Single crystal and powder diffraction characterization of three polymorphic forms of Acitretin

Area of Science:

• Crystallography
• Solid-state chemistry
• Pharmaceutical science

Background:

• Acitretin is a synthetic retinoid used to treat psoriasis.
• Polymorphism, the ability of a solid material to exist in multiple crystalline forms, can impact drug properties.
• Understanding Acitretin's polymorphic forms is crucial for its pharmaceutical development and efficacy.

Purpose of the Study:

• To determine the crystal structures of Acitretin's three polymorphic forms (I, II, and III).
• To investigate the molecular arrangements and hydrogen bonding within each polymorph.
• To explore the potential for interconversion between polymorphic forms.

Main Methods:

• Single-crystal X-ray diffractometry for Polymorph I.
• X-ray powder diffraction (XRPD) combined with real-space techniques (simulated annealing, whole-profile pattern matching) for Polymorphs II and III.
• Thermal analysis to study polymorphic transformations.

Main Results:

• Three distinct polymorphic forms of Acitretin (I, II, III) were identified and structurally characterized.
• Polymorph I exhibits four independent molecules with paired hydrogen-bonded carboxylic dimers.
• Polymorph II features carboxylic dimers at inversion centers, while Polymorph III shows a catameric arrangement forming 1D chains.
• Polymorph I can transform into Polymorph II upon heating near 200°C under vacuum.

Conclusions:

• Ab initio structural studies using XRPD are effective for complex pharmaceutical compounds lacking single crystals.
• The distinct crystal structures and potential for transformation highlight the importance of polymorphic control in Acitretin.
• This research provides fundamental insights into the solid-state chemistry of Acitretin, relevant for its pharmaceutical applications.