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The prediction of the solubility of active pharmaceutical ingredients (APIs) is a significant challenge which is of importance in pharmaceutical applications and solvent selection. Here, we extend the table of group interactions (3 like interactions, 47 unlike interactions) of the SAFT- γ Mie group-contribution equation of state to model the phase behaviour and solubility of mefenamic acid, a nonsteroidal anti-inflammatory drug, in a range of solvents. In addition to mefenamic acid, we also consider its molecular synthons: benzoic acid and diphenylamine. New experimental solubility data are presented for the three molecules in a range of solvents, and three new SAFT- γ Mie functional groups are defined (aCCOOH, aCNHaC and CH 3 CO) and characterised, together with their interactions with solvent groups. Literature data for the vapour pressure, single-phase density, saturation density, vapourisation enthalpy, bubble temperature, dew temperature, and bubble pressure are used to characterise the new group interactions. Solubility data are used to characterise the new group-group interactions only if there are no other experimental data available. The transferability and predictive accuracy of the new models are assessed by comparing the theoretical predictions with the experimental solubility data. Our comparison includes alcohols, ketones, and esters as families of solvents and mixed-solvent solubility predictions.

Group contribution (GC) methodologies have been combined with the statistical associating fluid theory (SAFT), to couple the predictive capabilities of GC methods with the accuracy of the SAFT description of complex fluids and fluid mixtures. An example of such an procedure is the SAFT-γ group contribution approach [A. Lymperiadis, C.S. Adjiman, A. Galindo, G. Jackson, J. Chem. Phys., 127 (2007) 234903], which was developed based on the SAFT-VR equation of state and employs a heteronuclear molecular model of fused segments which represent the various chemical groups. In this work we examine the predictive capabilities of the method focusing on the fluid phase behaviour of aqueous mixtures. Within SAFT-γ it is often possible to obtain information for both the like and unlike group interactions from pure component fluid thermophysical data alone. When this is not possible, e.g., in the case of water where the whole molecule represents a distinct chemical “group”, the interactions can be obtained, in the usual activity coefficient GC fashion, from a minimal amount of experimental fluid phase equilibrium data of the appropriate mixtures. The group like and unlike parameters can then be successfully transferred to represent the thermophysical properties and fluid phase behaviour of a wide range of mixtures in a predictive manner. The binary systems investigated in this work are aqueous solutions of alkanes and alkanols. The successful description of the highly non-ideal fluid phase behaviour of systems of this kind with transferable interaction parameters within the SAFT-γ approach and the simultaneous prediction of both vapour–liquid and liquid–liquid equilibria using the same parameters are the key contributions of our work.

We present a simplified but consistent picture of asphaltene precipitation from crude oil from a thermodynamic perspective, illustrating its relationship to the familiar bubble curve via the calculation of constant-composition p–T phase diagrams that incorporate both the bubble curve and the asphaltene precipitation boundary. Using the statistical associating fluid theory (SAFT) we show that the position of the precipitation boundary can be explained using a very simple fluid model including relatively few components. Our results support the view that the precursor to asphaltene precipitation is a liquid–liquid phase separation due to a demixing instability in the fluid. Moreover, the bubble curve for these systems is seen to represent a boundary between regions of two-phase (liquid–liquid) and three-phase (vapour–liquid–liquid) equilibria.

The methodology presented in Part I of this work is applied to a large number of pressure–temperature flash calculations, and to the automated construction of constant temperature pressure–composition phase diagrams, and constant pressure temperature–composition phase diagrams for binary mixtures modeled with an augmented van der Waals equation of state. An automated prototype implementation of the algorithm is developed for this purpose. We follow the classification of Scott and van Konynenburg [R.L. Scott, P.H. van Konynenburg, Discuss. Faraday Soc. 49 (1970) 87] and present phase diagrams corresponding to non-azeotropic mixtures of the five main types of fluid phase behavior (I–V), studying in detail representative diagrams at constant pressure and constant temperature. Special attention is given to the solution of numerically problematic equilibrium regions, such as those close to three-phase equilibria where metastable and unstable critical points can also be found. Of the order of 10 4 flash calculations at varying temperatures and pressures, and for different intermolecular parameters of the components in the mixture, have been carried out. The algorithm provides the correct stable equilibrium state for all of the points considered. Despite the fact that our implementation is not optimised for performance, we find that the algorithm identifies the stable solution in difficult regions of the phase space without any penalty in terms of computational time, when compared to simpler regions.

