Abstract
The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings.
Highlights
Enhancing the solubility and dissolution behavior of poorly-water-soluble active pharmaceutical ingredients (APIs) is a key challenge in the development of new formulations
A successful strategy along this line are amorphous solid dispersions (ASDs) where the APIs are molecularly dissolved in a suitable polymer carrier and converted into an amorphous state [1,2]
The long-term stability of these ASDs is determined by their thermodynamic phase behavior as it determines the maximum API weight fraction of the formulation at which it is long-term stable against API recrystallization as well as amorphous-amorphous phase separation (APS) [2]
Summary
Enhancing the solubility and dissolution behavior of poorly-water-soluble active pharmaceutical ingredients (APIs) is a key challenge in the development of new formulations. A successful strategy along this line are amorphous solid dispersions (ASDs) where the APIs are molecularly dissolved in a suitable polymer carrier and converted into an amorphous state [1,2]. From thermodynamic point of view, this is a liquid-liquid demixing. This immiscibility is—like crystallization—highly unwanted as it causes
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