COSMO-SAC Activity Coefficient Model Research Articles

COSMOPharm: Drug-Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC.

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.

Towards design of phase separation solvent for CO2 capture using COSMO-SAC model

There is a growing interest in developing CO2 capture processes based on phase separation solvents due to its much lower energy consumption compared to the reference amine process using monoethanolamine (MEA). In this work, the predictive COSMO-SAC activity coefficient model was applied to describe phase behavior for phase separation solvent composed of amine + water + glycol ether. From the calculated ternary liquid-liquid equilibrium (LLE) phase diagram, ternary mixtures of fourteen selected amines + water + glycol ether can be classified into miscible- or immiscible-type solvents. The work presented here indicates that amines having comparable affinity to water and glycol ether generally result in a smaller two-phase region and form type I phase behavior near the amine-lean region. The amines having a strong affinity to water or glycol ether show a larger two-phase region and result in type II phase behavior. Further analysis shows that KOW and σ-profile can be good indicators for the affinity of amine to water and glycol ether, which is the key factor to determine the phase behavior of investigated ternary mixtures. The feed composition and operating temperature of phase separation solvent should be judged by the interaction between solvent molecules. This study demonstrates that COSMO-SAC is a useful tool for exploiting the phase behavior of potential phase separation solvents with limited available experimental data.

Fully Automated Molecular Design with Atomic Resolution for Desired Thermophysical Properties

The value of fine and specialty chemicals is often determined by the specific requirements in their physical and chemical properties. Therefore, it is most desirable to design the structure of chemicals to meet some targeted material properties. In the past, the design of specialty chemicals has been based largely on experience and trial-and-error. However, recent advances in computational chemistry and machine learning can offer a new path to this problem. In this presentation, we demonstrate a successful example where the structure of a chemical of specified value of octanol–water partition coefficient (Kow) can be predicted by computers. This method consists of two parts, the first being a robust method, the COSMO-SAC activity coefficient model, that predicts the activity coefficient with input of only the molecular structure. The second component of this method is a derivative-free optimization algorithm that searches in the multidimensional structure space for the desired value of Kow. In particular,...

A Critical Evaluation on the Performance of COSMO-SAC Models for Vapor–Liquid and Liquid–Liquid Equilibrium Predictions Based on Different Quantum Chemical Calculations

The performance of two versions of the COSMO-SAC activity coefficient model is carefully examined based on eight sets of quantum chemical computations [VWN-BP/DNP, b3lyp/6-31G(d,p), b3lyp/6-31G(2d,p), b3lyp/6-31+G(d,p), b3lyp/6-311G(d,p), wb97xd/6-31G(d,p), wb97xd/6-31G(2d,p), and wb97xd/6-31+G(d,p)] and one semiempirical calculation (PM6). Furthermore, the effect of the molecular geometry is examined based on equilibrium structures determined both in a vacuum, representing a nonpolar environment, and in a conductor, representing a highly polar environment. The model parameters are reoptimized for each quantum chemical calculation method, and the performance is evaluated using a large set of databases covering the vapor–liquid equilibrium, liquid–liquid equilibrium, infinite-dilution activity coefficient of binary mixtures, and octanol–water partition coefficient (Kow; containing over 22000 data points). It is found that the original COSMO-SAC model is sensitive to the quantum chemical method used, wherea...

Prediction of pH Effect on the Octanol–Water Partition Coefficient of Ionizable Pharmaceuticals

The octanol–water partition coefficient (KOW) is a measure of the relative hydrophobicity and hydrophilicity of a chemical. Knowledge regarding how this value changes with the acidity (pH value) in the aqueous phase is important for understanding many biological activities. In this work, we develop a computational method to predict the effect of pH on the partition coefficient of ionizable drugs. In particular, three dissociation mechanisms were examined based on four relevant properties: the acid dissociation constant (pKa), and the octanol–water partition coefficient of the molecule in the neutral form (KOW,N), in the form of free ions (KOW,I) and in the form of an ion pair (KOW,IP). The values of KOW,N, KOW,I, and KOW,IP are predicted based on the COSMO-SAC activity coefficient model, and the value of pKa is determined using the SMD solvation model. The root-mean-square (RMS) error in the predicted log KOW,N, log KOW,IP, and pKa for 41 pharmaceuticals are found to be 0.636, 0.816, and 2.59, respectivel...

