Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Drug Delivery

Background:

• Amorphous solid dispersions are key for oral drug delivery of poorly soluble compounds.
• The "kinetic solubility" or "parachute effect" describes the transient supersaturation achieved, crucial for bioavailability.
• Understanding the duration of this effect is vital for optimizing drug formulation and predicting in vivo performance.

Purpose of the Study:

• To evaluate two semiempirical models based on dispersive kinetics for describing the loss of supersaturation over time.
• To determine the applicability of these models to different drug recrystallization mechanisms.
• To assess the utility of these models in guiding formulation development for oral small-molecule drugs.

Main Methods:

• Modeling experimental kinetic solubility profiles using dispersive kinetics theory.
• Analyzing drug recrystallization transients, distinguishing between denucleation and nucleation/growth mechanisms.
• Applying classical and dispersive kinetic models to literature data for glibenclamide, indomethacin, loratadine, and terfenadine.

Main Results:

• The models accurately describe the loss of supersaturation due to drug recrystallization.
• Denucleation kinetics characterize systems where drug solubility significantly exceeds crystal solubility long-term.
• "Nucleation and growth" kinetics best describe rapid, complete recrystallization.
• A combination of models achieved a high-quality fit (R² = 0.993) for terfenadine's dissolution-recrystallization transient.

Conclusions:

• The proposed semiempirical models effectively characterize the duration of the amorphous "parachute effect".
• Precise in vitro characterization of kinetic solubility aids in predicting in vivo drug exposure.
• These models offer valuable tools for optimizing oral drug formulations and guiding development strategies.