Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery

ABSTRACT

Introduction: Amorphous solid dispersions (ASDs) are one of the key formulation technologies that aid the development of poorly soluble candidates. However, their dynamic behaviors, including dissolution and crystallization processes, are still full of mystery. Further understanding of these processes should enhance their wider use.

Areas covered: The first part of this review describes the current understanding of the dissolution of ASDs, where phase separation behavior is frequently involved and attempts to develop appropriate dissolution tests to achieve an in vitro–in vivo correlation are examined. The second part of this review discusses crystallization of the drug molecule with the eventual aim of establishing an accelerated testing protocol for predicting its physical stability.

Expert opinion: The phase separation behavior from the supersaturated state during the dissolution test must be understood, and its relevance to the oral absorption behavior needs to be clarified. Research efforts should focus on the differences between the phase behavior in in vitro and in vivo situations. Initiation time of the crystallization was shown to be predicted only from storage and glass transition temperatures. This finding should encourage the establishment of testing protocol of the physical stability of ASDs.

KEYWORDS:

• Amorphous solid dispersion
• poorly soluble drug
• supersaturation
• phase separation
• in vitro–in vivo correlation (IVIVC)
• crystallization
• stability
• miscibility

Article highlights

• Supersaturated solution created by ASDs may involve phase separation into condensed and diluted phases, which may not be visible to the eyes.

• Dissolution tests must be performed under non-sink conditions for establishing IVIVC. Focus on the dissolution rate under sink conditions may be useful for quality control purposes, but unavailing for predicting the absorption behaviors.

• Presence of the absorption-sink is effective for maintaining the supersaturation during dissolution, because it suppresses the degree of supersaturation.

• Use of the normal flow-through apparatus with a modified sampling procedure may work for predicting oral absorption of the supersaturatable formulations.

• The initiation time for crystallization can be predicted solely from information on the glass transition temperature. If the applicability of the universal rule is confirmed, the shelf life of ASD may be predicted from the calculation.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.