Experimental and Machine-Learning-Assisted Design of Pharmaceutically Acceptable Deep Eutectic Solvents for the Solubility Improvement of Non-Selective COX Inhibitors Ibuprofen and Ketoprofen.

Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.

Experimental and Theoretical Insights into the Intermolecular Interactions in Saturated Systems of Dapsone in Conventional and Deep Eutectic Solvents.

Solubility is not only a crucial physicochemical property for laboratory practice but also provides valuable insight into the mechanism of saturated system organization, as a measure of the interplay between various intermolecular interactions. The importance of these data cannot be overstated, particularly when dealing with active pharmaceutical ingredients (APIs), such as dapsone. It is a commonly used anti-inflammatory and antimicrobial agent. However, its low solubility hampers its efficient applications. In this project, deep eutectic solvents (DESs) were used as solubilizing agents for dapsone as an alternative to traditional solvents. DESs were composed of choline chloride and one of six polyols. Additionally, water-DES mixtures were studied as a type of ternary solvents. The solubility of dapsone in these systems was determined spectrophotometrically. This study also analyzed the intermolecular interactions, not only in the studied eutectic systems, but also in a wide range of systems found in the literature, determined using the COSMO-RS framework. The intermolecular interactions were quantified as affinity values, which correspond to the Gibbs free energy of pair formation of dapsone molecules with constituents of regular solvents and choline chloride-based deep eutectic solvents. The patterns of solute-solute, solute-solvent, and solvent-solvent interactions that affect solubility were recognized using Orange data mining software (version 3.36.2). Finally, the computed affinity values were used to provide useful descriptors for machine learning purposes. The impact of intermolecular interactions on dapsone solubility in neat solvents, binary organic solvent mixtures, and deep eutectic solvents was analyzed and highlighted, underscoring the crucial role of dapsone self-association and providing valuable insights into complex solubility phenomena. Also the importance of solvent-solvent diversity was highlighted as a factor determining dapsone solubility. The Non-Linear Support Vector Regression (NuSVR) model, in conjunction with unique molecular descriptors, revealed exceptional predictive accuracy. Overall, this study underscores the potency of computed molecular characteristics and machine learning models in unraveling complex molecular interactions, thereby advancing our understanding of solubility phenomena within the scientific community.

Deep Eutectic Solvents as Agents for Improving the Solubility of Edaravone: Experimental and Theoretical Considerations.

In this study, both practical and theoretical aspects of the solubility of edaravone (EDA) in Deep Eutectic Solvents (DESs) were considered. The solubility of edaravone in some media, including water, can be limited, which creates the need for new efficient and environmentally safe solvents. The solubility of EDA was measured spectrophotometrically and the complex intermolecular interactions within the systems were studied with the COSMO-RS framework. Of the four studied DES systems, three outperformed the most efficient classical organic solvent, namely dichloromethane, with the DES comprising choline chloride and triethylene glycol, acting as hydrogen bond donor (HBD), in a 1:2 molar proportion yielding the highest solubility of EDA. Interestingly, the addition of a specific amount of water further increased EDA solubility. Theoretical analysis revealed that in pure water or solutions with high water content, EDA stacking is responsible for self-aggregation and lower solubility. On the other hand, the presence of HBDs leads to the formation of intermolecular clusters with EDA, reducing self-aggregation. However, in the presence of a stoichiometric amount of water, a three-molecular EDA-HBD-water complex is formed, which explains why water can also act as a co-solvent. The high probability of formation of this type of complexes is related to the high affinity of the components, which exceeds all other possible complexes.

Predicting sulfanilamide solubility in the binary mixtures using a reference solvent approach.

