Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous solid dispersions (ASDs) are crucial for enhancing drug solubility and bioavailability.
• Controlling drug crystallization in ASDs is vital for maintaining their amorphous state and therapeutic efficacy.
• Previous work established the critical cooling rate (CR_crit) to prevent nifedipine (NIF) crystallization in ASDs using time-temperature transformation (TTT) diagrams.

Purpose of the Study:

• To determine the critical cooling rate to prevent drug nucleation (CR_{crit N}) during ASD preparation.
• To investigate the influence of polymer type (polyvinylpyrrolidone - PVP, and hydroxypropyl methylcellulose acetate succinate - HPMCAS) and concentration on nucleation.
• To generate TTT diagrams specifically for nucleation kinetics of NIF ASDs.

Main Methods:

• Preparation of NIF ASDs with varying polymers (PVP, HPMCAS).
• Storage of dispersions under nucleation-promoting conditions followed by heating to induce crystallization.
• Determination of crystallization onset time (t_C) using differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry (XRD).
• Generation of TTT diagrams for nucleation kinetics.

Main Results:

• TTT diagrams for nucleation were successfully generated, identifying a critical nucleation temperature of 50 °C.
• The critical cooling rate to avoid nucleation (CR_{crit N}) was determined for NIF ASDs.
• Drug-polymer interaction strength and polymer concentration significantly affected CR_{crit N}. PVP exhibited stronger interactions than HPMCAS.
• The CR_crit for amorphous NIF was approximately 17.5 °C/min.
• With 20% w/w polymer, CR_crit values were ~0.05 °C/min (PVP) and ~0.2 °C/min (HPMCAS).
• Corresponding CR_{crit N} values were ~4.1 °C/min (PVP) and ~8.1 °C/min (HPMCAS).

Conclusions:

• The study successfully established a method to determine the critical cooling rate for preventing nucleation in NIF ASDs using TTT diagrams.
• Polymer selection (PVP vs. HPMCAS) and concentration are critical factors in controlling NIF nucleation kinetics.
• Understanding and controlling nucleation rates are essential for the successful formulation of stable amorphous solid dispersions.