Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality.
Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality.
复制标题
DOI：
10.1021/acs.molpharmaceut.8b00219
复制
发表时间：
2018-07-02
影响因子：
4.9
通讯作者：
Matzger AJ
中科院分区：
文献类型：
--
作者：
Frank DS;Matzger AJ
相对于纯无定形形式，含有聚合物组分的无定形固体分散体通常赋予小分子改善的抗结晶稳定性。然而，聚合物上的侧链官能度与聚合物稳定抗结晶的能力之间的关系尚未得到很好的理解。为了阐明这种关系，一系列的聚合物官能化的聚-（氯甲基苯乙烯-共-苯乙烯）的母体批次，以研究功能的无定形固体分散体中的稳定性的影响，而不改变聚合物的物理参数，如平均分子量或主链化学。非甾体抗炎药萘丁美酮从含有每个官能化聚合物的无定形固体分散体中结晶的动力学被解释为两个相互作用的基础上：药物和聚合物之间的氢键和聚合物在无定形药物中的溶解度。发现官能化聚合物和萘丁美酮之间的氢键可以赋予抗结晶的稳定性，但仅当聚合物在无定形萘丁美酮中显示出显著的溶解度时。质子官能团的甲基化可以通过增加在药物中的溶解度来改善聚合物抑制萘丁美酮结晶的能力，即使当所得聚合物缺乏与药物相互作用的氢键合官能团时。此外，因素，如纯聚合物的玻璃化转变温度，是不相关的等温成核速率。这些研究结果通知框架相关的聚合物功能和稳定性从聚合物链长或主链化学解卷积的潜力，以帮助聚合物的设计，以抑制从无定形固体分散体的疏水药物的结晶。
Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly-(chloromethylstyrene-co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from amorphous solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the amorphous drug. It was found that hydrogen bonding between functionalized polymers and nabumetone can impart stability against crystallization, but only if the polymer shows significant solubility in amorphous nabumetone. Methylation of a protic functionality can improve the ability of a polymer to inhibit nabumetone crystallization by increasing the solubility in the drug, even when the resulting polymer lacks hydrogen bonding functionalities to interact with the pharmaceutical. Furthermore, factors, such as the glass transition temperature of pure polymers, were uncorrelated with isothermal nucleation rates. These findings inform a framework relating polymer functionality and stability deconvoluted from the polymer chain length or backbone chemistry with the potential to aid in the design of polymers to inhibit the crystallization of hydrophobic drugs from amorphous solid dispersions.
登录
查看更多内容
影响因子：
3.8
作者：
Chyall, LJ;Tower, JM;Childs, SL
通讯作者：
Childs, SL
影响因子：
3.7
作者：
Matsumoto, T;Zografi, G
通讯作者：
Zografi, G
影响因子：
3.7
作者：
Hancock, BC;Parks, M
通讯作者：
Parks, M
影响因子：
3.3
作者：
Liu, XY
通讯作者：
Liu, XY
影响因子：
3.7
作者：
Marsac, Patrick J.;Konno, Hajime;Taylor, Lynne S.
通讯作者：
Taylor, Lynne S.