Crystallisation Kinetics in ASDs

3/13/2019 14:05 - 14:40

Several approaches exist to increase the bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs). A promising approach is to transform the -usually crystalline- API into its amorphous form, which is better water soluble, but at the same time only metastable against crystallization. A common stabilizing strategy for this type of APIs is to embed the amorphous API in a polymer matrix resulting in a so-called amorphous solid dispersion (ASD). However, as the API loading usually exceeds its solubility in the polymer, the API tends to recrystallize during storage. In order to estimate the shelf life of such metastable ASDs, methods are required to determine the crystallization velocity during storage.

In this work, spray-dried ASDs composed of the API nifedipine and the polymer poly (vinyl acetate were transferred into a magnetic suspension balance, where the water sorption in the ASD was measured as function of time at fixed temperature and relative humidity conditions. ASDs with different drug loadings were exposed to different temperatures and RHs. The water content in the ASDs first increased quickly and then slowly decreased over time. In previous works, we could show that the water sorption of ADSs differs depending on the physical state of the ASD (amorphous vs. crystallized) and can be predicted with adequate thermodynamic tools, e.g. the PC-SAFT model. By coupling the measured water content with thermodynamic predictions and mass balances, it was possible to determine the amount of crystals in the ASDs form the water-sorption measurements only without any additional measurements. This method is completely calibration free and thus is a very cheap and easy method to estimate the amount of API crystals in an ASD.