BACKGROUND: Solubility is a fundamental physicochemical property of active pharmaceutical ingredients. The optimization of a dissolution medium aims not only to increase solubility and other aspects are to be included such as environmental impact, toxicity degree, availability, and costs. Obtaining comprehensive solubility characteristics of chemical compounds is a non-trivial and demanding process. Therefore, support from theoretical approaches is of practical importance. OBJECTIVES: This study aims to examine the accuracy of the reference solubility approach in the case of sulfanilamide dissolution in a variety of binary solvents. This pharmaceutically active substance has been extensively studied, and a substantial amount of solubility data is available. Unfortunately, using this set of data directly for theoretical modeling is impeded by noticeable inconsistencies in the published solubility data. Hence, this aspect is addressed by data curation using theoretical and experimental confirmations. MATERIAL AND METHODS: In the experimental part of our study, the popular shake-flask method combined with ultraviolet (UV) spectrophotometric measurements was applied for solubility determination. The computational phase utilized the conductor-like screening model for real solvents (COSMO-RS) approach. RESULTS: The analysis of the results of solubility calculations for sulfonamide in binary solvents revealed abnormally high error values for acetone-ethyl acetate mixtures, which were further confirmed with experimental measurements. Additional confirmation was obtained by extending the solubility measurements to a series of homologous acetate esters. CONCLUSIONS: Our study addresses the crucial issue of coherence of solubility data used for many theoretical inquiries, including parameter fitting of semi-empirical models, in-depth thermodynamic interpretations and application of machine learning protocols. The effectiveness of the proposed methodology for dataset curation was demonstrated for sulfanilamide solubility in binary mixtures. This approach enabled not only the formulation of a consistent dataset of sulfanilamide solubility binary solvent mixtures, but also its implementation as a qualitative tool guiding rationale solvent selection for experimental solubility screening.

Solubility of dapsone in deep eutectic solvents: Experimental analysis, molecular insights and machine learning predictions.

BACKGROUND: Dapsone (DAP) is an anti-inflammatory and antimicrobial active pharmaceutical ingredient used to treat, e.g., AIDS-related diseases. However, low solubility is a feature hampering its efficient use. OBJECTIVES: First, deep eutectic solvents (DES) were used as solubilizing agents for DAP as an alternative to traditional solvents. Second, intermolecular interactions in the systems were described and quantified. Finally, the solubility prediction model, previously created using the machine learning protocol, was extended and improved using new data obtained for eutectic systems. MATERIAL AND METHODS: New DES were created by blending choline chloride (ChCl) with 6 selected polyols. The solubility of DAP in these solvents was measured spectrophotometrically. The impact of water dilution on the solubility curve was investigated. Experimental research was enriched with theoretical interpretations of intermolecular interactions, identifying the most probable pairs in the systems. Dapsone self-association and its ability to interact with components of the analyzed systems were considered. Thermodynamic characteristics of pairs were utilized as molecular descriptors in the machine learning process, predicting solubility in both traditional organic solvents and the newly designed DES. RESULTS: The newly formulated solvents demonstrated significantly higher efficiency compared to traditional organic solvents, and a small addition of water increased solubility, indicating its role as a co-solvent. The interpretation of the mechanism of DAP solubility highlighted the competitive nature of self-association and pair formation. Thermodynamic parameters characterizing affinity were instrumental in developing an efficient model for theoretical screening across diverse solvent classes. The study emphasized the necessity of retraining models when introducing new experimental data, as exemplified by enriching the model with data from DES. CONCLUSIONS: The research showcased the efficacy of developing new DES for enhancing solubility and creating environmentally and pharmaceutically viable systems, using DAP as an example. Molecular interactions proved valuable in understanding solubility mechanisms and formulating predictive models through machine learning processes.

Exploring the Solubility Limits of Edaravone in Neat Solvents and Binary Mixtures: Experimental and Machine Learning Study.

