Prediction of polymorphic transformations of paracetamol in solid dispersions

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Solid-State Chemistry

Background:

• Polymorphic transformations of active pharmaceutical ingredients (APIs) can impact drug product performance.
• Melt extrusion is a common technique for formulating APIs with polymers, but can induce physical changes.
• Understanding API behavior within polymer matrices during processing is crucial for formulation development.

Purpose of the Study:

• To evaluate variable-temperature X-ray powder diffraction (VTXRPD) as an off-line predictive tool for paracetamol (PMOL) polymorphic transformations.
• To investigate the polymorphic behavior of PMOL in hydrophilic polymer matrices (Soluplus® and Kollidon®) after melt extrusion.
• To correlate VTXRPD findings with in-line near-infrared (NIR) monitoring during extrusion.

Main Methods:

• Variable-temperature X-ray powder diffraction (VTXRPD) was employed to study solid-state polymorphic changes.
• Differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and scanning electron microscopy (SEM) characterized physical mixtures (PMs) and extruded formulations.
• In-line near-infrared (NIR) spectroscopy monitored polymorphic transformations during melt extrusion processing.

Main Results:

• VTXRPD revealed that paracetamol (PMOL) Form I transforms to Form II between 112°C and 120°C in both physical mixtures and extruded formulations.
• The polymorphic transformation was influenced by both temperature and the specific polymer matrix (Soluplus® or Kollidon®).
• NIR monitoring confirmed the VTXRPD findings, showing consistent polymorphic transformation patterns during extrusion.

Conclusions:

• VTXRPD serves as a reliable off-line predictive tool for assessing drug polymorphic transformations in polymer matrices during melt extrusion.
• This study provides valuable insights into the influence of polymer type and processing temperature on API solid-state behavior.
• The findings support the use of VTXRPD for optimizing extrusion processing parameters and ensuring drug product stability.