A new group contribution (GC) approach based on the statistical associating fluid theory (SAFT- γ ) has recently been proposed [A. Lymperiadis, C. S. Adjiman, A. Galindo, G. Jackson, J. Chem. Phys. 127 (2007) 234903]. In this continuum equation of state GC approach, the molecules are formed from fused heteronuclear spherical segments each of which represents a distinct chemical functional group. The different segments are characterised by size and attractive energy (well-depth and range) parameters, and a shape-factor parameter which describes the contribution that each segment makes to the overall molecular properties. In addition a number of bonding sites are included on a given segment to deal with association interactions where appropriate; the association between sites introduces two additional energy and range parameters. Our heteronuclear molecular models are thus fundamentally different from the homonuclear models employed with other GC versions of SAFT in which the GC concept is introduced to obtain average molecular parameters. In the current work, we generalise the SAFT- γ equation of state to treat chemical groups which are represented by more than a single spherical segment. This allows for a good description of the properties of large functional groups such as carboxyl and carbonyl groups. The original parameter table for the CH3, CH2, CH3CH, ACH (where AC denotes an aromatic carbon), ACCH2, CH2 , CH and OH groups is now extended to include the C O, COOH, and NH2 groups by examining the vapour–liquid equilibria (VLE) of pure 2-ketones, carboxylic acids, and primary amines. It is demonstrated that the proposed theory provides an excellent description of the vapour–liquid equilibria for all of the chemical families considered, and that the new group parameters can be used in a predictive fashion to model the phase behaviour of larger compounds not included in the estimation database. One of the principal advantages of the SAFT- γ formalism is that the binary interaction parameters between groups of different types can be estimated from pure component data alone. This is particularly useful in describing the properties of fluid mixtures. The adequacy of the method in predicting the VLE is assessed for selected binary mixtures of associating and non-associating compounds. A strict test of any GC method is its ability to capture both vapour–liquid and liquid–liquid equilibria (LLE) with the same set of group parameters. It is very gratifying to find that with SAFT- γ one is able to reproduce the VLE and LLE behaviour for several mixtures simultaneously, for example, n- hexane + propanone , and n- pentane + polyethylene .

The estimation of two primary properties by group contribution and five secondary properties by correlation is proposed in this work. The primary properties are Abraham’s hydrogen-bond basicity and acidity. The secondary properties are the Hildebrand solubility parameter, the macroscopic surface tension, the dipole moment, the refractive index and the dielectric constant. Temperature-dependent properties are estimated at 298 K. A database of experimental data for up to 870 compounds that can be represented by 41 UNIFAC groups is developed in order to perform regressions. The only information required to estimate the properties is the number and type of UNIFAC groups in the compound of interest. Several statistics, including confidence intervals on group parameters, are considered during the development of the techniques. Because no connectivity information is required, the methods are expected to perform well for compounds where there are no significant proximity effects.

The identification of the global minimum energy configuration of molecular clusters has found many useful applications, including the calculation of solvent–solute interactions for phase equilibria prediction. Given the need to reliably identify the global minimum and other low-energy configurations, a fully deterministic global optimization algorithm is proposed. The potential energy is calculated using the OPLS force field [J. Am. Chem. Soc. 118 (1996) 11225] and the minimization problem is formulated using 3 N –6 independent internal coordinates where N is the total number of atoms. A branch-and-bound framework is used to solve the problem. Tight convex underestimators have been derived for the non-convex terms and bounds for the dependent variables are calculated using interval arithmetic. The algorithm generates a converging sequence of upper and lower bounds. The algorithm is illustrated through the calculation of the global minimum configuration of a butane molecule, and a butane-ethylamine pair.

The speciation reactions that take place in mixtures of water (H2O), carbon dioxide (CO2), and alkanolamines make the modelling of the chemical and fluid-phase equilibria of these systems challenging. We demonstrate for the first time that the statistical associating fluid theory (SAFT), formulated within a group-contribution (GC) framework based on transferable intermolecular square-well (SW) potentials (SAFT-γ SW), can be used to model successfully such complex reacting systems. The chemical reactions in these mixtures are described via a physical association model. The concept of second-order groups is introduced in the SAFT-γ SW approach in order to deal with the multifunctional nature of the alkanolamines. In developing the models, several compounds including ethylamine, propylamine, ethanol, propanol, 2-aminoethanol, and 3-amino-1-propanol are considered. We present calculations and predictions of the fluid-phase behaviour of these compounds and a number of their aqueous mixtures with and without CO2. The group-contribution nature of the models is used to predict the absorption of CO2 in aqueous solutions of 5-amino-1-pentanol and 6-amino-1-hexanol. The proposed predictive approach offers a robust platform for the identification of new solvents and mixtures that are viable candidates for CO2 absorption, thereby guiding experimental studies.