Indomethacin polymorphs: Experimental and conformational analysis.

Area of Science:

• Solid-state chemistry
• Physical chemistry
• Materials science

Background:

• Indomethacin exists in multiple polymorphic forms, including alpha, gamma, and amorphous states.
• Polymorphism significantly impacts drug properties such as dissolution rate and solubility.
• Understanding solid-state transitions is crucial for pharmaceutical development.

Purpose of the Study:

• To investigate the thermal behavior and phase transitions of indomethacin alpha and gamma polymorphs.
• To characterize the thermal events observed in amorphous indomethacin.
• To correlate solid-state properties with theoretical calculations of molecular interactions and solubility.

Main Methods:

• Differential Scanning Calorimetry (DSC) for thermal analysis.
• X-ray diffraction (XRD) and Near-Infrared Spectroscopy (NIR) for phase transformation detection.
• Ab initio and Density Functional Theory (DFT) for theoretical calculations.

Main Results:

• Indomethacin alpha and gamma polymorphs exhibited temperature transitions at 429.2 K and 435.8 K, respectively, not detected by XRD or NIR.
• DSC of amorphous indomethacin showed an endothermic event, potentially explained by conformational rotational changes.
• The alpha form displayed the highest intrinsic dissolution rate, while the amorphous form had the lowest.
• Theoretical calculations indicated that double interactions are key to observed solubility differences.

Conclusions:

• Thermal analysis provides insights into indomethacin solid-state transitions beyond standard spectroscopic methods.
• Conformational changes in amorphous indomethacin contribute to its thermal behavior.
• The alpha polymorph's superior dissolution rate is linked to its molecular interactions, as supported by theoretical studies.