Exploring a solvated dimer of Gefitinib: a quantitative analysis

Area of Science:

• Crystallography and Solid-State Chemistry
• Pharmaceutical Sciences
• Materials Science

Background:

• Gefitinib (Iressa) is an anilinoquinazoline used in cancer chemotherapy, known to exist in stable (Form I) and metastable (Form II) polymorphic forms.
• Understanding Gefitinib's solid-state properties is crucial for optimizing drug formulation and efficacy.

Purpose of the Study:

• To investigate the crystallization and structural characterization of a novel Gefitinib methanol solvate.
• To elucidate the intermolecular interactions and stabilization mechanisms within the crystal lattice of the Gefitinib-methanol complex.

Main Methods:

• Single-crystal X-ray diffraction for detailed structural analysis.
• Infrared (IR) spectroscopy and Thermogravimetric/Differential Scanning Calorimetry (TG-DSC) for thermal and vibrational characterization.
• Hirshfeld surface analysis and CLP-PIXEL methods for quantifying intermolecular interactions and energies.

Main Results:

• Successful crystallization of Gefitinib as a methanol hemisolvate [N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine methanol hemisolvate, C22H24ClFN4O3·0.5CH3OH].
• The crystal structure features a dimer of Gefitinib molecules (A and B) stabilized by methanol through various hydrogen bonding and C-H...Cl interactions.
• The dimer exhibits three-dimensional isostructurality with the reported Gefitinib Form II, with distinct IR fingerprint values.

Conclusions:

• The methanol solvate formation and stabilization are well-defined by hydrogen bonding and other intermolecular forces.
• The findings align with existing patent literature on Gefitinib cocrystals, providing further structural validation.
• This study enhances the understanding of Gefitinib's solid-state behavior, relevant for pharmaceutical development.