Thermodynamics for the Stabilization of Amorphous Active Pharmaceutical Ingredients via Polymer-Based Formulations

大多数活性药物成分（api）是非常疏水的，并且在水介质中表现出极低的溶解度，导致非常低的生物利用度。因此，超过80%的新开发的、有前途的原料药从未被制成药物。此外，它们大多数是结晶固体，溶解动力学非常缓慢，因此在通过肠道的过程中不能被人体充分吸收。改善溶解度和溶解动力学的一种可能性是原料药的非晶化。例如，这可以通过原料药在聚合物基质中的分子溶解或原料药在聚合物基质上的吸附（导致原料药/聚合物配方）来实现。目前，通过试错程序找到合适的聚合物，而结果通常不能转移到其他api。此外，众所周知，无定形原料药在聚合物配方中倾向于再结晶或在暴露于湿度时从聚合物中分解，例如在储存条件下。这个项目的重点是应用热力学原理系统地研究非晶原料药在聚合物基配方中的稳定性。由于适当聚合物的化学性质受到监管机构（例如FDA）的限制，因此该项目将研究如何通过改变其共聚物组成、构象或3d结构来影响聚合物的稳定性能。原料药和聚合物的溶解度和混溶性将作为这些聚合物性质的功能来研究。首次定量测量了原料药与聚合物的非晶态混相。此外，湿度对原料药/聚合物相行为的影响将通过实验和模型研究。在热力学稳定性无法实现的情况下（例如，原料药浓度高于溶解度），配方至少可以在低于原料药/聚合物配方的玻璃化转变温度的温度下动力学稳定。因此，还将研究玻璃化转变温度以及湿度的影响。为此，将开发一个模型，该模型将首次允许预测分支聚合物的玻璃化转变温度，作为聚合物结构、聚合物半柔韧度和添加剂（api或改性剂）存在的函数。该模型还可以优化用于API配方的3d聚合物网络（气凝胶）的制造。本项目将通过对原料药/聚合物配方的相行为和玻璃化转变温度进行系统实验和热力学建模，为选择最适合在给定温度、湿度和原料药浓度下稳定非晶原料药的聚合物性能提供良好的物理依据。

Most active pharmaceutical ingredients (APIs) are very hydrophobic and show an extremely low solubility in aqueous media leading to a very low bioavailability. For that reason, more than 80% of the newly-developed, promising APIs never make it into a medicine. Moreover, most of them are crystalline solids exhibiting very slow dissolution kinetics and can therefore not be sufficiently absorbed by the body during their way through the intestinal tract. One possibility to improve both, solubility and dissolution kinetics is the amorphization of the APIs. This can e.g. be achieved via molecular dissolution of the API in a polymer matrix or adsorption of the API at a polymer matrix (leading to API/polymer formulations). Appropriate polymers are today found by trial-and-error procedures whereas the results are usually not transferable to other APIs. Moreover, it is known that amorphous APIs tend to re-crystallize in polymer formulations or to demix from the polymer when exposed to humidity, e.g. under storage conditions. This project focuses on the application of thermodynamic principles to systematically investigate the stabilization of amorphous APIs in polymer-based formulations. Since the chemistry of appropriate polymers is restricted by regulatory authorities (e.g. FDA), the project will investigate, how the stabilizing properties of the polymer can be influenced by changing its copolymer composition, conformation, or 3D-structure. Solubility and miscibility of APIs and polymers will be studied as function of these polymer properties. For the first time, amorphous miscibility of APIs and polymers will be measured quantitatively. Moreover, the influence of humidity on the API/polymer phase behavior will be studied by both, experiments and modeling. In cases, where thermodynamic stability cannot be achieved (e.g. at API concentrations higher than solubility), formulations might at least kinetically be stabilized at temperatures below the glass-transition temperature of the API/polymer formulation. Therefore, also the glass-transition temperature as well as the influence of humidity will be investigated. For that purpose, a model will be developed that will for the first time allow to predict the glass-transition temperature of branched polymers as function of polymer architecture, polymer semi flexibility, and in the presence of additives (APIs or modifiers). This model will also allow optimizing the manufacturing of 3D-polymer networks (aeorogels) used for API formulations. Based on systematic experiments and thermodynamic modeling of both, phase behavior and glass-transition temperature of API/polymer formulations, this project will provide a physically-sound basis to choose appropriate polymer properties which are best suitable to stabilize an amorphous API at given temperature, humidity and API concentration.