Towards physics-based solubility computation for pharmaceuticals to rival informatics

Fowles, Daniel J. and Palmer, David S. and Guo, Rui and Price, Sarah L. and Mitchell, John B. O. (2021) Towards physics-based solubility computation for pharmaceuticals to rival informatics. Journal of Chemical Theory and Computation, 17 (6). pp. 3700-3709. ISSN 1549-9618 (https://doi.org/10.1021/acs.jctc.1c00130)

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Abstract

We demonstrate that physics-based calculations of intrinsic aqueous solubility can rival cheminformatics-based machine learning predictions. A proof-of-concept was developed for a physics-based approach via a sublimation thermodynamic cycle, building upon previous work that relied upon several thermodynamic approximations, notably the 2RT approximation, and limited conformational sampling. Here, we apply improvements to our sublimation free-energy model with the use of crystal phonon mode calculations to capture the contributions of the vibrational modes of the crystal. Including these improvements with lattice energies computed using the model-potential-based ψmol method leads to accurate estimates of sublimation free energy. Combining these with hydration free energies obtained from either molecular dynamics free-energy perturbation simulations or density functional theory calculations, solubilities comparable to both experiment and informatics predictions are obtained. The application to coronene, succinic acid, and the pharmaceutical desloratadine shows how the methods must be adapted for the adoption of different conformations in different phases. The approach has the flexibility to extend to applications that cannot be covered by informatics methods.

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• Item metadata

  Item type:	Article
  ID code:	76293
  Dates:	Date Event 8 June 2021 Published 14 May 2021 Published Online 30 April 2021 Accepted 4 February 2021 Submitted
  Subjects:	Science > Chemistry
  Department:	Faculty of Science > Pure and Applied Chemistry
  Depositing user:	Pure Administrator
  Date deposited:	04 May 2021 07:56
  Last modified:	12 Apr 2024 00:27
  URI:	https://strathprints.strath.ac.uk/id/eprint/76293