Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture

Abstract

Abstract. Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API-polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous-amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity. Infrared spectroscopy was used as the primary method to investigate the phase behavior of the systems. In general, it was observed that stronger drug-polymer interactions, low-ASD hygroscopicity, and a less hydrophobic API led to the formation of systems resistant to moisture-induced amorphous-amorphous phase separation. Orthogonal partial least squares analysis provided further insight into the systems, confirming the importance of the aforementioned properties. In order to design a more physically stable ASD that is resistant to moisture-induced amorphous-amorphous phase separation, it is important to consider the interplay between these properties.

Amorphous Solid Dispersions

“…The extent of water sorption depends on the hygroscopicity of both polymer and drug, in addition to the strength of the intermolecular interactions. Thus, a system that has strong drug-polymer interactions, low hygroscopicity of the amorphous solid dispersion, and a less hydrophobic drug may lead to the best resistance against moisture-induced phase separation (Rumondor et al 2011).…”

“…Vibrational spectroscopy can also be used to detect amorphous phase separation. When interactions between species within the mixture manifest as a change in the frequency and distribution of vibrational modes, this may be detected using approaches such as IR spectroscopy Rumondor et al 2011). Raman spectroscopy has also shown sensitivity to detect amorphous phase separation.…”

Melt Extrusion in Drug Delivery: Three Decades of Progress

“…Storage temperature (Taylor and Zografi 1997;Matsumoto and Zografi 1999;Khougaz and Clas 2000;Miyazaki et al 2004;Konno and Taylor 2006) and presence of moisture (inherent, during processing or storage) (Rumondor et al 2009;Marsac et al 2010) is an important factor resulting in recrystallization and amorphousamorphous phase separation (Rumondor et al 2011). The primary packaging component also needs to be properly designed to minimize the water permeation.…”

Investigating the molecular structures of solid dispersions by the simulated annealing method

“…As different technologies arise, some new techniques have been developed to overcome some of these issues in manufacture, such as hot-melt extrusion technology [4,5] and direct capsule-filling technology [6]. However, physical stability, one of the main issues of solid dispersions, is yet to be solved [7,8]. Poor physical stability is usually caused by the re-crystallization of amorphous drugs under various storage conditions, such as relative humidity, temperature, preparation methods, drug/polymer ratios and carriers types [1,7,8].…”

“…However, physical stability, one of the main issues of solid dispersions, is yet to be solved [7,8]. Poor physical stability is usually caused by the re-crystallization of amorphous drugs under various storage conditions, such as relative humidity, temperature, preparation methods, drug/polymer ratios and carriers types [1,7,8]. Generally speaking, the re-crystallization of amorphous drug molecules in solid dispersions is mainly caused by the mobility of drug molecules and the structural change of solid dispersions [9].…”