Machine learning-based solubility prediction and methodology evaluation of active pharmaceutical ingredients in industrial crystallization

Abstract

Solubility has been widely regarded as a fundamental property of small molecule drugs and drug candidates, as it has a profound impact on the crystallization process. Solubility prediction, as an alternative to experiments which can reduce waste and improve crystallization process efficiency, has attracted increasing attention. However, there are still many urgent challenges thus far. Herein we used seven descriptors based on understanding dissolution behavior to establish two solubility prediction models by machine learning algorithms. The solubility data of 120 active pharmaceutical ingredients (APIs) in ethanol were considered in the prediction models, which were constructed by random decision forests and artificial neural network with optimized data structure and model accuracy. Furthermore, a comparison with traditional prediction methods including the modified solubility equation and the quantitative structure-property relationships model was carried out. The highest accuracy shown by the testing set proves that the ML models have the best solubility prediction ability. Multiple linear regression and stepwise regression were used to further investigate the critical factor in determining solubility value. The results revealed that the API properties and the solute-solvent interaction both provide a nonnegligible contribution to the solubility value.

Graphical abstract

Keywords

solubility prediction / machine learning / artificial neural network / random decision forests

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21938009).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://dx.doi.org/10.1007/s11705-021-2083-5 and is accessible for authorized users.

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