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.

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探讨非晶固体分散体稳定性与聚合物功能之间的相互作用

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进的抗结晶稳定性。然而，聚合物侧链官能团与聚合物稳定结晶的能力之间的关系尚不清楚。为了阐明这种关系，我们对聚（氯甲基苯乙烯-苯乙烯共聚物）母料进行了一系列聚合物的官能化，以研究官能团对无定形固体分散体稳定性的影响，而不改变聚合物的物理参数，例如平均分子量或主链化学。非甾体抗炎药物萘丁美酮从含有每种官能化聚合物的无定形固体分散体中结晶的动力学基于两种相互作用进行解释：药物和聚合物之间的氢键以及聚合物在无定形药物中的溶解度。研究发现，官能化聚合物和萘丁美酮之间的氢键可以赋予结晶稳定性，但前提是聚合物在无定形萘丁美酮中表现出显着的溶解度。质子官能团的甲基化可以通过增加在药物中的溶解度来提高聚合物抑制萘丁美酮结晶的能力，即使所得聚合物缺乏与药物相互作用的氢键官能团。此外，纯聚合物的玻璃化转变温度等因素与等温成核速率不相关。这些发现提供了一个与聚合物功能性和稳定性相关的框架，该框架从聚合物链长度或主链化学中解卷积，有可能有助于设计聚合物以抑制疏水性药物从无定形固体分散体中结晶。