Rask Malte Bille, Knopp Matthias Manne, Olesen Niels Erik, Holm René, Rades Thomas
Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark; Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, D-55128 Mainz, Germany.
Eur J Pharm Sci. 2016 Mar 31;85:10-7. doi: 10.1016/j.ejps.2016.01.026. Epub 2016 Jan 28.
In this study, the influence of copolymer composition on drug-polymer solubility was investigated. The solubility of the model drug celecoxib (CCX) in various polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w) and the pure homopolymers polyvinylpyrrolidone (PVP) and polyvinyl acetate (PVA) was predicted at 25 °C using a thermal analysis method based on the recrystallization of a supersaturated amorphous dispersion (recrystallization method). These solubilities were compared with a prediction based on the solubility of CCX in the liquid monomeric precursors of PVP/VA, N-vinylpyrrolidone (NVP) and vinyl acetate (VA), using the Flory-Huggins lattice theory (liquid monomer solubility approach). The solubilities predicted from the liquid monomer solubility approach increased linearly with increasing VP/VA ratio from 0.03-0.60 w/w. Even though the solubilities predicted from the recrystallization method also increased with increasing VP/VA ratio from 0.02-0.40 w/w, the predicted solubility seemed to approach a plateau at high VP/VA ratios. Increasing positive deviations from the Gordon-Taylor equation with increasing VP/VA ratio indicated strong interactions between CCX and the VP repeat unit, which was in accordance with the relatively high solubilities predicted using both methods. As the solubility plateau may be a consequence of steric hindrance caused by the size differences between CCX and the VP repeat units, it is likely that a CCX molecule interacting with a VP repeat unit hinders another CCX molecule from binding to the neighboring repeat units in the polymer chain. Therefore, it is possible that replacing these neighboring hygroscopic VP repeat units with hydrophobic VA repeat units, could increase the physical stability of an amorphous solid dispersion without compromising the drug-polymer solubility. This knowledge could be used advantageously in future development of amorphous drug delivery systems as copolymers could be customized to provide optimal drug-polymer solubility and physical stability.
在本研究中，研究了共聚物组成对药物 - 聚合物溶解度的影响。使用基于过饱和无定形分散体重结晶的热分析方法（重结晶法），在25℃下预测了模型药物塞来昔布（CCX）在各种聚乙烯吡咯烷酮/醋酸乙烯酯（PVP/VA）共聚物组成（70/30、60/40、50/50和30/70 w/w）以及纯均聚物聚乙烯吡咯烷酮（PVP）和聚醋酸乙烯酯（PVA）中的溶解度。使用弗洛里 - 哈金斯晶格理论（液体单体溶解度方法），将这些溶解度与基于CCX在PVP/VA的液体单体前体N - 乙烯基吡咯烷酮（NVP）和醋酸乙烯酯（VA）中的溶解度预测进行比较。从液体单体溶解度方法预测的溶解度随着VP/VA比从0.03 - 0.60 w/w增加而线性增加。尽管从重结晶法预测的溶解度也随着VP/VA比从0.02 - 0.40 w/w增加而增加，但在高VP/VA比时预测的溶解度似乎接近一个平台。随着VP/VA比增加，与戈登 - 泰勒方程的正偏差增加，表明CCX与VP重复单元之间存在强相互作用，这与使用两种方法预测的相对较高溶解度一致。由于溶解度平台可能是CCX与VP重复单元之间尺寸差异导致的空间位阻的结果，与VP重复单元相互作用的CCX分子可能会阻碍另一个CCX分子与聚合物链中相邻重复单元结合。因此，用疏水性VA重复单元取代这些相邻的吸湿性VP重复单元，有可能在不影响药物 - 聚合物溶解度的情况下提高无定形固体分散体的物理稳定性。在未来无定形药物递送系统的开发中，可以有利地利用这一知识，因为可以定制共聚物以提供最佳的药物 - 聚合物溶解度和物理稳定性。
