Polymorphic transformation of anhydrous caffeine under compression and grinding: a re-evaluation

Area of Science:

• Pharmaceutical science
• Solid-state chemistry
• Materials science

Background:

• Polymorphic transformations are critical in pharmaceutical solid production.
• Anhydrous caffeine exhibits polymorphic behavior, but literature results are contradictory.
• Understanding mechanical effects on caffeine polymorphs is essential.

Purpose of the Study:

• To investigate polymorphic transformations of anhydrous caffeine under mechanical stress (compression and grinding).
• To clarify contradictory findings in existing literature regarding caffeine's polymorphic behavior.
• To identify any intermediate forms generated during mechanical treatment.

Main Methods:

• Compression of anhydrous caffeine (Form I and Form II) using an instrumented alternative press.
• Grinding of anhydrous caffeine (Form I and Form II).
• Analysis before and after mechanical treatment using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

Main Results:

• Compression of Form II showed no changes.
• Compression of Form I resulted in a slow, partial transformation to Form II, detectable only after several days.
• Grinding also induced transformations, with an intermediate form observed that slowly converted to Form II.
• This slow transformation and intermediate form were not previously reported.

Conclusions:

• Mechanical treatment of anhydrous caffeine, particularly Form I, induces a slow polymorphic transformation to Form II via an intermediate.
• The kinetics of this transformation are crucial and were previously overlooked.
• Accurate characterization of pharmaceutical solids requires considering these slow solid-state changes.