Chain length effect of ionic liquid 1-alkyl-3-methylimidazolium chloride on the phase equilibrium of methane hydrate

A high pressure differential scanning calorimeter was used to determine the dissociation temperature of methane hydrate in the presence of ionic liquid 1-alkyl-3-methylimidazolium chloride under a constant pressure ranging from 5 to 35 MPa. A homologous series of 1-alkyl-3-methylimidazolium chloride with different alkyl chain lengths: 1-ethyl-3-methylimidazolium chloride, 1-hexyl-3-methylimidazolium chloride and 1-decyl-3-methylimidazolium chloride, were chosen to examine the chain length effect on the dissociation temperature for methane hydrates. All these ionic liquids have inhibition effect on methane hydrate formation. Moreover, the shorter the alkyl chain length is, the stronger the inhibition effect is. That is, the inhibition effect of these ionic liquids on the methane hydrate formation is in the order of 1-ethyl-3-methylimidazolium chloride>1-hexyl-3-methylimidazolium chloride>1-decyl-3-methylimidazolium chloride. The three-phase vapor–liquid–hydrate equilibrium condition of methane hydrate in the presence of 1-alkyl-3-methylimidazolium chloride was successfully described by a predictive thermodynamic model. The Peng–Robinson–Stryjek–Vera equation of state incorporated with COSMO-SAC activity coefficient model and the first order modified Huron–Vidal mixing rule were applied to evaluate the fugacity of vapor and liquid phase. An explicit pressure dependence of the Langmuir adsorption constant in the modified van der Waals and Platteeuw model was applied to determine the fugacity of hydrate phase. The average absolute relative deviation in predicted dissociation temperature from the predictive thermodynamic model was 0.54%. In addition, these experimental data of dissociation temperatures were further correlated to a general correlation of Østergaard et al. (J. Petroleum Sci. Eng. 48 (2005) 70–80) and the average absolute relative deviation in the correlated dissociation temperature was 0.05%.

Inhibition effect of 1-ethyl-3-methylimidazolium chloride on methane hydrate equilibrium

The dissociation conditions of methane hydrate in the presence of 0.1, 0.2, 0.3 and 0.4 mass fraction of 1-ethyl-3-methylimidazolium chloride (abbreviated by EMIM-Cl hereafter) were experimentally determined. A high pressure micro-differential scanning calorimeter equipped with a motorized pump was applied to measure the dissociation temperature of the (hydrate+liquid water+vapor) three-phase equilibrium under a constant pressure process with a pressure ranging from (5.0 to 35.0)MPa. The addition of EMIM-Cl would inhibit the methane hydrate formation. The most significant inhibition effect was observed at 0.4 mass fraction of EMIM-Cl in aqueous solution to lower the dissociation temperature by 12.82K at 20.00MPa in comparison to that of the (methane+water) system. The Peng–Robinson–Stryjek–Vera equation of state incorporated with COSMO-SAC activity coefficient model and the first order modified Huron–Vidal mixing rule were applied to evaluate the fugacity of vapor and liquid phase. A modified van der Waals and Platteeuw model with an explicit pressure dependence of the Langmuir adsorption constant was applied to determine the fugacity of hydrate phase. The predictive thermodynamic model successfully describes the tendency of phase behavior of methane hydrate in the presence of EMIM-Cl in the range from 0.1 to 0.4 mass fraction with absolute average relative deviation in predicted temperature of 0.70%.

Screening of ionic liquids for CO2 capture using the COSMO-SAC model

In this work, we develop a simple method that can be used to screen for the ionic liquid (IL) candidates for use in various CO2 capture processes. In particular, Henry׳s law constant, an important physical quantify determining the capacity and selectivity of CO2 absorption, is determined from the product of infinite dilution activity coefficient (IDAC) of a gas molecule in an IL and the fugacity of the gas in a hypothetical liquid state. The IDAC is calculated using the predictive COSMO-SAC activity coefficient model, where the interaction between the gas and the IL are determined through the screening charges on the molecular surfaces obtained from quantum mechanical solvation calculations. We have developed a simple model for the fugacity of 4 gas molecules, including CO2, CH4, N2 and H2, and examined the solubility, selectivity, and the temperature dependency of solubility. The predicted results for Henry׳s law constant of CO2 in ILs are in good agreement with experimental data (53 data points) over a wide range of temperatures (from 283K to 303K), with an average absolute relative deviation (ARD) of 17%. This method is used to screen for the best IL candidates for CO2 capture from a set of 2080 ILs combined from 65 cations and 32 anions. The computational time used for screening for this set of IL is less than 3min on a personal computer. Our results show that the COSMO-SAC model can be a powerful method for the design and screening of new ILs as a medium for CO2 capture.

Prediction of Phase Equilibrium of Methane Hydrates in the Presence of Ionic Liquids

In this work, a predictive method is applied to determine the vapor–liquid-hydrate three-phase equilibrium condition of methane hydrate in the presence of ionic liquids and other additives. The Peng–Robinson–Stryjek–Vera Equation of State (PRSV EOS) incorporated with the COSMO-SAC activity coefficient model through the first order modified Huron–Vidal (MHV1) mixing rule is used to evaluate the fugacities of vapor and liquid phases. A modified van der Waals and Platteeuw model is applied to describe the hydrate phase. The absolute average relative deviation in predicted temperature (AARD-T) is 0.31% (165 data points, temperature ranging from 273.6 to 291.59 K, and pressure ranging from 1.01 to 20.77 MPa). The method is further used to screen for the most effective thermodynamic inhibitors from a total of 1722 ionic liquids and 574 electrolytes (combined from 56 cations and 41 anions). The valence number of ionic species is found to be the primary factor of inhibition capability, with the higher valence lea...

