Prediction of the physical stability of amorphous solid dispersions: relationship of aging and phase separation with the thermodynamic and kinetic models along with characterization techniques

ABSTRACT

Introduction: Solid dispersion has been considered to be one of the most promising methods for improving the solubility and bioavailability of insoluble drugs. However, the physical stability of solid dispersions (SDs), including its aging and recrystallization, or phase separation, has always been one of the most challenging problems in the process of formulation development and storage.

Areas covered: The high energy state of SDs is one of the primary reasons for the poor physical stability. The factors affecting the physical stability of SDs have been described from the perspective of thermodynamics and kinetics, and the corresponding theoretical model is put forward. We briefly summarize several commonly used techniques to characterize the thermodynamic and kinetic properties of SDs. Specific measures to improve the physical stability of SDs have been proposed from the perspective of prescription screening, process parameters, and storage conditions.

Expert opinion: The separation of the drug from the polymer, the formation, and migration of drug crystals will cause the SDs to shift toward the direction of energy reduction, which is the intrinsic cause of instability. Furthermore, computational simulation can be used for efficient and rapid screening suitable for the excipients to improve the physical stability of SDs.

KEYWORDS:

• Solid dispersions
• high energy state
• physical stability
• thermodynamics
• kinetics
• computational simulation

Article highlights

• The solid-liquid equilibrium equation, Flory-Huggins theory and FOX equation have been used to illustrate the effect of polymer and glass transition temperature on the physical stability of SDs, which is conducive for the quantitative screening of polymers and the more intuitive optimization of prescription.

• The combination of molecular migration, crystal nucleus formation and growth, and energy further demonstrated that the instability of SDs was inseparable from its high energy state.

• Drug–polymer interaction and the anti-plasticizing effect of the polymer carrier contributed to the physical stability.

• Through the structural optimization based on COMPASSII force field, the dynamic model of solid dispersions can be constructed. The release rate of drug molecules and the strength of interaction among components can be characterized in real time.

• For pH-dependent drugs, the interaction between the drug and the regulator may improve the stability of SDs by adding a pH regulator to prepare ternary solid dispersions.

• 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors gratefully acknowledge the financial support provided by Natural Science Foundation of Ningxia Province (No. 2020AAC03140).