An evaluation of thermodynamic models for the prediction of drug and drug-like molecule solubility in organic solvents

Prediction of solubility of active pharmaceutical ingredients (API) in different solvents is one of the main issue for crystallization process design. Experimental determination is not always possible because of the small amount of product available in the early stages of a drug development. Thus, one interesting perspective is the use of thermodynamic models, which are usually employed for predicting the activity coefficients in case of Vapour–Liquid equilibria or Liquid–Liquid equilibria (VLE or LLE). The choice of the best thermodynamic model for Solid–Liquid equilibria (SLE) is not an easy task as most of them are not meant particularly for this. In this paper, several models are tested for the solubility prediction of five drugs or drug-like molecules: Ibuprofen, Acetaminophen, Benzoic acid, Salicylic acid and 4-aminobenzoic acid, and another molecule, anthracene, a rather simple molecule. The performance of predictive (UNIFAC, UNIFAC mod., COSMO-SAC) and semi-predictive (NRTL-SAC) models are compared and discussed according to the functional groups of the molecules and the selected solvents. Moreover, the model errors caused by solid state property uncertainties are taken into account. These errors are indeed not negligible when accurate quantitative predictions want to be performed. It was found that UNIFAC models give the best results and could be an useful method for rapid solubility estimations of an API in various solvents. This model achieves the order of magnitude of the experimental solubility and can predict in which solvents the drug will be very soluble, soluble or not soluble. In addition, predictions obtained with NRTL-SAC model are also in good agreement with the experiments, but in that case the relevance of the results is strongly dependent on the model parameters regressed from solubility data in single and mixed solvents. However, this is a very interesting model for quick estimations like UNIFAC models. Finally, COSMO-SAC needs more developments to increase its accuracy especially when hydrogen bonding is involved. In that case, the predicted solubility is always overestimated from two to three orders of magnitude. Considering the use of the most accurate equilibrium equation involving the ΔCp term, no benefits were found for drug predictions as the models are still too inaccurate. However, in function of the molecules and their solid thermodynamic properties, the ΔCp term can be neglected and will not have a great impact on the results

Cristallisation non-stoechiométrique et modélisation d’un flash thermodynamique : Cas des hydrates mixtes de gaz

National audienceClathrate Hydrates are ice-like compounds that can be formed under high pressure and low temperature. They are composed of water and small molecules of ‘’gas’’. Hence they are usually called gas hydrates. They are involved in a significant issue of the oil industry, the hydrate plugs in pipelines (flow-assurance), as well as gas capture and storage, air conditioning… Moreover, methane hydrates can be found in sediments in deep sea and permafrost. That is why they are also considered as a significant methane resource on earth.Since they are non-stoichiometric compounds, it is difficult to model these crystals in process simulation. Furthermore, the speed of crystallization seems to influence the hydrate composition. Therefore, a modeling of the hydrate crystallization taking into account the history of the solid formation could be an interesting tool.In this work, a successive thermodynamic flash approach is presented according to two different hypotheses: heterogeneous hydrate phase during the crystal growth, and homogeneous hydrate phase. The main idea of these procedures is to discretize the crystal growth while the hydrate volume is increasing. Hence, three phase flash calculations are performed on the system. Each time, the previous amount of hydrate that has been formed is removed (at each iteration).The results of such algorithms are compared to batch experiments at low and quick crystallization rates (Duyen et al. 2016). The flash algorithms at given temperature (only one degree of freedom) give accurate results. The predicted final pressure and the hydrate volume are calculated within 7% accuracy. Moreover, the flash calculation results with no hydrate reorganization are closer to experiments at quick crystallization rate, whereas the experiment at low crystallization rate is better predicted with the second hypothesis (reorganization of the hydrate phase during growth). This work and its results provide a more realistic and comprehensive view of gas hydrate crystallization (more details in Bouillot and Herri, 2016).Les hydrates mixtes de gaz sont des cristaux solides dont la composition n’est pas stoechiométrique. Cette spécificité entraine des difficultés de modélisation lorsque qu’un volume significatif peut être formé. Il faut dans ce cas faire l’hypothèse d’un solide homogène (cas le plus simple), ou tenir compte de l’historique de la cristallisation si on suppose qu’un cristal formé à un temps t1 ne se met pas en équilibre rapidement avec sa solution, dont la composition peut avoir varié, à un temps t2.Dans le présent travail, une approche de modélisation de la cristallisation d’hydrates mixtes de gaz est proposée. Cette approche tient compte de l’évolution du milieu au cours de la cristallisation par des calculs successifs de flash thermodynamique.Deux hypothèses sont considérées. Dans la première, les cristaux d’hydrates mixtes croissent à l’équilibre thermodynamique à chaque instant. Il en résulte un cristal non homogène. La deuxième hypothèse forte est une ré-homogénéisation de la phase hydrate au cours de la cristallisation.Ces deux approches sont comparées à des mesures expérimentales obtenues par cristallisation lente ou rapide à partir de mélange d’hydrocarbures (CO2, CH4, C2H6). Les données importantes sont notamment : la pression finale, la composition des cristaux d’hydrates et leur volume.Les résultats obtenus par simulation s’accordent bien avec les données expérimentales. Les erreurs obtenues sur la pression d’équilibre et le volume d’hydrate sont généralement inférieures à 7%. Plus particulièrement, les résultats montrent qu’une cristallisation lente est plus proche d’un cas où le cristal se réorganise (équilibre thermodynamique), tandis qu’une cristallisation rapide est mieux simulée par une croissance non homogène. Une cristallisation rapide des hydrates mixtes de gaz peut donc se produire hors équilibre thermodynamique

