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Objective <p>This research aimed to investigate the compatibility of the Ketoconazole-Adipic Acid (KTZ-AA) co-crystal, which exhibits an improved dissolution profile over pure Ketoconazole, with various solid pharmaceutical excipients, as well as its <i>in silico</i> antifungal potential.</p> Methods <p>Binary physical mixtures (1:1 w/w) of KTZ-AA co-crystal and excipients were analyzed using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The molecular docking study targeting the sterol 14α-demethylase (CYP51) enzyme of the pathogenic yeast <i>Candida albicans</i> was performed.</p> Results <p>DSC results indicated compatibility between co-crystal and six tested excipients: lactose monohydrate, polyvinylpyrrolidone K90, microcrystalline cellulose, corn starch, colloidal silicon dioxide, and talc. In the case of the co-crystal and magnesium stearate mixture, DSC revealed a change in the thermal behavior, suggesting the formation of a eutectic system. However, TGA demonstrated that the decomposition profile of the co-crystal remained unaffected in all binary mixtures. PXRD and FT-IR further confirmed the absence of chemical interactions between the co-crystal and all excipients under ambient conditions. Moreover, the KTZ-AA co-crystal maintained its chemical stability without degradation after three months storage under accelerated conditions (40°C/75% RH). The molecular docking study demonstrated that co-crystallization of KTZ with AA enhances its binding affinity to CYP51 enzyme compared to KTZ alone.</p> Conclusion <p>The excipient compatibility study conducted on the Ketoconazole-Adipic Acid co-crystal confirmed its potential for development as a solid oral dosage form with improved antifungal activity, presenting a promising alternative to the parent drug.</p>

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Pharmaceutical Co-crystal of Ketoconazole-adipic Acid: Excipient Compatibility and In Silico Antifungal Potential Studies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月4日

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  • Flavia Martin,
  • Maria Miclaus,
  • Ana Maria Raluca Gherman,
  • Monica Dan,
  • Ioana Grosu,
  • Xenia Filip,
  • Irina Kacso

摘要

Objective

This research aimed to investigate the compatibility of the Ketoconazole-Adipic Acid (KTZ-AA) co-crystal, which exhibits an improved dissolution profile over pure Ketoconazole, with various solid pharmaceutical excipients, as well as its in silico antifungal potential.

Methods

Binary physical mixtures (1:1 w/w) of KTZ-AA co-crystal and excipients were analyzed using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The molecular docking study targeting the sterol 14α-demethylase (CYP51) enzyme of the pathogenic yeast Candida albicans was performed.

Results

DSC results indicated compatibility between co-crystal and six tested excipients: lactose monohydrate, polyvinylpyrrolidone K90, microcrystalline cellulose, corn starch, colloidal silicon dioxide, and talc. In the case of the co-crystal and magnesium stearate mixture, DSC revealed a change in the thermal behavior, suggesting the formation of a eutectic system. However, TGA demonstrated that the decomposition profile of the co-crystal remained unaffected in all binary mixtures. PXRD and FT-IR further confirmed the absence of chemical interactions between the co-crystal and all excipients under ambient conditions. Moreover, the KTZ-AA co-crystal maintained its chemical stability without degradation after three months storage under accelerated conditions (40°C/75% RH). The molecular docking study demonstrated that co-crystallization of KTZ with AA enhances its binding affinity to CYP51 enzyme compared to KTZ alone.

Conclusion

The excipient compatibility study conducted on the Ketoconazole-Adipic Acid co-crystal confirmed its potential for development as a solid oral dosage form with improved antifungal activity, presenting a promising alternative to the parent drug.