Solubility prediction of paracetamol in polyvinyl pyrrolidone using the SAFT-γ Mie group-contribution approach Shubhani Paliwal, Andrew J. Haslam, George Jackson and Amparo Galindo Imperial College London, United Kingdom Understanding the phase behaviour of poorly soluble active pharmaceutical ingredients (APIs) in excipients that might lead to an increase in their bioavailability is a crucial step in the formulation of amorphous solid dispersions. Solubility is identified as a key property to study as it determines the load of API that can be dissolved in the polymer and how the shelf life can be increased without recrystallization of the API. Recent theoretical progress is making the accurate modelling of phase behaviour, including solubility, a reality and can account for a wide range of complex features of molecules. The SAFT-Mie group contribution approach [1] has been shown to deliver accurate predicted solubilities of APIs in liquid solvents, e.g., Febra et al. [2] developed group interactions for mefenamic acid, diphenylamine, and benzoic acid drugs in a range of pure and mixed solvents The approach has also been used to study the pH-solubility profile of aqueous solutions of acidic APIs [3]. Here, the approach is used to study the solubility of paracetamol (APAP) in polyvinyl pyrrolidone (PVP). The matrix of group interactions available is extended to incorporate groups relevant to the molecules of interest. In particular, the C=ONH, aCH, aCOH, and aC groups are characterised in order to model APAP. Experimental data for the bubble and dew pressure, single-phase excess enthalpy and single-phase density of N-methyl acetamide mixtures with benzene, phenol, and naphthalene are used to parameterise the unlike interactions. Solubility and excess enthalpy data of the same mixtures are used to assess the predictive accuracy of the estimated parameters. The groups relevant to PVP (cN, cCH 2, and cC=O) are parameterised to treat the pure polymer. The solid—liquid solubility prediction of APAP in PVP is presented. References 1. V. Papaioannou et al. , ‘Group contribution methodology based on the statistical associating fluid theory for heteronuclear molecules formed from Mie segments’, Journal of Chemical Physics , vol. 140, no. 5, Feb. 2014, doi: 10.1063/1.4851455. 2. S. A. Febra et al. , ‘Extending the SAFT-γ Mie approach to model benzoic acid, diphenylamine, and mefenamic acid: Solubility prediction and experimental measurement’, Fluid Phase Equilib , vol. 540, 2023. 3. M. Wehbe, A. J. Haslam, G. Jackson, and A. Galindo, ‘Phase behaviour and pH-solubility profile prediction of aqueous buffered solutions of ibuprofen and ketoprofen’, Fluid Phase Equilib , vol. 560, Sep. 2022, doi: 10.1016/j.fluid.2022.113504.
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