This study explores the edaravone solubility space encompassing both neat and binary dissolution media. Efforts were made to reveal the inherent concentration limits of common pure and mixed solvents. For this purpose, the published solubility data of the title drug were scrupulously inspected and cured, which made the dataset consistent and coherent. However, the lack of some important types of solvents in the collection called for an extension of the available pool of edaravone solubility data. Hence, new measurements were performed to collect edaravone solubility values in polar non-protic and diprotic media. Such an extended set of data was used in the machine learning process for tuning the parameters of regressor models and formulating the ensemble for predicting new data. In both phases, namely the model training and ensemble formulation, close attention was paid not only to minimizing the deviation of computed values from the experimental ones but also to ensuring high predictive power and accurate solubility computations for new systems. Furthermore, the environmental friendliness characteristics determined based on the common green solvent selection criteria, were included in the analysis. Our applied protocol led to the conclusion that the solubility space defined by ordinary solvents is limited, and it is unlikely to find solvents that are better suited for edaravone dissolution than those described in this manuscript. The theoretical framework presented in this study provides a precise guideline for conducting experiments, as well as saving time and resources in the pursuit of new findings.

Intermolecular Interactions as a Measure of Dapsone Solubility in Neat Solvents and Binary Solvent Mixtures.

Dapsone is an effective antibacterial drug used to treat a variety of conditions. However, the aqueous solubility of this drug is limited, as is its permeability. This study expands the available solubility data pool for dapsone by measuring its solubility in several pure organic solvents: N-methyl-2-pyrrolidone (CAS: 872-50-4), dimethyl sulfoxide (CAS: 67-68-5), 4-formylmorpholine (CAS: 4394-85-8), tetraethylene pentamine (CAS: 112-57-2), and diethylene glycol bis(3-aminopropyl) ether (CAS: 4246-51-9). Furthermore, the study proposes the use of intermolecular interactions as molecular descriptors to predict the solubility of dapsone in neat solvents and binary mixtures using machine learning models. An ensemble of regressors was used, including support vector machines, random forests, gradient boosting, and neural networks. Affinities of dapsone to solvent molecules were calculated using COSMO-RS and used as input for model training. Due to the polymorphic nature of dapsone, fusion data are not available, which prohibits the direct use of COSMO-RS for solubility calculations. Therefore, a consonance solvent approach was tested, which allows an indirect estimation of the fusion properties. Unfortunately, the resulting accuracy is unsatisfactory. In contrast, the developed regressors showed high predictive potential. This work documents that intermolecular interactions characterized by solute-solvent contacts can be considered valuable molecular descriptors for solubility modeling and that the wealth of encoded information is sufficient for solubility predictions for new systems, including those for which experimental measurements of thermodynamic properties are unavailable.

Finding the Right Solvent: A Novel Screening Protocol for Identifying Environmentally Friendly and Cost-Effective Options for Benzenesulfonamide.

This study investigated the solubility of benzenesulfonamide (BSA) as a model compound using experimental and computational methods. New experimental solubility data were collected in the solvents DMSO, DMF, 4FM, and their binary mixtures with water. The predictive model was constructed based on the best-performing regression models trained on available experimental data, and their hyperparameters were optimized using a newly developed Python code. To evaluate the models, a novel scoring function was formulated, considering not only the accuracy but also the bias-variance tradeoff through a learning curve analysis. An ensemble approach was adopted by selecting the top-performing regression models for test and validation subsets. The obtained model accurately back-calculated the experimental data and was used to predict the solubility of BSA in 2067 potential solvents. The analysis of the entire solvent space focused on the identification of solvents with high solubility, a low environmental impact, and affordability, leading to a refined list of potential candidates that meet all three requirements. The proposed procedure has general applicability and can significantly improve the quality and speed of experimental solvent screening.

Intermolecular Interactions of Edaravone in Aqueous Solutions of Ethaline and Glyceline Inferred from Experiments and Quantum Chemistry Computations.