Approches thermodynamiques pour la prédiction de la solubilité de molécules d'intérêt pharmaceutique

La cristallisation est un procédé majeur de l’industrie pharmaceutique. Dans la mise au point d’un nouveau procédé de cristallisation, l’information essentielle est la solubilité de la molécule produite dans le solvant de cristallisation. Cette donnée n’est généralement pas connue lors de la phase de développement d’un nouveau principe actif. Elle doit donc être déterminée. L’objectif de cette thèse est d’étudier, et d’approfondir, l’utilisation de modèles thermodynamiques pour prédire la solubilité de molécules organiques complexes. Pour cela, six molécules sont prises pour référence : l’ibuprofène, le paracétamol, les acides salicylique, benzoïque et 4-aminobenzoïque et l’anthracène. Les modèles étudiés sont UNIFAC et ses modifications, COSMO-SAC, NRTL-SAC et PC-SAFT. Dans un premier temps, les potentialités de chaque modèle pour prédire la solubilité dans des solvants purs et des mélanges de solvants sont analysées. Dans un second temps, le modèle COSMO-SAC est approfondi et amélioré pour la prédiction des équilibres liquide-solide mettant en jeu des molécules complexes. Enfin, une nouvelle voie de mesure expérimentale de la solubilité dans de très faibles volumes est ouverte par l’intermédiaire de l’outil microfluidique. ABSTRACT : Crystallization is a key process of the pharmaceutical industry. When developing a new crystallization process, the most important thing to discover is the final product solubility in a given solvent. However, it is generally unknown at this early step of drug development. The solubility has to be determined. The objective of this work is to study, and deepen, the use of thermodynamic models for solubility predictions of molecules of pharmaceutical interest. To do so, six complex organic molecules have been chosen : ibuprofen, paracetamol, salicylic acid, benzoic acid, 4-aminobenzoic acid and anthracene. The studied models are UNIFAC and its modifications, COSMO-SAC, NRTL-SAC and PC-SAFT. Initially, these models are analysed and used for predicting solubility in pure and mixed solvents. Subsequent work concerns the COSMO-SAC model in more details. It is more particularly improved for solubility predictions. Finally, a road is opened for solubility measurements in low volumes with the use of microfluidics

Discussion and improvement of the refined COSMO-SAC parameters for solubility predictions: part 2

Solubility of drugs is a key piece of information for the pharmaceutical industry. Despite its importance, particularly at the beginning of a new drug process development, this thermodynamic property of the solid-liquid equilibria (SLE) can hardly be predicted for a given molecule in a given solvent. In our recent works, some thermodynamic models (UNIFAC and its modifications, COSMO-SAC and its refinements, NRTL-SAC) were investigated and compared for solubility prediction. The main drawbacks of these methods concern the strongest molecular interactions (dipole-dipole, hydrogen bonding), which are not properly taken into account. In the present study, we propose a new optimization of the last two COSMO-SAC refinements (2007 and 2010) for solubility prediction. To do that, a parameters optimization upon 352 solubility data of complex organic molecules was performed. Also, to improve hydrogen bonding influence, new σ-profiles are generated by applying another probability function for the solute. The results of this work are encouraging, especially for the calculation of crystallization yields given that the solubility temperature dependence is well represented. Solubility predictions in polar solvents are improved. However, this improvement is not as good as expected since it seems that the parameters balance between hydrogen bonding and electrostatic interactions is not the best. To confirm this, a short computation of anthracene solubility in toluene and heptane was performed

