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pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs.
Bo Wang1, Matthew J Nethercott2, Akshay Narula3
1Pharmaceutical Development, Biogen, 115 Broadway, Cambridge, Massachusetts, 02142, USA.
Pharmaceutical Research
|December 10, 2021
Summary
Drug release from amorphous solid dispersions (ASDs) is pH-dependent when both components are ionizable. This study shows drug-polymer interactions in the solid state drive pH-independent solubility suppression in ASDs.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
Background:
- Amorphous solid dispersions (ASDs) can reduce drug chemical potential, potentially lowering drug release, especially with insoluble polymers.
- When both drug and polymer in an ASD are ionizable, drug release becomes sensitive to solution pH.
Purpose of the Study:
- To investigate the mechanisms underlying pH-dependent solubility suppression in ASD formulations.
- To understand how drug-polymer interactions influence solubility suppression across varying pH conditions.
Main Methods:
- Determined clotrimazole release from ASDs with insoluble, pH-responsive polymers at different pH levels.
- Characterized drug-polymer interactions using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance (SSNMR) spectroscopy.
Main Results:
- Solubility suppression extent varied with polymer type and drug loading.
- Stronger drug-polymer interactions correlated with greater solubility suppression.
- Solubility suppression remained consistent across tested pH ranges, indicating pH-independent solid-state interactions.
Conclusions:
- Solid-state drug-polymer interactions are the primary mechanism for solubility suppression in these ASDs.
- The concentration of free drug in the solid state is constant regardless of external pH.
- Total drug concentration in solution follows the Henderson-Hasselbalch relationship, consistent with pH-independent amorphous solubility.
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