Edaravone, acting as a cerebral protective agent, is administered to treat acute brain infarction. Its poor solubility is addressed here by means of optimizing the composition of the aqueous choline chloride (ChCl)-based eutectic solvents prepared with ethylene glycol (EG) or glycerol (GL) in the three different designed solvents compositions. The slurry method was used for spectroscopic solubility determination in temperatures between 298.15 K and 313.15 K. Measurements confirmed that ethaline (ETA = ChCl:EG = 1:2) and glyceline (GLE = ChCl:GL = 1:2) are very effective solvents for edaravone. The solubility at 298.15 K in the optimal compositions was found to be equal xE = 0.158 (cE = 302.96 mg/mL) and xE = 0.105 (cE = 191.06 mg/mL) for glyceline and ethaline, respectively. In addition, it was documented that wetting of neat eutectic mixtures increases edaravone solubility which is a fortunate circumstance not only from the perspective of a solubility advantage but also addresses high hygroscopicity of eutectic mixtures. The aqueous mixture with 0.6 mole fraction of the optimal composition yielded solubility values at 298.15 K equal to xE = 0.193 (cE = 459.69 mg/mL) and xE = 0.145 (cE = 344.22 mg/mL) for glyceline and ethaline, respectively. Since GLE is a pharmaceutically acceptable solvent, it is possible to consider this as a potential new liquid form of this drug with a tunable dosage. In fact, the recommended amount of edaravone administered to patients can be easily achieved using the studied systems. The observed high solubility is interpreted in terms of intermolecular interactions computed using the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach and corrected for accounting of electron correlation, zero-point vibrational energy and basis set superposition errors. Extensive conformational search allowed for identifying the most probable contacts, the thermodynamic and geometric features of which were collected and discussed. It was documented that edaravone can form stable dimers stabilized via stacking interactions between five-membered heterocyclic rings. In addition, edaravone can act as a hydrogen bond acceptor with all components of the studied systems with the highest affinities to ion pairs of ETA and GLE. Finally, the linear regression model was formulated, which can accurately estimate edaravone solubility utilizing molecular descriptors obtained from COSMO-RS computations. This enables the screening of new eutectic solvents for finding greener replacers of designed solvents. The theoretical analysis of tautomeric equilibria confirmed that keto-isomer edaravone is predominant in the bulk liquid phase of all considered deep eutectic solvents (DES).

Solubility Characteristics of Acetaminophen and Phenacetin in Binary Mixtures of Aqueous Organic Solvents: Experimental and Deep Machine Learning Screening of Green Dissolution Media.

The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from theoretical screening seems to be valuable. Here, a collection of acetaminophen and phenacetin solubility data in neat and binary solvent mixtures was used for the development of a nonlinear deep machine learning model using new intuitive molecular descriptors derived from COSMO-RS computations. The literature dataset was augmented with results of new measurements in aqueous binary mixtures of 4-formylmorpholine, DMSO and DMF. The solubility values back-computed with the developed ensemble of neural networks are in perfect agreement with the experimental data, which enables the extensive screening of many combinations of solvents not studied experimentally within the applicability domain of the trained model. The final predictions were presented not only in the form of the set of optimal hyperparameters but also in a more intuitive way by the set of parameters of the Jouyban-Acree equation often used in the co-solvency domain. This new and effective approach is easily extendible to other systems, enabling the fast and reliable selection of candidates for new solvents and directing the experimental solubility screening of active pharmaceutical ingredients.

Collagen type II-hyaluronan interactions - the effect of proline hydroxylation: a molecular dynamics study.

Hyaluronan-collagen composites have been employed in numerous biomedical applications. Understanding the interactions between hyaluronan and collagen is particularly important in the context of joint cartilage function and the treatment of joint diseases. Many factors affect the affinity of collagen for hyaluronan. One of the important factors is the ratio of 3- or 4-hydroxy proline to proline residues. This article presents the results from molecular dynamics calculations of HA-collagen type II interactions with hyaluronan. The applied protocol employed docking and geometry optimization of complexes built using collagen structures with different numbers of hydroxyl groups attached to proline moieties. It was established that the hydroxyproline/proline ratio affects both structural and energetic features of the collagen-hyaluronan complex. Proline hydroxylation was found to significantly influence the number of all identified types of molecular forces, hydrophobic interactions, water bridges and hydrogen bonds, which can be formed between collagen and hyaluronan. Importantly, an increase in the hydroxyproline/proline ratio in the collagen chain increases the binding affinity for hyaluronan. This is illustrated by the linear correlation between the binding free energy and the hydroxylation degree. A comparison of the results obtained for 3 and 4 hydroxylation of proline indicates that the hydroxyl group attachment position plays a minor role in complex stabilization. However, a slightly stronger affinity was observed for 4 hydroxylation. In order to evaluate the effect of the aqueous environment on the collagen-hyaluronan complex stability, the enthalpic and entropic contributions to the free energy of solvation were analyzed.