An evaluation of COSMO-SAC model and its evolutions for the prediction of drug-like molecule solubility: part 1

COSMO-SAC model and its evolutions have been investigated for solubility prediction of six pharmaceutical ingedients (ibuprofen, paracetamol, benzoic acid, salicylic acid, 4-aminobenzoic acid, and anthracene) in 35 solvents. The aim is to check the relevancy of the last improvements of the COSMO-SAC method for solubility prediction. The performance of each COSMO-SAC version has been evaluated following different criteria: the mean quadratic error (mse), the predicted solubility order of magnitude, and the solubility temperature dependence. In addition, solubility predictions in mixed solvents have also been analyzed. The results obtained show that the model refinements are relevants for solid-liquid equilibrium predictions. Compared to the original model, the solubility prediction in polar solvents is more accurate, and the solubility temperature dependences are well-represented. Moreover, the refined models (especially the 2010 version) are also more able to predict the solubility maxima in mixed solvents. However, the methods still have problems in representing complex interactions (hydrogen bond and dipole-dipole) and weaker electrostatic ones

Approches thermodynamiques pour la prédiction de la solubilité de molécules d'intérêt pharmaceutique

La cristallisation est un procédé majeur de l industrie pharmaceutique. Dans la mise au point d un nouveau procédé de cristallisation, l information essentielle est la solubilité de la molécule produite dans le solvant de cristallisation. Cette donnée n est généralement pas connue lors de la phase de développement d un nouveau principe actif. Elle doit donc être déterminée. L objectif de cette thèse est d étudier, et d approfondir, l utilisation de modèles thermodynamiques pour prédire la solubilité de molécules organiques complexes. Pour cela, six molécules sont prises pour référence : l ibuprofène, le paracétamol, les acides salicylique, benzoïque et 4-aminobenzoïque et l anthracène. Les modèles étudiés sont UNIFAC et ses modifications, COSMO-SAC, NRTL-SAC et PC-SAFT. Dans un premier temps, les potentialités de chaque modèle pour prédire la solubilité dans des solvants purs et des mélanges de solvants sont analysées. Dans un second temps, le modèle COSMO-SAC est approfondi et amélioré pour la prédiction des équilibres liquide-solide mettant en jeu des molécules complexes. Enfin, une nouvelle voie de mesure expérimentale de la solubilité dans de très faibles volumes est ouverte par l intermédiaire de l outil microfluidique.Crystallization is a key process of the pharmaceutical industry. When developing a new crystallization process, the most important thing to discover is the final product solubility in a given solvent. However, it is generally unknown at this early step of drug development. The solubility has to be determined. The objective of this work is to study, and deepen, the use of thermodynamic models for solubility predictions of molecules of pharmaceutical interest. To do so, six complex organic molecules have been chosen : ibuprofen, paracetamol, salicylic acid, benzoic acid, 4-aminobenzoic acid and anthracene. The studied models are UNIFAC and its modifications, COSMO-SAC, NRTL-SAC and PC-SAFT. Initially, these models are analysed and used for predicting solubility in pure and mixed solvents. Subsequent work concerns the COSMO-SAC model in more details. It is more particularly improved for solubility predictions. Finally, a road is opened for solubility measurements in low volumes with the use of microfluidics.TOULOUSE-ENSIACET (315552325) / SudocSudocFranceF

Analyse de gazouillis en ligne

National audienceLes tweets échangés sur Internet constituent une source d'information importante même si leurs caractéristiques les rendent difficiles à analyser (140 caractères au maximum, notations abrégées, . . .). Dans cet article, nous définissons un modèle d'entrepôt de données permettant de valoriser et d'analyser de gros volumes de tweets en proposant des mesures pertinentes dans un contexte de découverte de connaissances. L'utilisation des entrepôts de données comme outil de stockage et d'analyse de documents textuels n'est pas nouvelle mais les mesures ne sont pas adaptées aux spécificités des données manipulées. Les résultats des expérimentations sur des données réelles soulignent la pertinence de notre proposition. / Exchanged tweets on the Internet are an important information source, even if their characteristics make them difficult to analyze (a maximum of 140 characters, shorthand notations, ...). In this paper, we define a model of data warehouse to develop and analyze large volumes of tweets by proposing relevant measures in a knowledge discovery context. Using data warehouses in order to store and analyze textual documents is not new. Traditionally they adapt classical measures which are not really adapted to the data specificities. Furthermore we propose that, if a hierarchy is available, we can automatically detect the context. Conducted experiments on real data show the relevance of our approach

Cyclopentane hydrates – A candidate for desalination?

