Thermal, spectroscopic, and ab initio structural characterization of carprofen polymorphs

Area of Science:

• Solid-state chemistry
• Pharmaceutical sciences
• Crystallography

Background:

• Carprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID).
• Polymorphism, the ability of a solid material to exist in multiple crystalline forms, can significantly impact drug properties.
• Understanding carprofen's polymorphic behavior is crucial for its formulation and efficacy.

Purpose of the Study:

• To investigate the polymorphic forms of carprofen.
• To elucidate the structural and thermodynamic relationships between different carprofen polymorphs.
• To determine the crystal structures of carprofen polymorphs and understand the mechanism of polymorphic transformation.

Main Methods:

• Thermal analysis (Differential Scanning Calorimetry)
• Spectroscopic techniques
• Synchrotron X-ray powder diffraction
• Ab initio structure determination
• Density functional theory calculations

Main Results:

• Recrystallized carprofen exists as a single stable polymorph (polymorph I) at room temperature.
• Heating induces an isostructural polymorphic transformation from polymorph I to a metastable form (polymorph II).
• Commercial carprofen samples are mixtures of polymorph I and II.
• Both polymorphs crystallize in the monoclinic space group P2(1)/c, exhibiting conformational differences in the propanoic skeleton.

Conclusions:

• The temperature-induced polymorphic transformation in carprofen is isostructural.
• Polymorphs I and II are conformational polymorphs with similar hydrogen bonding but distinct packing arrangements.
• The observed low transition enthalpy and internal energy are consistent with the minor conformational changes between the polymorphs.