Thermodynamics for the Stabilization of Amorphous Active Pharmaceutical Ingredients via Polymer-Based Formulations
November 1, 2016
October 31, 2019
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.