聚合物相变过程的分子动力学研究

Polymers are widely used as drug solid dispersion reagents. They can cause the amorphization of drugs and improve their solubility, stability, and bioavailability. However, the mechanism about why amorphous polymers are stable is unclear. Molecular modelling is unique key technique to solve it. In this proposal, we will systematically investigate thermodynamic and dynamic behaviors during the nucleations and phase transitions of polymers using molecular dynamics(MD) simulations. The above MD simulations need reliable potential parameters of polymers. Therefore, the development of potential parameters is very important and challenging. We will examine how polymerization degree, structure, temperature, pressure, intermolecular interactions affect the nucleation rates, diffusion behavior, aggregative state, and stability of polymers from MD simulation results. The creative points of this proposal are as follows. Based on the decompsition of free energys and interactions of polymers, we will establish the relationship between the stability of amporphous polymers and main interaction types as well as key groups, reveal thermodynamic and dynamic driving forces in stabilizing amorphous polymers, and provide theoretical guides for designing and synthsizing new drugs or drug solid dispersion reagents with similar properties to the polymers. The applicant has worked on the investigations about nuleation and phase transition of condense maters using MD simulation technique for a long time, which establishes a good foundation for fufilling of this proposal.

聚合物广泛用作药物固体分散剂，它能使药物无定形化并提高药物的溶解性、稳定性和生物利用率。然而，无定形高聚物的稳定机理尚不清楚。分子模拟方法是唯一能解决该问题的关键技术。本项目通过分子动力学模拟，系统研究高聚物的相变和成核的热力学和动力学行为。聚合物相变的分子模拟研究需要可靠的势参数。所以建立聚合物势参数是极其重要而又是极具挑战性的。通过分子动力学模拟研究，考察聚合度和分子几何结构、外界条件（温度和压力）、分子间的相互作用等如何影响聚合物的成核速率、扩散行为、聚集状态和稳定性。本项目的创新点是：通过体系自由能和相互作用能分解研究，建立聚合物的稳定性与主要相互作用类型和关键基团的内在关系，揭示稳定无定形聚合物的热力学和动力学驱动力，为设计和合成与聚合物性质类似的药物或药物固体分散剂提供理论指导。申请人长期从事凝聚态物质的成核和相变的分子动力学模拟研究，这为本项目工作的完成奠定了良好的基础。

聚合物广泛用作药物固体分散剂，它能使药物无定形化并提高药物的溶解性、稳定性和生物利用率。然而，无定形高聚物的稳定机理尚不清楚。分子动力学模拟方法是唯一能解决上述问题的关键技术。在本研究工作中，我们利用分子动力学模拟方法系统地研究了聚乙二醇二甲醚(PEGDME)等聚合物在相变过程中的结构、聚集态、热力学和动力学行为。聚合物的模拟熔化（和玻璃态转化）温度与可利用的实验值的较好的线性关系证实了模拟结果的可靠性。热力学和动力学分析结果揭示了PEGDME2000 具有相对较高的稳定性，与Sadowski 等人的实验结果一致。大的构型熵和较低的分子淌度是无定形PEGDME2000高稳定性的主要原因。由于无定形PEGDME3000具有相对较大的粘度，所以它的构型熵小于无定形PEGDME2000的构型熵。另一方面，对于每种聚合物, 在特定的聚合度范围内，它们的无定形态的稳定性都高于对应的结晶态。本研究工作对于设计新型的与PEGDME2000性质相似药物固体分散剂及加速将来的实验研究是有帮助的。