New Insights into Thermodynamics of Solutes in Neat and Complex Solvents.

Solubility is one of the most important physicochemical properties, both from a practical and theoretical perspective [...].

Application of COSMO-RS-DARE as a Tool for Testing Consistency of Solubility Data: Case of Coumarin in Neat Alcohols.

Coumarin is a naturally occurring lactone-type benzopyrone with various applications in the pharmaceutical, food, perfume, and cosmetics industries. This hydrophobic compound is poorly soluble in water but dissolves well in protic organic solvents such as alcohols. Despite the extensive use of coumarin, there are only a few reports documenting its solubility in organic solvents, and some reported data are incongruent, which was the direct impulse for this study. To resolve this problem, a theoretical congruency test was formulated using COSMO-RS-DARE for the determination of intermolecular interaction parameters, which allowed for the identification of outliers as suspicious datasets. The perfect match between back-computed values of coumarin solubility and the experimental ones confirms the reliability of the formulated theoretical approach and its adequacy for testing solubility data consistency. As the final approval, the temperature-related coumarin solubility in seven neat alcohols was determined experimentally. Four solvents (methanol, ethanol, 1-propanol, and 2-propanol) were used for reproducibility purposes, and an additional three (1-butanol, 1-pentanol, and 1-octanol) were used to extend the information on the homologous series. The consistency of this extended solubility dataset is discussed in terms of the comparison of remeasured solubility values with the ones already published and within the series of structurally similar solvents. The proposed procedure extends the range of applicability of COSMO-RS-DARE and provides a real and useful tool for consistency tests of already published solubility data, allowing for the approval/disapproval of existing data and filling gaps in datasets. Linear regressions utilizing a 2D molecular descriptor, SpMin2_Bhm, or the distance between solute and solvent in the Hansen solubility space, Ra, were formulated for the estimation of COMSO-RS-DARE integration parameters.

Quantification of Caffeine Interactions in Choline Chloride Natural Deep Eutectic Solvents: Solubility Measurements and COSMO-RS-DARE Interpretation.

Solubility of active pharmaceutical ingredients is an important aspect of drug processing and formulation. Although caffeine was a subject of many studies aiming to quantify saturated solutions, many applied solvents suffer from not being environmentally friendly. This work fills this gap by presenting the results of solubility measurements in choline chloride natural deep eutectic solvents, ccNADES, comprising one of seven of the following polyalcohols: glycerol, sorbitol, xylitol, glucose, sucrose, maltose and fructose. The ratio of ccNADES components was optimized for maximizing caffeine solubility at room temperature. Additionally, temperature dependent solubility was measured for the first four systems exhibiting the highest solubility potential, both in their neat forms and in mixtures with water. Results were used for intermolecular interactions assessments using the COSMO-RS-DARE approach, which led to a perfect match between experimental and computed solubility values. An important methodological discussion was provided for an appropriate definition of the systems. Surprising linear trends were observed between the values of fitting parameters and water-ccNADES composition. In addition, comments on selection of the values of the fusion thermodynamic parameters were provided, which led to the conclusion that COSMO-RS-DARE solubility computations can effectively compensate for the inaccuracies of these important physicochemical properties.

New Screening Protocol for Effective Green Solvents Selection of Benzamide, Salicylamide and Ethenzamide.

