Searching for Suitable Kojic Acid Coformers: From Cocrystals and Salt to Eutectics

Area of Science:

• Materials Science
• Crystallography
• Pharmaceutical Chemistry

Background:

• Kojic acid is a valuable compound with various applications.
• Cocrystallization is a strategy to modify the physicochemical properties of active pharmaceutical ingredients.
• Understanding the cocrystallization behavior of kojic acid is crucial for its formulation development.

Purpose of the Study:

• To investigate the cocrystallization potential of kojic acid with a diverse range of organic coformers.
• To characterize the resulting crystalline forms and elucidate their structures.
• To evaluate the stability and intermolecular interactions of the identified cocrystals.

Main Methods:

• Cocrystallization screening using solution, slurry, and mechanochemical techniques with approximately 50 coformers.
• Powder X-ray diffraction (PXRD) for initial compound analysis.
• Single crystal X-ray diffraction for detailed structural elucidation of cocrystals and salts.
• Differential scanning calorimetry (DSC) for eutectic system investigation.
• Computational methods (electronic structure and pairwise energy calculations) for stability and interaction analysis.

Main Results:

• Successful synthesis of five kojic acid cocrystals with 3-hydroxybenzoic acid, imidazole, 4-pyridone, DABCO, and urotropine.
• Formation of a salt with piperazine, and uncertain crystalline complexes with theophylline and 4-aminopyridine.
• Eutectic systems identified with panthenol, nicotinamide, urea, and salicylic acid.
• Detailed structural characterization of the five cocrystals and the salt via single crystal X-ray diffraction.
• Computational analysis provided insights into the stability and intermolecular forces governing the observed crystalline structures.

Conclusions:

• Cocrystallization is a viable approach to generate novel crystalline forms of kojic acid.
• The study identified specific coformers that effectively form cocrystals or salts with kojic acid.
• The characterized cocrystals and salt offer potential for improved properties and applications of kojic acid.