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An evaluation of thermodynamic models for the prediction of drug and drug-like molecule solubility in organic solvents

Bouillot, Baptiste and Teychené, Sébastien and Biscans, Béatrice An evaluation of thermodynamic models for the prediction of drug and drug-like molecule solubility in organic solvents. (2011) Fluid Phase Equilibria, 309 (1). 36-52. ISSN 0378-3812

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Official URL: http://dx.doi.org/10.1016/J.FLUID.2011.06.032


Prediction of solubility of active pharmaceutical ingredients (API) in different solvents is one of the main issue for crystallization process design. Experimental determination is not always possible because of the small amount of product available in the early stages of a drug development. Thus, one interesting perspective is the use of thermodynamic models, which are usually employed for predicting the activity coefficients in case of Vapour–Liquid equilibria or Liquid–Liquid equilibria (VLE or LLE). The choice of the best thermodynamic model for Solid–Liquid equilibria (SLE) is not an easy task as most of them are not meant particularly for this. In this paper, several models are tested for the solubility prediction of five drugs or drug-like molecules: Ibuprofen, Acetaminophen, Benzoic acid, Salicylic acid and 4-aminobenzoic acid, and another molecule, anthracene, a rather simple molecule. The performance of predictive (UNIFAC, UNIFAC mod., COSMO-SAC) and semi-predictive (NRTL-SAC) models are compared and discussed according to the functional groups of the molecules and the selected solvents. Moreover, the model errors caused by solid state property uncertainties are taken into account. These errors are indeed not negligible when accurate quantitative predictions want to be performed. It was found that UNIFAC models give the best results and could be an useful method for rapid solubility estimations of an API in various solvents. This model achieves the order of magnitude of the experimental solubility and can predict in which solvents the drug will be very soluble, soluble or not soluble. In addition, predictions obtained with NRTL-SAC model are also in good agreement with the experiments, but in that case the relevance of the results is strongly dependent on the model parameters regressed from solubility data in single and mixed solvents. However, this is a very interesting model for quick estimations like UNIFAC models. Finally, COSMO-SAC needs more developments to increase its accuracy especially when hydrogen bonding is involved. In that case, the predicted solubility is always overestimated from two to three orders of magnitude. Considering the use of the most accurate equilibrium equation involving the ΔCp term, no benefits were found for drug predictions as the models are still too inaccurate. However, in function of the molecules and their solid thermodynamic properties, the ΔCp term can be neglected and will not have a great impact on the results.

Item Type:Article
Additional Information:Thanks to Elsevier editor. The definitive version is available at http://www.sciencedirect.com The original PDF of the article can be found at :http://www.sciencedirect.com/science/article/pii/S0378381211003141
HAL Id:hal-03539264
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Université de Toulouse > Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Laboratory name:
Laboratoire de Génie Chimique - LGC (Toulouse, France) - Génie des Interfaces & Milieux Divisés (GIMD)
Deposited On:02 Jul 2012 14:14

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