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Fakultät Bio- und Chemieingenieurwesen

Amorphous-Amorphous Phase Separation in Polymeric API Systems

01/01/2015 - 06/15/2018

More than 90% of newly-developed active pharmaceutical ingredients (API) are currently rejected during drug development due to their low bioavailability. One promising approach to overcome this limitation is the formulation of an API in its amorphous state. This thermodynamically instable state is effectively stabilized by incorporating the API in a polymeric matrix. The project focuses on the experimental investigation and thermodynamic modeling of the amorphous-amorphous phase separation in API/polymer systems.


Polymer/API systems are capable of increasing the bioavailability of poorly water soluble drugs. Recently, this technology was applied in numerous products to increase and control the dissolution in the gastrointestinal tract [1]. Such systems are therefore highly relevant in pharmaceutical industry. Knowing the phase behavior is crucial for the design of a long-term stable formulation. The solubility of APIs in polymeric carriers has recently been investigated [2] and can be considered in the screening process searching for long-term stable formulations. Besides crystallization, amorphous-amorphous phase separation might occur during storage or processing leading to an API-rich and an API-poor phase. Amorphous-amorphous phase separation is reported only for few systems so far [1]. A systematic and thermodynamic investigation of this phenomenon is not available so far. Amorphous-amorphous phase separation in API-polymer formulations particularly occurs when exposed to high relative humidity. The water uptake of a formulation accelerates API recrystallization and thereby decreasing the thermodynamic stability. This phenomenon is elucidated experimentally for spray- dried formulations by DSC, PXRD and Raman microscopy and thermodynamically modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT)[3].

Lübbert Illustration © Lübbert ​/​ Thermodynamik


[1] Y. Huang, W.-G. Dai:
"Fundamental aspects of solid dispersion technology for poorly soluble drugs"
Acta Pharmaceutica Sinica B, vol. 4 pp. 18–25, 2014.
[2] A. Prudic, Y. Ji, G. Sadowski:
"Thermodynamic Phase Behavior of API/Polymer Solid Dispersions"
Molecular Pharmaceutics, vol. 11, pp. 2294–2304, 2014.
[3] J. Gross and G. Sadowski:
"Perturbed-chain SAFT: An equation of state based on a perturbation theory for chain molecules"
Industrial & Engineering Chemistry Research, vol. 40, pp. 1244-1260, Feb 21 2001.