Kolisnyk Tetiana, Mohylyuk Valentyn, Fil Nataliia, Bickerstaff Ellen, Li Shu, Jones David S, Andrews Gavin P
Pharmaceutical Engineering Group, Medical Biology Centre, 97, Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
Leading Research Group, Faculty of Pharmacy, Rīga Stradiņš University, 21 Konsula Street, Riga LV-1007, Latvia.
Int J Pharm. 2025 Feb 10;670:125095. doi: 10.1016/j.ijpharm.2024.125095. Epub 2024 Dec 15.
Enhancing the aqueous solubility via amorphization of crystalline poor glass-forming drugs represents a challenge, particularly when drug dosing is high. In such scenarios, there is often a need for high polymer loadings, leading to an increase in the dosage form mass and less patient acceptability. This work investigated the role that polymer type and after-melt cooling rate had upon the amorphicity of solid dispersions (SDs) containing high levels of naproxen and three commonly used polymeric excipients: Eudragit® EPO, Kollidon® VA64, and Soluplus®. Using a combination of thermogravimetry, conventional and fast-scan DSC, oscillatory rheology, in silico Hansen solubility parameter computation, FTIR, and PXRD, we have shown that amorphicity could be affected by the cooling rate with the specific polymer type and amount playing a significant role in the degree of this impact. The amorphous drug content, evident at higher cooling rates, was found to be dependent on drug-polymer interaction and polymer melt viscosity. Higher polymer concentration and faster cooling produced less melt crystallization upon cooling, which was attributed to a shift in nucleation to lower temperatures where it could be inhibited by polymer matrix viscosity. Amorphous drug content, which contained drug nuclei, was evidenced by cold crystallization upon reheating. After 4 weeks of 'gentle' storage, cold crystallization increased if nucleation was the dominant process, whereas cold crystallization decreased if crystal growth prevailed. Storage at elevated temperature and humidity resulted in the absence of cold crystallization, and increased melt crystallisation. Thus, faster cooling could serve as an additional tool to improve amorphous yield and stability of high drug-loaded SDs, however, intermolecular polymer-drug interaction, melt viscosity of the drug-polymer matrix, and storage conditions are of critical importance to achieve this goal.
通过将结晶性差的玻璃形成药物非晶化来提高其水溶性是一项挑战，尤其是在药物剂量较高时。在这种情况下，通常需要高聚合物负载量，这会导致剂型质量增加且患者接受度降低。这项工作研究了聚合物类型和熔体冷却速率对含有高含量萘普生以及三种常用聚合物辅料（尤特奇®EPO、聚乙烯吡咯烷酮VA64和固体分散体®）的固体分散体（SDs）非晶性的影响。通过结合热重分析、传统和快速扫描DSC、振荡流变学、计算机辅助汉森溶解度参数计算、傅里叶变换红外光谱（FTIR）和粉末X射线衍射（PXRD），我们发现冷却速率会影响非晶性，特定的聚合物类型和用量在这种影响程度中起着重要作用。发现在较高冷却速率下明显的无定形药物含量取决于药物 - 聚合物相互作用和聚合物熔体粘度。较高的聚合物浓度和更快的冷却在冷却时产生较少的熔体结晶，这归因于成核向较低温度的转变，在该温度下聚合物基质粘度可以抑制成核。重新加热时的冷结晶证明了含有药物核的无定形药物含量。在“温和”储存4周后，如果成核是主要过程，冷结晶会增加，而如果晶体生长占主导，则冷结晶会减少。在高温高湿条件下储存会导致冷结晶消失，并增加熔体结晶。因此，更快的冷却可以作为提高高载药量固体分散体无定形产率和稳定性的额外工具，然而，分子间聚合物 - 药物相互作用、药物 - 聚合物基质的熔体粘度和储存条件对于实现这一目标至关重要。
