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Structural Modifications of Polyethylenimine to Control Drug Loading and Release Characteristics of Amorphous Solid
Kristen N Kelsall1,2, Leila M Foroughi1, Derek S Frank3
1Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Molecular Pharmaceutics
|January 31, 2023
Summary
Amorphous solid dispersions (ASDs) improve drug delivery for poorly soluble drugs. Modifying polymer hydrophobicity enhanced flufenamic acid delivery and stability in ASDs, enabling higher drug loadings.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Drug Delivery
Background:
- Crystalline drugs with poor solubility benefit from amorphous solid dispersions (ASDs).
- Polymer properties critically influence ASD performance, affecting drug loading, solubility, dissolution, and stability.
- Polyethylenimine (PEI) is a polymer with high functional group concentration, suitable for ASD development.
Purpose of the Study:
- To investigate the impact of crosslinked polyethylenimine (PEI) hydrophobicity on amorphous solid dispersions (ASDs) of flufenamic acid (ffa).
- To explore how modifying PEI synthesis impacts drug loading, solubility, and physical stability of ffa-loaded ASDs.
Main Methods:
- Crosslinking of hyperbranched polyethylenimine (PEI) with terephthaloyl chloride, followed by benzoyl chloride capping to tune hydrophobicity.
- Synthesis of amorphous solid dispersions (ASDs) with varying drug loadings (50 and 60 wt %) of flufenamic acid (ffa).
- Evaluation of drug solubility, dissolution rates in acidic media, and physical stability under various humidity conditions.
Main Results:
- All synthesized ASDs showed enhanced drug delivery of flufenamic acid (ffa) in acidic media compared to crystalline ffa.
- Increased hydrophobicity and reduced basicity of PEI led to a mix of amorphous deprotonated and neutral ffa at high drug loadings.
- No crystallization was observed in ASDs after 29 weeks of storage under various relative humidity conditions, indicating excellent physical stability.
Conclusions:
- Hydrophobicity modification of crosslinked PEI is a viable strategy for developing stable amorphous solid dispersions (ASDs) with enhanced drug delivery.
- The findings support the use of polymers with high functional group concentrations for achieving high drug loadings in ASDs.
- This approach broadens the scope of polymers for ASD formulation, potentially overcoming limitations of existing materials.
Keywords:
crosslinkedcrystallization inhibitiondissolutionphysical stabilitypolymer pharmaceutical interactionswellingMore Related Videos
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