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978-3-8439-2508-2, Reihe Thermodynamik
Phase behavior of polymer based pharmaceutical formulations (Band 18)
148 Seiten, Dissertation Technische Universität Dortmund (2015), Softcover, A5
Many crystalline active pharmaceutical ingredients (APIs) have a low solubility and/or slow dissolution rate in aqueous media and thus a limited bioavailability. A promising way to enhance bioavailability of APIs is the transformation from the crystalline state into the metastable amorphous one. The recrystallization can be inhibited by integrating the amorphous API into a polymer. The stability of the resulting amorphous API/polymer formulation is dependent on the thermodynamic phase behavior. However, the phase behavior is a function of API type, polymer type, polymer’s molecular weight and, if the polymer is a copolymer, a function of copolymer composition. Additionally, the phase behavior is influenced by the storage conditions like pressure, temperature and relative humidity. Thus, the screening for appropriate API/polymer combinations as well as API/polymer compositions for long-term stable amorphous formulations requires a systematic and excessive experimental investigation. The application of a thermodynamic model can reduce the amount of experiments to a minimum.
In this work, the phase behavior of API/polymer formulations was systematically investigated. Seven different APIs and five different (co)polymers were selected to demonstrate the effect of API and (co)polymer, molecular weight of the polymer as well as copolymer composition on the phase behavior of API/polymer formulations. The influence of all factors, which were mentioned before, on the phase behavior were modelled or even predicted with the thermodynamic model, PC-SAFT. The modeling results were verified with experimental data. The different API/polymer formulations were prepared by ball milling or spray drying procedure. The phase behavior was measured with differential scanning calorimetry and the solid state of the API was determined with powder X-ray diffraction.
The effect of absorbed water from the atmosphere on the phase behavior was evaluated by a new developed theoretical approach that could account for the presence of a three phase system: vapor water phase, liquid water-API-polymer phase and a solid API phase. This approach could be used to predict the water sorption in API/polymer formulations as function of relative humidity and further to determine the influence of relative humidity on the phase behavior. The obtained results were in very good accordance with experimental water sorption data as well as with results from stability tests.