Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous active pharmaceutical ingredients (APIs) offer enhanced solubility and dissolution rates.
• Physical aging and crystallization can negatively impact the performance of amorphous APIs.
• Understanding these solid-state transformations is crucial for drug formulation and stability.

Purpose of the Study:

• To investigate the effects of physical aging and crystallization on the supersaturation potential and crystallization kinetics of various amorphous APIs.
• To compare the performance of freshly prepared amorphous APIs with aged or partially crystallized counterparts.
• To elucidate the relationship between solid-state changes and drug release characteristics.

Main Methods:

• Utilized spray-dried amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole as model APIs.
• Aged samples under high humidity (75% RH) for 168 days or until crystallization.
• Monitored solid-state changes using differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction.
• Assessed supersaturation potential (C_max,app, AUC) and crystallization kinetics (k) using the µDISS Profiler.

Main Results:

• Physically aged indapamide and metolazone, and minimally crystallized glibenclamide and hydrocortisone showed no significant changes in supersaturation potential.
• Ketoconazole (23% crystalline) exhibited a 50% reduction in C_max,app and AUC, reaching crystalline solubility levels.
• Aged metolazone demonstrated improved AUC and decreased crystallization kinetics, while glibenclamide showed the greatest improvement in supersaturation potential.
• Crystallization during dissolution was identified as a significant factor compromising supersaturation potential.

Conclusions:

• The impact of aging and crystallization on amorphous API performance is API-specific.
• Partial crystallization can significantly reduce supersaturation potential, while some amorphous APIs may show improved properties upon aging.
• Crystallization occurring during the dissolution process itself can severely limit the therapeutic benefits of amorphous formulations.