Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous phase separation (APS) is a common phenomenon in amorphous solid dispersions (ASDs) upon moisture exposure.
• Understanding APS is crucial for predicting the stability and performance of ASDs.
• BMS-817399, a poorly water-soluble drug with low crystallization propensity, was used to study APS and its effects.

Purpose of the Study:

• To investigate the phase behavior of amorphous solid dispersions (ASDs) of BMS-817399 and PVP under varying relative humidity (RH).
• To assess the impact of moisture-induced phase separation on the intrinsic dissolution rate of the ASDs.
• To evaluate the risk associated with using ASD technology for drugs with low crystallization tendencies.

Main Methods:

• Amorphous solid dispersions (ASDs) of BMS-817399 and PVP were prepared at different drug loadings.
• Exposure to various relative humidity (RH) levels to induce phase separation.
• Characterization using infrared (IR) spectroscopy and water vapor sorption analysis to confirm drug-polymer interactions.
• Surface morphology and composition analysis at micro-/nano-scale before and after RH exposure.
• Intrinsic dissolution rate (IDR) measurements of the amorphous drug and PVP.

Main Results:

• Drug-polymer interactions in ASDs persisted at low RH (≤75%) but were disrupted at high RH, leading to phase separation.
• Hydrophobic drug enriched on the ASD surface after amorphous phase separation (APS).
• The intrinsic dissolution rate (IDR) of amorphous BMS-817399 was minimally affected by APS, attributed to its low crystallization tendency and surface enrichment.
• The IDR of PVP decreased post-APS, but supersaturation maintenance was not significantly altered due to limited precipitation inhibition by PVP.

Conclusions:

• For hydrophobic drugs with low crystallization propensity, moisture-induced APS is likely but may not significantly impair drug dissolution performance.
• ASD technology presents low risks for physical stability and dissolution performance when applied to slow-crystallizing drugs.
• The study highlights the importance of considering drug properties like crystallization tendency and hydrophobicity when designing ASDs.