New protocol for screening efficient and environmentally friendly solvents was proposed and experimentally verified. The guidance for solvent selection comes from computed solubility via COSMO-RS approach. Furthermore, solute-solvent affinities computed using advanced quantum chemistry level were used as a rationale for observed solvents ranking. The screening protocol pointed out that 4-formylomorpholine (4FM) is an attractive solubilizer compared to commonly used aprotic solvents such as DMSO and DMF. This was tested experimentally by measuring the solubility of the title compounds in aqueous binary mixtures in the temperature range between 298.15 K and 313.15 K. Additional measurements were also performed for aqueous binary mixtures of DMSO and DMF. It has been found that the solubility of studied aromatic amides is very high and quite similar in all three aprotic solvents. For most aqueous binary mixtures, a significant decrease in solubility with a decrease in the organic fraction is observed, indicating that all systems can be regarded as efficient solvent-anti-solvent pairs. In the case of salicylamide dissolved in aqueous-4FM binary mixtures, a strong synergistic effect has been found leading to the highest solubility for 0.6 mole fraction of 4-FM.

Application of the Solute-Solvent Intermolecular Interactions as Indicator of Caffeine Solubility in Aqueous Binary Aprotic and Proton Acceptor Solvents: Measurements and Quantum Chemistry Computations.

The solubility of caffeine in aqueous binary mixtures was measured in five aprotic proton acceptor solvents (APAS) including dimethyl sulfoxide, dimethylformamide, 1,4-dioxane, acetonitrile, and acetone. The whole range of concentrations was studied in four temperatures between 25 °C and 40 °C. All systems exhibit a strong cosolvency effect resulting in non-monotonous solubility trends with changes of the mixture composition and showing the highest solubility at unimolar proportions of organic solvent and water. The observed solubility trends were interpreted based on the values of caffeine affinities toward homo- and hetero-molecular pairs formation, determined on an advanced quantum chemistry level including electron correlation and correction for vibrational zero-point energy. It was found that caffeine can act as a donor in pairs formation with all considered aprotic solvents using the hydrogen atom attached to the carbon in the imidazole ring. The computed values of Gibbs free energies of intermolecular pairs formation were further utilized for exploring the possibility of using them as potential solubility prognostics. A semi-quantitative relationship (R2 = 0.78) between caffeine affinities and the measured solubility values was found, which was used for screening for new greener solvents. Based on the values of the environmental index (EI), four morpholine analogs were considered and corresponding caffeine affinities were computed. It was found that the same solute-solvent structural motif stabilizes hetero-molecular pairs suggesting their potential applicability as greener replacers of traditional aprotic proton acceptor solvents. This hypothesis was confirmed by additional caffeine solubility measurements in 4-formylmorpholine. This solvent happened to be even more efficient compared to DMSO and the obtained solubility profile follows the cosolvency pattern observed for other aprotic proton acceptor solvents.

Effect of Chitosan Deacetylation on Its Affinity to Type III Collagen: A Molecular Dynamics Study.

The ability to form strong intermolecular interactions by linear glucosamine polysaccharides with collagen is strictly related to their nonlinear dynamic behavior and hence bio-lubricating features. Type III collagen plays a crucial role in tissue regeneration, and its presence in the articular cartilage affects its bio-technical features. In this study, the molecular dynamics methodology was applied to evaluate the effect of deacetylation degree on the chitosan affinity to type III collagen. The computational procedure employed docking and geometry optimizations of different chitosan structures characterized by randomly distributed deacetylated groups. The eight different degrees of deacetylation from 12.5% to 100% were taken into account. We found an increasing linear trend (R2 = 0.97) between deacetylation degree and the collagen-chitosan interaction energy. This can be explained by replacing weak hydrophobic contacts with more stable hydrogen bonds involving amino groups in N-deacetylated chitosan moieties. In this study, the properties of chitosan were compared with hyaluronic acid, which is a natural component of synovial fluid and cartilage. As we found, when the degree of deacetylation of chitosan was greater than 0.4, it exhibited a higher affinity for collagen than in the case of hyaluronic acid.

