Institute for Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences FHNW, Hofackerstr. 30, 4132 Muttenz, Switzerland.
Nano Imaging Lab, Swiss Nanoscience Institute, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Mol Pharm. 2024 Nov 4;21(11):5619-5631. doi: 10.1021/acs.molpharmaceut.4c00592. Epub 2024 Oct 10.
A majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.
大多数以无定形制剂销售的药物具有良好的成玻璃能力，而在无定形状态下不太稳定的化合物仍然构成制剂挑战。这项工作探索了两种模型药物与聚合物（即羟丙纤维素）和共晶形成剂的三元固体分散体。目的是通过使用溶解度参数间隔（即溶解度参数的重叠范围，ORSP）预先选择添加剂来引入计算方法，然后使用更先进的 COSMO-RS 理论建模。因此，提出了一种计算混合焓和熔点的映射，以便在热熔挤出之前进行评估。在对工艺可行性进行了实验测试后，使用常规的散装分析以及共聚焦激光扫描和原子力显微镜成像对所选制剂进行物理稳定性测试。与筛选一致，HPC 制剂中的 dl-苹果酸和 l-酒石酸（20%，w/w）在 3 个月后没有出现早期药物结晶的迹象。然而，l-酒石酸制剂表面只有少量晶体，这可能是湿度引起的表面现象。尽管还需要进一步研究，但结论是，所提出的用于三元固体分散体的计算小规模挤出方法在具有挑战性的药物制剂开发中具有很大的潜力。
