Effect of Electrolytes on Octanol‐Water Partition Coefficients: Calculations with COSMO‐RS

Abstract

In this work, the possibility of the a priori predictive model COSMO-RS to describe partitioning of pharmaceutically active compounds in the octanol-water system (P OW ) in the presence of electrolytes is investigated. It is shown that the calculated values of P OW depend on the pH and the ionic strength of the solution for both dissociated and non-dissociated solutes. Whereas the partitioning of the non-dissociated form in the presence of salts or buffers can be explicitly described by COSMO-RS, the partitioning of the ionized pharmaceuticals is taken into account by their dissociation constants. Overall, reasonable agreement with experimental values is achieved. Principally, these types of calculations can be extended to other two-phase systems used for extraction and formulations of pharmaceuticals and further organic solutes. IntroductionPartition coefficients of organic solutes in the octanol-water system play an important role in chemical engineering and the pharmaceutical industry, being one of the standards to characterize the lipophilicity of a given substance. Therefore, methods to predict partition coefficients are of special value, especially those which are based on structural information and require no further experimental data. Among those, the method of Leo and Hansch (ClogP) became widespread in the scientific community because of its simplicity and high availability of the model parameters [1]. Besides this, thermodynamics-based models for the prediction of activity coefficients, like UNIFAC (UNIFAC-Kow) [2] and COSMO-RS [3], were successfully used for this purpose. A large number of octanolwater and other solvent-water partition coefficients of different solute classes were well predicted with COSMO-RS [4,5]. However, the presence of ions in the form of salts, buffers, or dissociated solutes limits the modeling possibilities considerably. The Leo and Hansch model is not able to describe the influence of electrolytes on the solute partitioning explicitly, whereas UNIFAC (modification for electrolytes) [6 and citations therein] and COSMO-RS [3], as well as several QSAR models [7] are principally able to do so. The ability of COSMO-RS to describe systems containing ionic compounds was demonstrated for the systems containing ionic liquids and ionic surfactants [5,8]. Although the prediction of the activity coefficients of single ions is not directly possible, activity coefficients of neutral compounds in the presence of ions can be calculated.The purpose of this work is to prove the applicability of COSMO-RS to the prediction of the change of partition coefficients of both neutral and dissociating organic substances as a function of pH and salt concentration in the solution. Since the pH influence on partitioning is especially important in the area of drug development, the calculations are performed for pharmaceutically active compounds. Methods COSMO-RSThe COSMO-RS model (Conductor-like Screening Model for Real Solvents) allows for an a priori prediction of thermodynamic properties, such as activ...

Partition Coefficients for Continuous Micellar Reaction Processes

“…Both models are able to calculate partition coefficients in micellar systems as reported in [9]. In addition, COSMO-RS is able to calculate activity coefficients in the mixtures containing ionic species [10]. The goal of the current study is to demonstrate the applicability of these models for a preliminary screening of micellar systems in order to determine those that can be used in a desired MEUF process.…”

“…As already indicated in [8][9][10], it is possible to calculate activity coefficients and thus partition coefficients in micellar systems containing nonionic or ionic surfactants by COSMO-RS. In this work, COSMO-RS (COSMOtherm 2.1 Rev.01.04 package) is applied to calculate micelle-water partition coefficients of reactants, products, and catalyst ligands.…”

“…If ionic surfactants are considered (this option is for COSMO-RS only), the activity coefficients of solute are additionally recalculated as described in [10], and the partition coefficient is then obtained based on the recalculated values.…”

Partition Coefficients of Alkyl Parabens and Ibuprofen in Micellar Systems

“…As shown in [20,21], COSMO-RS is able to model partitioning of non-dissociating solutes in the presence of ionic substances (e.g., surfactants, additives). In this case, however, the value of the activity coefficient obtained as an output of the COSMOtherm program should be recalculated accounting for the electrolyte dissociation (completely dissociated electrolytes).…”

“…Based on quantum mechanics and statistical thermodynamics, it gives the possibility to a priori calculate activity coefficients of non-dissociating substances in solutions, and the only information needed for such calculations is the molecular structure of the mixture constituents. Thus, the activity coefficients of non-dissociating substances in the presence of ions can be predicted in its frame [20,21].…”