Modeling the solid–liquid equilibrium in pharmaceutical‐solvent mixtures: Systems with complex hydrogen bonding behavior

Abstract

in Wiley InterScience (www.interscience.wiley.com).A methodology is suggested for modeling the phase equilibria of complex chemical mixtures with an equation of state (EoS) for the case where only limited experimental data exist. The complex hydrogen bonding behavior is explicitly accounted for and the corresponding parameters are adopted from simpler molecules of similar chemical structure and/or are fitted to Hansen's partial solubility parameters. The methodology is applied to modeling the solubility of three pharmaceuticals, namely acetanilide, phenacetin, and paracetamol, using the nonrandom hydrogen bonding (NRHB) EoS. In all cases, accurate correlations were obtained. The prediction ability of the approach was evaluated against predictions from the COSMO-RS model. A thorough discussion is made for the appropriate modeling of solid solubility considering the effect of the difference of the heat capacities of the solute in liquid and solid state, DCp 5 Cp l 2 Cp s , in the determination of solid chemical potential and, also, of the polymorphism of drugs.

Towards predictive association theories

“…We have recently presented [41,42] a semi-predictive version of the NRHB equation of state for applications to pharmaceuticals. The semi-predictive character lies both in the way the pure compound parameters are estimated for pharmaceuticals (using few data on sublimation pressures, densities and Hansen solubility parameters) as well as on the use of a quasi-group contribution approach adopted for obtaining the interaction parameters between functional groups needed in the association term of the model.…”

“…Consequently, CPA, which is a model more oriented to industrial applications, is used in mixtures with water, glycols, acid gases and hydrocarbons, which are common chemicals in many petroleum related processes. On the other hand, the NRHB model was recently extended to pharmaceuticals and systems with complex hydrogen bonding interactions [41,42]. Consequently, in this work NRHB is applied to predict the solubility of some pharmaceuticals in pure and in mixed solvents as well as to predict the phase behavior of aqueous mixtures of glycols, in which more than one cross-hydrogen bonding interactions are observed.…”

The Role of Chemical Engineering in Medicinal Research Including Alzheimer’s

“…Moreover, these models do not explicitly account for complex interactions present in pharmaceutical mixtures, which are due to the strong intermolecular forces especially polarity and hydrogen bonding. We have recently developed [6,15] for mixtures with pharmaceuticals a theoretically oriented model (called NRHB; non-random hydrogen bonding), based on an advanced theory, which explicitly accounts for hydrogen bonding and other complex interactions. The model is in a form of an equation of state and can thus be used both at low and high pressures, both for single and mixed solvents, wide temperature range and for both pharmaceuticals and polymers.…”

“…The model is described in recent publications [6,15] Experimental data (points), and model predictions using binary interaction parameters from the corresponding binary systems. From Tsivintzelis et al [15].…”

“…The significant role of chemical engineering in medicinal research and biotechnology has been intensively recognized, especially during the last 20 or so years, with thermodynamics being one of the disciplines of importance [1][2][3][4][5][6]. In downstream biotechnology, the main interest is in the design of separation processes such as chromatography and crystallization.…”