order drug release through water diffusion across a semi-permeable membrane and extrusion of the drug in the active layer through a laser-drilled orifice. The membranes must be mechanically robust to channel the internal osmotic pressure towards drug extrusion. The study reports an instance in which the solvent coating produced opaque cellulose acetate/PEG3350 semi-permeable membranes. This reduced the visual contrast between the push and pull layers-creating a potential risk for accurate laser drilling-and led to incomplete dissolution of investigational drug MK-8189 after 24 h. Scanning electron microscopy, light microscopy, differential scanning calorimetry, nanoindentation, x-ray micro-computed tomography, and dissolution testing were used to identify the origin and impact of the opacity. Results showed that opacity was driven by coating-induced membrane porosity, rather than phase separation. Although both presentations retained the zero-order release kinetics, the opaque membranes were more porous and mechanically weaker-exhibiting a three-fold increase in the number of pores, a statistically significant increase in pore size distribution, and a 26% reduction Young's Modulus than the transparent membranes. During dissolution, the softer opaque membranes deformed substantially, increasing internal tablet volume and reducing the fraction of swelling capacity available to drive the drug extrusion. Consequently, opaque tablets plateaued at ∼85% drug release, whereas transparent tablets achieved complete release. By understanding the edges of failure for the solvent coating process, optimization of the air-to-spray ratio, product temperature, and pattern air pressure eliminated the microstructural porosity.