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Hydration Mechanism and Its Effect on the Solubility of Aripiprazole

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Abstract

Propose

The propose is to investigate the reasons for the insolubility of Form III in water and to explore the mechanism of the hydration process of Form III.

Methods

The conformational and cohesive energies of Form III and Form H1 were calculated using Gaussian 16 and Crystal Explorer 17. Gaussian 16 and Multiwfn 3.8 was used to calculate the molecular surface electrostatic potential of Form III and Form H1 and to calculate the energies of the stronger intermolecular interactions in the crystal structure. The behaviors of Form III in water were simulated using Gromacs 2020.6. Finally, the hydration process from Form III to Form H1 was monitored in situ using Raman spectroscopy.

Results

The conformational energies of Form III and H1 are almost the same. The cohesion energy of Form H1 is much larger than that of Form III because both number of hydrogen bonds and van der Waals interactions are higher in the Form H1. During the simulation, the supercell of APZ form a supramolecular cluster. Several molecules manually dismantled from the cluster spontaneously combine to form new molecular clusters. Both increases in temperature and external energy input accelerate the hydration process.

Conclusions

More hydrogen bonds and strong van der Waals interactions in Form H1 lead to a greater stability. The overall decrease in polarity and the strong binding effect on APZ molecule clusters due to intermolecular interactions lead to the water insolubility of Form III. The hydration process from Form III to Form H1 follows a novel, dandelion sowing-like hydration mechanism.

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Data Availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

This research was financially supported by National Natural Science Foundation of China (No. 21978201 and No. 21908159).

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Authors and Affiliations

  1. The National Engineering Research Center of Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China

    Zhixin Zheng, Xin Huang, Na Wang, Ting Wang, Lina Zhou, Zhao Xu & Hongxun Hao

  2. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300072, China

    Xin Huang, Na Wang, Ting Wang & Hongxun Hao

  3. Zhejiang Institute of Tianjin University, Ningbo, Zhejiang, 315201, China

    Xin Huang

  4. Zhejiang Sundoc Pharmaceutical Science and Tech Co., Ltd, Hangzhou, China, 310051, Zhejiang

    Guibin Chen & Wan Cao

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  1. Zhixin Zheng
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Zheng, Z., Huang, X., Wang, N. et al. Hydration Mechanism and Its Effect on the Solubility of Aripiprazole. Pharm Res 41, 113–127 (2024). https://doi.org/10.1007/s11095-023-03618-6

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