International audienceThis article presents a systematic review on the past developments of Hydrate-Based Desalination process using Cyclopentane as hydrate guest. This is the first review that covers all required fundamental data, such as multiphase equilibria data, kinetics, morphology, or physical properties of cyclopentane hydrates, in order to develop an effective and sustainable desalination process. Furthermore, this state-of-the-art describes research and commercialization perspectives. When compared to traditional applications, cyclopentane hydrate-based desalination process could be a promising solution. Indeed, it operates under normal atmospheric pressure, lower operation energies are required, etc… However, there are some challenges yet to overcome. A decision aid in the form of a diagram is proposed for a new cyclopentane hydrates-based desalination process. Hopefully, concepts reviewed in this study will suggest new ideas to advance technical solutions in order to make commercial hydrate-based desalination processes a reality

Solubility of pharmaceuticals: A comparison between SciPharma, a PC-SAFT-based approach, and NRTL-SAC

The solubility of seven pharmaceutical compounds (paracetamol, benzoic acid, 4-aminobenzoic acid, salicylic acid, ibuprofen, naproxen and temazepam) in pure and mixed solvents as a function of temperature is calculated with SciPharma, a semi-empirical approach based on PC-SAFT, and the NRTL-SAC model. To conduct a fair comparison between the approaches, the parameters of the compounds were regressed against the same solubility data, chosen to account for hydrophilic, polar and hydrophobic interactions. Only these solubility data were used by both models for predicting solubility in other pure and mixed solvents for which experimental data were available for comparison. A total of 386 pure solvent data points were used for the comparison comprising one or more temperatures per solvent. SciPharma is found to be more accurate than NRTL-SAC on the pure solvent data used especially in the description of the temperature dependence. This is due to the appropriate parameterization of the pharmaceuticals and the temperature-dependent description of the activity coefficient in PC-SAFT. The solubility in mixed solvents is predicted satisfactorily with SciPharma. NRTL-SAC tends to overestimate the solubility in aqueous solutions of alcohols or shows invariable solubility with composition in other cases

Thermodynamics of cyclopentane hydrates formation from brine: experimental and modelling study

International audienceCyclopentane hydrates-based salt-removal has been considered to be one promising technologies for desalination because it requires a low amount of operating compared to traditional methods such as thermal distillation, membrane separation, or freezing. In order to design a desalination, or water treatment, plant, it is necessary to understand both the thermodynamics of crystallization of hydrates (CPH) in presence of salt, and the kinetics. Therefore, this study aims to determine and model the equilibria of cyclopentane hydrates in the presence of electrolytes. Eight salt mixtures have been considered: NaCl, KCl, NaCl-KCl, CaCl2, Na2SO4, MgCl2, MgCl2-NaCl, MgCl2-NaCl-KCl, with a wide range of concentrations. Two successive experimental procedures, quick and slow, have been applied to determine equilibrium temperatures. The objective of the quick procedure is to provide an initial estimate of the equilibrium temperature. Then, the slow procedure is used to obtain more accurate data. Experimental results show that equilibrium temperatures dropped significantly with an increase in salt concentration, whatever the kinds of salt. In comparison with the literature, the final slow procedure in pure water provides, or with NaCl, provide results very close to studies of Kishimoto et al. [2] and Zylyftari et al. [3], obtained either by slow dissociation or micro Differential Scanning Calorimetry (&#0181-DSC). Moreover, salt co-precipitation can be achieved simultaneously with the cyclopentane hydrate formation. For instance, the eutectic point of four phase equilibrium of {liquid water + liquid CP + CPH + Na2SO4.10H2O} has been obtained in this study. This provides possibility for by-products, or value added products, recovery thanks to CPH. Afterward, four thermodynamic approaches have been considered for the results modelling. One is based on Standard Freezing Point Depression method. Another one considers the very new Hu-Lee-Sum (HLS) correlation, designed to predict the suppression temperature of clathrate hydrates when an additive is introduced into the system. The two last models are based on van der Waals and Platteeuw model, using either Kihara potential, or a correlation instead (ABOC).All models provide data with a difference lower than 0.7°C compared to experimental results. However, the best method is the ABOC method (activity based occupancy correlation). This approach uses a correlation between the clathrate occupancy, and the water activity. It furnishes equilibrium temperatures within 0.2°C uncertainty