(414g) Predicting Optimal Salt Forms for Active Pharmaceutical Ingredients Using the SAFT-? Mie Equation of State

The pharmaceutical industry is facing a constantly rising demand for drugs of growing complexity and more efficient manufacturing processes. The solubility of pharmaceuticals is a key property during the drug formulation and the subsequent design of the processes involved in the manufacturing of the drug. Common challenges in these manufacturing processes include: the large number of experiments required and the extremely low solubilities of active pharmaceutical ingredients (APIs) in water for which experiments are difficult to perform. Computer-aided approaches provide an attractive alternative to performing time-consuming and costly experiments. In this context, molecular modelling approaches can deliver physical properties predictively are key enabling tools.

The SAFT-γ Mie group contribution (GC) equation of state (EoS) [1, 2] is such a predictive thermodynamic modelling technique. In the SAFT-γ Mie framework, molecules are modelled as heteronuclear chains formed from fused spherical segments, which represent the distinct functional groups comprising the molecule. In this framework, it is assumed that the properties of a molecule or a mixture can be determined from the weighted contributions of the functional groups present in the system of interest, with the assumption that the parameters characterizing the functional groups are fully transferable across molecules.

We demonstrate the validity of the SAFT-γ Mie EoS in the prediction of thermodynamic properties of ionizable APIs. The pH-solubility profiles and the complete phase diagrams of the APIs in water, outlining the solid-liquid, liquid-liquid and vapour-liquid equilibria for these mixtures, are successfully predicted. It is well known that the bioavailability of a drug is improved by salt formulation, which is the preferred method to enhance the solubility of ionizable drugs. The SAFT-γ Mie EoS accounts for the complex speciation phenomena that take place under pH changes including partially ionised (weak electrolytes) systems. We demonstrate the effect on the pH-solubility profile of ibuprofen of multiple inorganic counter ions including sodium, potassium, lithium, calcium and magnesium. This is followed by studying the impact of organic counter ions, particularly the amines, on the pH-solubility profile of ibuprofen and the selection of its optimal salt form.

[1] Papaioannou, V. et al. J. Chem. Phys. 140, (2014).

[2] Dufal, S. et al. J. Chem. Eng. Data 59, (2014).