Luebbert Christian, Stoyanov Edmont, Sadowski Gabriele
amofor GmbH, Otto-Hahn-Str. 15, D-44227 Dortmund, Germany.
Nisso Chemical Europe GmbH, Berliner Allee 42, D-40212 Düsseldorf, Germany.
Int J Pharm X. 2020 Dec 19;3:100070. doi: 10.1016/j.ijpx.2020.100070. eCollection 2021 Dec.
Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies. The glass-transition temperature is a crucial attribute of a polymer, but in case of HPC hardly detectable by differential scanning calorimetry. By investigating the glass transition of HPC blends with a miscible polymer, we were for the first time able to estimate the HPC glass transition. Although both, fenofibrate and itraconazole reveal a very low crystalline solubility in HPC regardless of the HPC molecular weight, we observed that low-molecular weight HPC grades such as HPC-UL prevent fenofibrate crystallization for a longer period than the higher molecular weight HPC grades. As predicted, the ASDs with higher drug load underwent amorphous phase separation according to the differential scanning calorimetry thermograms. This work thus showed that it is possible to predict critical drug loads above which amorphous phase separation and/or crystallization occurs in HPC ASDs.
制药行业迫切需要用于无定形固体分散体（ASD）的新型聚合物载体，以提高难溶性候选药物的生物利用度。除了已有的聚合物候选物外，羟丙基纤维素（HPC）越来越受到ASD生产的关注，因为它们能够在水性介质中稳定药物分子以防止结晶。在这项工作中，使用PC-SAFT预测了HPC与伊曲康唑和非诺贝特形成的ASD的热力学长期稳定性，并与为期三个月的长期稳定性研究进行了比较。玻璃化转变温度是聚合物的一个关键属性，但对于HPC来说，用差示扫描量热法很难检测到。通过研究HPC与可混溶聚合物的共混物的玻璃化转变，我们首次能够估算HPC的玻璃化转变温度。尽管非诺贝特和伊曲康唑在HPC中的结晶溶解度都非常低，与HPC的分子量无关，但我们观察到，低分子量的HPC等级（如HPC-UL）比高分子量的HPC等级能更长时间地防止非诺贝特结晶。正如预测的那样，根据差示扫描量热法热谱图，具有较高药物载量的ASD发生了非晶相分离。因此，这项工作表明，可以预测HPC ASD中发生非晶相分离和/或结晶的临界药物载量。
