Abstract
Previous research has shown that controlled release (CR) formulations with hydrox- ypropyl methylcellulose (HPMC) as hydrophilic matrix former produced via twin-screw wet granulation (TSWG) yield granules with an inhomogeneous active pharmaceutical ingredient (API) distribution (Denduyver et al., 2024). This was attributed to the fast hydration and swelling behaviour of HPMC upon addition of granulation liquid, limiting granule breakage and continuous exchange of particles during granule growth. Altering the liquid-to-solid ratio (L/S-ratio), using a more aggressive screw configuration or using fillers with different sol- ubility did not yield granules with a homogeneous API distribution. Therefore, the effect of the filler particle size on the content uniformity and granule growth mechanism of CR granules was studied using filler grades with a smaller and larger particle size distribution (PSD) than the API. As granule growth in TSWG occurs spatially along the granulator unit, a compartmental analysis was performed to collect granules from each zone. The small particle size fillers yielded a more homogeneous API distribution compared to the large particle size fillers in each compartment throughout the granulator unit. However, for lactose-, mannitol- and dicalcium phosphate (DCP)-based formulations, underdosing in the fines fraction (<150 µm) was observed. The small particle size microcrystalline cellulose (MCC)-based formulation yielded a homogeneous API distribution. The inter- play of the swelling behavior of MCC and the smaller particle size facilitated wetting, favoring the homogeneous API distribution over the granule sieve fractions.
Published Version
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