Prediction of Phase Behaviors of Polymer–Solvent Mixtures from the COSMO-SAC Activity Coefficient Model

An efficient method for prediction of the vapor–liquid and liquid–liquid phase behaviors of polymer–solvent mixtures is proposed using the COSMO-SAC activity coefficient model. In particular, we examine various approaches for generating the screening charge distribution of homepolymers and copolymers from quantum mechanical calculations and propose a novel method to generate such data efficiently using a finite number of repeating units. The free volume effects known to be important in polymer solutions are considered through the free volume model of Elbro and co-workers. We have examined this model using 2249 vapor–liquid equilibria data points from 25 homopolymers, 8 copolymers, and 48 solvents. The overall average deviation (AAD%) of solvent activity is found to be about 16%, which is comparable to that from other UNIFAC-based models. The liquid–liquid equilibrium of polymer–solvent mixtures can be predicted in qualitative agreement with experiment. The proposed method is capable of describing the changes in solvent activity due to temperature, polymer molecular weight, and polymer tacticity. Our results suggest that the proposed method is a useful complementary to group contribution method for phase behavior of polymer solutions when group parameter or density information of polymers is unavailable.

Prediction of phase equilibrium for gas hydrate in the presence of organic inhibitors and electrolytes by using an explicit pressure-dependent Langmuir adsorption constant in the van der Waals–Platteeuw model

A new approach is developed for the prediction of the melting curve of gas hydrate with single or multiple additives, including organic inhibitors and electrolytes. This is made possible by combining a predictive equation of state for the fluid phase, the Peng–Robinson–Stryjek–Vera equation of state (PRSV EoS) combined with the COSMO-SAC activity coefficient model through the first order modified Huron–Vidal (MHV1) mixing rule, and a modified van der Waals–Platteeuw model for the hydrate phase. We have examined this method for the change of the melting condition of gas hydrate upon addition of single organic inhibitor, single electrolyte, and a mixture of organic and electrolyte. The absolute average relative deviation in temperature (AARD-T) for these three types of systems are 0.79% (695 data points, T from 230.2K to 294.0K, P from 0.10MPa to 33.9MPa), 0.16% (810 data points, T from 259.5K to 299.1K, P from 0.13MPa to 71.56MPa), and 1.56% (316 data points, T from 248.2K to 292.9K, P from 0.90MPa to 73.28MPa), respectively. We believe that the proposed model is useful for the exploitation of natural or synthetic gas hydrates with multiple additives.

Vapor–liquid and liquid–liquid equilibrium for binary systems ester + a new protic ionic liquid

This study reports the synthesis of a new protic ionic liquid, bis(2-hydroxyethyl)ammonium butyrate (2-HE2AB), performed by a Bronsted acid–base reaction between butanoic acid and bis(2-hydroxyethyl)ammonia. The new ionic liquid was characterized by 1D hydrogen NMR spectrum. The ionic liquid shows complete solubility in water, methanol, and ethanol, and is partially soluble in methyl acetate, ethyl acetate, and propyl acetate, while it is not soluble in some alkanes. Density, refractive index, and vapor–liquid equilibrium were measured for the binary system 2-HE2AB + methyl acetate at atmospheric pressure. Furthermore, density, refractive index, and liquid–liquid equilibrium were measured for the binary systems 2-HE2AB + ester (methyl acetate, ethyl acetate, or propyl acetate) at 293.2 K. The Peng-Robinson equation of state, coupled with the Wong-Sandler mixing rule, was used in the thermodynamic modeling of density, vapor–liquid, and liquid–liquid equilibrium data. The COSMO-SAC activity coefficient model was used to calculate the activity coefficient within the Wong-Sandler mixing rule. The calculations show deviations for density, for the vapor–liquid equilibrium, and for the non-polar and polar phases of the liquid–liquid equilibrium within 13.0, 0.1, 132.5, and 23.8 %, respectively.

Prediction of mixture vapor–liquid equilibrium from the combined use of Peng–Robinson equation of state and COSMO-SAC activity coefficient model through the Wong–Sandler mixing rule

In this work we examined the prediction of vapor–liquid equilibria (VLE) of mixtures from the combined use of the Peng–Robinson equation of state (PR EOS) and the COSMO-SAC liquid activity coefficient model (LM). Based on the results of quantum mechanical calculations, it has been shown that the COSMO-SAC model is capable of predicting VLE of mixtures away from the critical point of any constituent component. Following the Wong–Sandler mixing rule, we found that the combined model is capable of predicting the VLE of binary mixtures, including alkane and alkane, alkane and alcohol, alkane and ketone, and alcohol and water, over a wide range of temperature (183.15–623.15 K) and pressure (0.1–19 MPa). Furthermore, it is found that the accuracy can be greatly improved when the Stavermann–Guggenheim combinatorial term in the COSMO-SAC model is ignored. The average error in both the pressure and vapor phase composition from the latter approach, denoted as PR + WS + COSMOSAC res, is lowered by more than 50% compared to that from the PR EOS with the van der Waals one fluid mixing rule (PR + VDW). Our results show that PR + WS + COSMOSAC res is a promising approach for mixture VLE predictions over a large range of conditions.