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Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus

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Abstract

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (xe) was validated using the Van ʼt Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy ΔsolH°, entropy ΔsolS°, and Gibbs free energy ΔsolG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10−1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10−5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on xe gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of ΔsolH° and ΔsolG°. Interestingly, ΔsolG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of ΔsolG° and ΔsolS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.

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Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group number RG-1441-462.

Funding

This research was funded by the Deanship of Scientific Research at King Saud University, grant number “RG-1441-462”. The English language correction service was funded by the “Deanship of Scientific Research at King Saud University.”

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Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Afzal Hussain, Mohammad A. Altamimi, Sultan Alshehri, Syed Sarim Imam & Usamah Abdulrahman Alnemer

  2. Sai Nath University, Ranchi, Jharkhand, 835219, India

    Md. Wasimul Haque

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  1. Afzal Hussain
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  2. Mohammad A. Altamimi
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  3. Sultan Alshehri
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  5. Usamah Abdulrahman Alnemer
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  6. Md. Wasimul Haque
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Contributions

Afzal Hussain: conceptualization, software, writing—original draft preparation. Mohammad A. Altamimi: software, validation: data curation and reviewing. Sultan Alshehri: conceptualization, and software. Syed Sarim Imam: analysis and data curation. Osamah Abdulrahman Alnemer: drafting and review. Wasimul Haque: data curation and software analysis. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Afzal Hussain.

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Hussain, A., Altamimi, M.A., Alshehri, S. et al. Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus. AAPS PharmSciTech 22, 194 (2021). https://doi.org/10.1208/s12249-021-02075-x

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