Technical Portfolio and Project Management, Technical Research and Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 07936, USA.
Technical Research and Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 07936, USA.
AAPS PharmSciTech. 2023 Jul 7;24(6):149. doi: 10.1208/s12249-023-02601-z.
This technical note investigated the loss of dissolution rate during accelerated stability studies with a dry blend capsule formulation containing an amorphous salt of drug NVS-1 (T 76°C). After 6 m at 40°C/75%RH, dissolution of NVS-1 was ≤40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored at 50°C/75%RH for 3 weeks showed agglomeration with a distinct "melt and fuse" morphology of particles. At elevated temperature and humidity conditions, undesired sintering among the amorphous drug particles was observed. Humidity plasticizes the drug as the stability temperature (T) gets closer to the glass transition temperature (T) of the amorphous salt (i.e., smaller T-T); a decreased viscosity favors viscoplastic deformation and sintering of drug particles. When moisture is adsorbed onto agglomerated drug particles, partial dissolution of the drug forms a viscous surface layer, further reducing the rate of dissolution media penetration into the bulk solid, hence the slower dissolution rate. Formulation intervention focused on the use of L-HPC and fumed silica as disintegrant and glidant and the removal of the hygroscopic crospovidone. Reformulation improved dissolution performance at short-term accelerated stability conditions of 50°C (± 75%RH); however, sintering to a lesser extent was still observed at high humidity, impacting the dissolution rate. We infer reducing the impact of moisture at high humidity conditions in a formulation with a 34% drug load is challenging. Future formulation efforts will focus on the addition of water scavengers, reducing drug load by ~50% to physically separate drug particles by water-insoluble excipients, and optimizing disintegrant levels.
本技术说明研究了含有药物 NVS-1 无定形盐的干混胶囊制剂在加速稳定性研究中溶出率的损失。在 40°C/75%RH 下放置 6 个月后，NVS-1 的溶出度≤初始值的 40%。对在 50°C/75%RH 下储存 3 周的样品中未溶解的胶囊内容物进行扫描电子显微镜表征，发现颗粒有团聚现象，并有明显的“熔融和融合”形态。在高温高湿条件下，观察到无定形药物颗粒之间不期望的烧结。当稳定性温度（T）接近无定形盐的玻璃化转变温度（Tg）时（即 T-T 较小），湿度使药物塑性化；降低的粘度有利于药物颗粒的粘塑性变形和烧结。当水分被吸附到团聚的药物颗粒上时，部分药物溶解形成粘性表面层，进一步降低了溶解介质渗透到块状固体中的速率，因此溶出速率较慢。制剂干预的重点是使用 L-HPC 和气相二氧化硅作为崩解剂和助流剂，并去除吸湿的交联聚维酮。重新配方在短期加速稳定性条件 50°C（±75%RH）下改善了溶出性能；然而，在高湿度下仍观察到烧结程度较小，这影响了溶出速率。我们推断，在药物负荷为 34%的制剂中，减少高湿度条件下水分的影响具有挑战性。未来的制剂研究将侧重于添加水清除剂、将药物负荷降低约 50%以通过不溶性赋形剂将药物颗粒物理分离，以及优化崩解剂水平。
