Solution behavior of PVP-VA and HPMC-AS-based amorphous solid dispersions and their bioavailability implications

Area of Science:

• Pharmaceutical Sciences
• Materials Science

Background:

• Amorphous solid dispersions (ASDs) enhance drug solubility and bioavailability.
• The performance of ASDs depends on drug-polymer interactions and dissolution characteristics.

Purpose of the Study:

• To elucidate the mechanism behind the differing in vivo performance of two ASDs: BMS-A/PVP-VA and BMS-A/HPMC-AS.
• To investigate the role of polymer properties and drug-polymer interactions in ASD bio-performance.

Main Methods:

• Differential scanning calorimetry (DSC) to assess drug-polymer miscibility and crystallinity.
• Flory-Huggins modeling for drug-polymer interaction parameters.
• In vitro dissolution studies under various conditions.
• Supersaturation studies with pre-dissolved polymers.
• High-performance liquid chromatography (HPLC) and DSC for potency and crystallinity.
• In vivo pharmacokinetic assessment in canine models.

Main Results:

• Both PVP-VA and HPMC-AS are miscible with BMS-A, with PVP-VA showing higher drug solubilization.
• In vitro dissolution was similar for both ASDs, but HPMC-AS ASD exhibited superior in vivo bioavailability.
• HPMC-AS prolonged drug supersaturation more effectively than PVP-VA.
• Fast PVP-VA dissolution led to drug recrystallization within undissolved dispersions, reducing bioavailability.
• Slow HPMC-AS dissolution and hydrophobicity prevented drug recrystallization, maintaining supersaturation for over 24 hours.

Conclusions:

• Drug recrystallization within undissolved ASDs, driven by hydrophilic polymer dissolution (PVP-VA), is a key factor limiting in vivo performance.
• Polymer selection is critical for ASD development, influencing not only physical stability but also in vivo drug release and bioavailability.