Denduyver Phaedra, Vervaet Chris, Vanhoorne Valérie
Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Int J Pharm. 2025 Jan 25;669:124990. doi: 10.1016/j.ijpharm.2024.124990. Epub 2024 Dec 7.
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.
先前的研究表明，通过双螺杆湿法制粒（TSWG）制备的以羟丙基甲基纤维素（HPMC）为亲水性基质形成剂的控释（CR）制剂，得到的颗粒中活性药物成分（API）分布不均匀（登杜伊弗等人，2024年）。这归因于造粒液添加后HPMC的快速水合和溶胀行为，限制了颗粒破碎以及颗粒生长过程中颗粒的持续交换。改变液固比（L/S比）、使用更具攻击性的螺杆配置或使用具有不同溶解度的填充剂，都无法得到API分布均匀的颗粒。因此，使用粒径分布（PSD）比API小和大的填充剂等级，研究了填充剂粒径对CR颗粒含量均匀性和颗粒生长机制的影响。由于TSWG中的颗粒生长沿制粒单元在空间上发生，因此进行了分区分析，以从每个区域收集颗粒。在整个制粒单元的每个隔室中，与大粒径填充剂相比，小粒径填充剂产生的API分布更均匀。然而，对于基于乳糖、甘露醇和磷酸二钙（DCP）的制剂，在细粉部分（<150 µm）观察到剂量不足。基于小粒径微晶纤维素（MCC）的制剂产生了均匀的API分布。MCC的溶胀行为与较小粒径之间的相互作用促进了润湿，有利于在颗粒筛分部分实现均匀的API分布。
