Polymorphism in Cannabinol Piperazine Cocrystals: Structural, Morphological, and Energetic Perspectives.
Adéla Koryt'áková1, Argyro Chatziadi1, Jan Rohlíček2
1Department of Chemical Engineering, University of Chemistry and Technology in Prague, Technická 3, 16628 Prague 6, Czech Republic.
Crystal Growth & Design
|December 22, 2025
Summary
Researchers explored a new cannabinol piperazine cocrystal, discovering three polymorphic forms. Mechanochemical methods revealed a "disappearing polymorph" phenomenon, offering insights into crystal stability and transformations.
Area of Science:
- Crystallography and Materials Science
- Pharmaceutical Sciences
- Solid-State Chemistry
Background:
- Polymorphism significantly impacts pharmaceutical solid product development, affecting stability and solubility.
- Controlling crystal forms is crucial for consistent drug performance.
- Mechanochemical methods offer a solvent-reduced approach to cocrystal preparation.
Purpose of the Study:
- To prepare and characterize a novel cannabinol piperazine cocrystal.
- To investigate the formation and behavior of its polymorphic forms.
- To understand the underlying mechanisms of polymorphic transformations and stability.
Main Methods:
- Mechanochemical preparation using ball milling with systematic variation of solvents, temperature, and milling time.
- Structural analysis including crystal structure determination and morphology assessment.
- Energetic evaluation using density functional theory (DFT) calculations.
Main Results:
- Successfully prepared a novel cannabinol piperazine cocrystal with three distinct polymorphic forms.
- Observed a "disappearing polymorph" phenomenon under repeated milling conditions.
- Experimental findings correlated well with DFT-predicted relative stabilities and polymorphic behavior.
Conclusions:
- Mechanochemical synthesis provides a versatile route to explore cocrystal polymorphism.
- Integrating structural and energetic analyses is key to understanding and predicting polymorph stability.
- This study offers critical insights into cocrystal behavior and the disappearance of metastable forms, crucial for pharmaceutical development.
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