Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low T_g Amorphous Drug

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Dry blend capsule formulations containing amorphous drugs can face stability challenges, particularly concerning dissolution rate.
• Amorphous solid dispersions are susceptible to physical instability, including sintering, under accelerated storage conditions (elevated temperature and humidity).
• The glass transition temperature (Tg) of an amorphous material is a critical parameter influencing its physical stability and propensity for sintering.

Purpose of the Study:

• To investigate the loss of dissolution rate in a dry blend capsule formulation of amorphous drug NVS-1 during accelerated stability studies.
• To elucidate the mechanism behind the observed dissolution rate decrease, focusing on particle morphology and sintering.
• To evaluate the impact of formulation modifications on the stability and dissolution performance of the amorphous drug.

Main Methods:

• Accelerated stability studies were conducted on the NVS-1 capsule formulation at various temperature and relative humidity (RH) conditions (e.g., 40°C/75%RH, 50°C/75%RH).
• Dissolution rate testing was performed on stored samples to quantify the loss of drug release.
• Scanning electron microscopy (SEM) was used to characterize the particle morphology and identify evidence of sintering in stored samples.

Main Results:

• Significant loss of dissolution rate (≤40% of initial value) was observed after 6 months at 40°C/75%RH.
• SEM analysis revealed particle agglomeration with a 'melt and fuse' morphology, indicating sintering of amorphous NVS-1 particles.
• Humidity acts as a plasticizer, decreasing viscosity and promoting sintering as the storage temperature approaches the drug's Tg (76°C).
• Reformulation using L-HPC and fumed silica, and removing crospovidone, improved short-term stability but sintering persisted at high humidity.

Conclusions:

• Sintering of amorphous NVS-1 particles, driven by temperature, humidity, and proximity to Tg, is the primary cause of dissolution rate loss.
• Moisture adsorption leads to partial dissolution, forming a viscous layer that hinders dissolution media penetration and further slows release.
• Mitigating sintering in high-humidity conditions for formulations with high drug loads (34%) is challenging; future strategies include water scavengers, reduced drug load, and optimized disintegrants.