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Pharmaceutical profiling and molecular dynamics simulations reveal crystallization effects in amorphous formulations.
Khadijah Edueng1, Aleksei Kabedev1, Alyssa Ekdahl2
1Department of Pharmacy, Uppsala University, Husargatan 3, 75 123 Uppsala, Sweden.
International Journal of Pharmaceutics
|December 13, 2021
Summary
Understanding amorphous solid dispersions (ASDs) requires studying physical stability and supersaturation. Molecular dynamics simulations revealed drug-specific behaviors and the impact of nano-compartmentalization on crystallization, influencing drug performance.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Computational Chemistry
Background:
- Amorphous solid dispersions (ASDs) are crucial for drug delivery, but their in vivo performance relies on physical stability and supersaturation.
- The molecular mechanisms governing physical stability and supersaturation in ASDs remain incompletely understood.
- Predicting and controlling the behavior of ASDs is essential for reliable drug product development.
Purpose of the Study:
- To investigate the molecular drivers of physical stability and supersaturation in amorphous solid dispersions (ASDs).
- To explore the processes of supersaturation, nucleation, and crystal growth within ASDs using computational and experimental methods.
- To elucidate the impact of drug loading and storage conditions on ASD performance.
Main Methods:
- Molecular dynamics (MD) simulations were employed to model and analyze the behavior of ASDs at the molecular level.
- Experimental assessments were conducted to validate simulation findings and evaluate physical stability and dissolution.
- Analysis focused on drug loading effects, humid storage conditions, and nanostructure formation.
Main Results:
- The influence of drug loading on physical stability and supersaturation was found to be highly drug-specific.
- Humid storage conditions induced crystallization, particle fusion, and reduced dissolution rates.
- MD simulations highlighted the critical role of nano-compartmentalization in controlling ASD crystallization rates.
Conclusions:
- The performance of ASDs is not solely determined by nucleation but by a complex interplay of drug properties, formulation nanostructures, and crystallization behavior.
- Understanding drug-specific molecular interactions and nanostructure formation is key to designing stable and effective ASDs.
- This study provides insights into optimizing ASD formulations for improved in vivo drug performance.
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