Collagen Type II-Chitosan Interactions as Dependent on Hydroxylation and Acetylation Inferred from Molecular Dynamics Simulations.

Chitosan-collagen blends have been widely applied in tissue engineering, joints diseases treatment, and many other biomedical fields. Understanding the affinity between chitosan and collagen type II is particularly relevant in the context of mechanical properties modulation, which is closely associated with designing biomaterials suitable for cartilage and synovial fluid regeneration. However, many structural features influence chitosan's affinity for collagen. One of the most important ones is the deacetylation degree (DD) in chitosan and the hydroxylation degree (HD) of proline (PRO) moieties in collagen. In this paper, combinations of both factors were analyzed using a very efficient molecular dynamics approach. It was found that DD and HD modifications significantly affect the structural features of the complex related to considered types of interactions, namely hydrogen bonds, hydrophobic, and ionic contacts. In the case of hydrogen bonds both direct and indirect (water bridges) contacts were examined. In case of the most collagen analogues, a very good correlation between binding free energy and DD was observed.

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility.

Solubility enhancement of poorly soluble active pharmaceutical ingredients is of crucial importance for drug development and processing. Extensive experimental screening is limited due to the vast number of potential solvent combinations. Hence, theoretical models can offer valuable hints for guiding experiments aimed at providing solubility data. In this paper, we explore the possibility of applying quantum-chemistry-derived molecular descriptors, adequate for development of an ensemble of neural networks model (ENNM), for solubility computations of sulfamethizole (SMT) in neat and aqueous binary solvent mixtures. The machine learning procedure utilized information encoded in σ-potential profiles computed using the COSMO-RS approach. The resulting nonlinear model is accurate in backcomputing SMT solubility and allowed for extensive screening of green solvents. Since the experimental characteristics of SMT solubility are limited, the data pool was extended by new solubility measurements in water, five neat organic solvents (acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, and methanol), and their aqueous binary mixtures at 298.15, 303.15, 308.15, and 313.15 K. Experimentally determined order of decreasing SMT solubility in neat solvents is the following: N,N-dimethylformamide > dimethyl sulfoxide > methanol > acetonitrile > 1,4dioxane >> water, in all studied temperatures. Similar trends are observed for aqueous binary mixtures. Since N,N-dimethylformamide is not considered as a green solvent, the more acceptable replacers were searched for using the developed model. This step led to the conclusion that 4-formylmorpholine is a real alternative to N,N-dimethylformamide, fulfilling all requirements of both high dissolution potential and environmental friendliness.

Experimental and Theoretical Study on Theobromine Solubility Enhancement in Binary Aqueous Solutions and Ternary Designed Solvents.

The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 °C in neat organic solvents, aqueous binary mixtures, Natural Deep Eutectic Solvents (NADES) and ternary NADES mixtures with water. It was found that addition of water in unimolar proportions with some organic solvents increases theobromine solubility compared to neat solvents. Additionally, using NADES results in a solubility increase of the studied compound not only in relation to water but also DMSO. The addition of water (0.2 molar fraction) to NADES is responsible for an even larger increase of solubility. The measured solubilities were interpreted in terms of three theoretical frameworks. The first one-belonging to the set of data reduction techniques-proved to be very efficient in quantitative back-computations of excess solubility of theobromine in all studied systems. The default approach utilizing the well-recognized COSMO-RS (Conductor-like Screening Model for Real Solvents) framework offered at most a qualitative solubility description. The extended search for possible contacts provided evidence for the existence of many intermolecular complexes that alter the electron density of the solute molecule, thus influencing solubility computations. Taking into account such intermolecular contacts by using the COSMO-RS-DARE (Conductor-like Screening Model for Realistic Solvation-Dimerization, Aggregation, and Reaction Extension) framework seriously increased the accuracy of solubility computations.