{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:20:42Z","timestamp":1793071242498,"version":"4.5.0"},"reference-count":97,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 \u00b0C 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\u2014belonging to the set of data reduction techniques\u2014proved 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics13081118","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:35:31Z","timestamp":1626993331000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Experimental and Theoretical Study on Theobromine Solubility Enhancement in Binary Aqueous Solutions and Ternary Designed Solvents"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-6260","authenticated-orcid":false,"given":"Tomasz","family":"Jeli\u0144ski","sequence":"first","affiliation":[{"name":"Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kurpi\u0144skiego 5, 85-950 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawid","family":"Stasiak","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kurpi\u0144skiego 5, 85-950 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Kosmalski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, A. Jurasza 2, 85-089 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6220-2634","authenticated-orcid":false,"given":"Piotr","family":"Cysewski","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, Kurpi\u0144skiego 5, 85-950 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1070\/RC2012v081n05ABEH004220","article-title":"Methylxanthines: Properties and determination in various objects","volume":"81","author":"Andreeva","year":"2012","journal-title":"Russ. Chem. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Spiller, G.A. (1998). Caffeine, CRC Press. [1st ed.].","DOI":"10.1201\/9781420050134"},{"key":"ref_3","unstructured":"Craig, C.R., and Stitzel, R.E. (2003). Modern Pharmacology with Clinical Applications, Lippincott Williams and Wilkins. [6th ed.]."},{"key":"ref_4","unstructured":"Satoskar, R.S., Rege, N., and Bhandarkar, S.D. (2015). Pharmacology and Pharmacotherapeutics, Elsevier. [24th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1067\/mai.2001.119555","article-title":"Cyclic nucleotide phosphodiesterases","volume":"108","author":"Essayan","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1021\/jm00172a023","article-title":"7-Deaza-2-phenyladenines: Structure-Activity Relationships of Potent A1Selective Adenosine Receptor Antagonists","volume":"33","author":"Hide","year":"1990","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-3-642-13443-2_7","article-title":"Theobromine and the pharmacology of cocoa","volume":"200","author":"Smit","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104435","DOI":"10.1016\/j.jff.2021.104435","article-title":"The acute effect of cocoa and red-berries on visual acuity and cone-mediated dark adaptation in healthy eyes","volume":"81","author":"Puell","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijpharm.2006.02.042","article-title":"In vitro transdermal delivery of caffeine, theobromine, theophylline and catechin from extract of Guarana, Paullinia Cupana","volume":"317","author":"Heard","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"108591","DOI":"10.1016\/j.abb.2020.108591","article-title":"Efficacy of theobromine in preventing intestinal CaCo-2 cell damage induced by oxysterols","volume":"694","author":"Iaia","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"125875","DOI":"10.1016\/j.foodchem.2019.125875","article-title":"Purification and characterization of theobromine synthase in a Theobromine-Enriched wild tea plant (Camellia gymnogyna Chang) from Dayao Mountain, China","volume":"311","author":"Teng","year":"2020","journal-title":"Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ejmech.2019.04.044","article-title":"Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms","volume":"174","author":"Ma","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.saa.2019.03.001","article-title":"Study on the interaction and antioxidant activity of theophylline and theobromine with SOD by spectra and calculation","volume":"215","author":"Wu","year":"2019","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104293","DOI":"10.1016\/j.jff.2020.104293","article-title":"Effectiveness of theobromine on inhibition of 1,2-dimethylhydrazine-induced rat colon cancer by suppression of the Akt\/GSK3\u03b2\/\u03b2-catenin signaling pathway","volume":"75","author":"Rafraf","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fuggetta, M.P., Zonfrillo, M., Villiv\u00e0, C., Bonmassar, E., and Ravagnan, G. (2019). Inflammatory microenvironment and adipogenic differentiation in obesity: The inhibitory effect of theobromine in a model of human obesity in vitro. Mediat. Inflamm.","DOI":"10.1155\/2019\/1515621"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1093\/jn\/nxx056","article-title":"Theobromine is responsible for the effects of cocoa on the antibody immune status of rats","volume":"148","author":"Franch","year":"2018","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/5584_2017_17","article-title":"Synergistic activity for natural and synthetic inhibitors of angiogenesis induced by murine sarcoma L-1 and human kidney cancer cells","volume":"1020","author":"Siwicki","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","first-page":"649","article-title":"Inhibitory effect of theobromine on induction of angiogenesis and VEGF mRNA expression in v-raf transfectants of human urothelial cells HCV-29","volume":"2","author":"Janik","year":"1998","journal-title":"Int. J. Mol. Med."},{"key":"ref_19","first-page":"517","article-title":"The influence of theobromine on angiogenic activity and proangiogenic cytokines production of human ovarian cancer cells","volume":"5","author":"Barcz","year":"1998","journal-title":"Oncol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.2174\/1871520616666151217121138","article-title":"Guarana a Caffeine-Rich Food Increases Oxaliplatin Sensitivity of Colorectal HT-29 Cells by Apoptosis Pathway Modulation","volume":"16","author":"Barbisan","year":"2016","journal-title":"Anticancer. Agents Med. Chem."},{"key":"ref_21","unstructured":"Yalkovsky, S.H., He, Y., and Jain, P. (2010). Handbook of Aqueous Solubility Data, CRC Press. [2nd ed.]."},{"key":"ref_22","unstructured":"Hansch, C., Leo, A., and Hoekman, D. (1995). Exploring QSAR. [2] Hydrophobic, Electronic, and Steric Constants, American Chemical Society. [1st ed.]."},{"key":"ref_23","unstructured":"O\u2019Neil, M.J. (2013). The Merck Index\u2014An Encyclopedia of Chemicals, Drugs, and Biologicals, Royal Society of Chemistry. [15th ed.]."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.3109\/10837450.2010.535826","article-title":"A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept","volume":"17","author":"Ku","year":"2012","journal-title":"Pharm. Dev. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/mp0600182","article-title":"A Provisional Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and Japan","volume":"3","author":"Takagi","year":"2006","journal-title":"Mol. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1124\/pr.112.005660","article-title":"Strategies to address low drug solubility in discovery and development","volume":"65","author":"Williams","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1023\/A:1013651215061","article-title":"Influence of hydrodynamics and particle size on the absorption of felodipine in labradors","volume":"19","author":"Scholz","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.addr.2010.12.007","article-title":"Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology","volume":"63","author":"Liversidge","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ijpharm.2008.07.023","article-title":"Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products","volume":"364","author":"Augustijns","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1023\/A:1007516718048","article-title":"What is the true solubility advantage for amorphous pharmaceuticals?","volume":"17","author":"Hancock","year":"2000","journal-title":"Pharm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.addr.2003.10.007","article-title":"Impact of solid state properties on developability assessment of drug candidates","volume":"56","author":"Huang","year":"2004","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijpharm.2010.07.044","article-title":"Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives","volume":"399","author":"Shegokar","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.addr.2007.05.012","article-title":"Cyclodextrins as pharmaceutical solubilizers","volume":"59","author":"Brewster","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1021\/js960075u","article-title":"Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery","volume":"85","author":"Rajewski","year":"1996","journal-title":"J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1211\/jpp.61.12.0001","article-title":"Review: Physical chemistry of solid dispersions","volume":"61","author":"Janssens","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ejps.2005.04.018","article-title":"Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug","volume":"26","author":"Kranz","year":"2005","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1002\/jps.20612","article-title":"Microenvironmental pH Modulation Based Release Enhancement of a Weakly Basic Drug from Hydrophilic Matrices","volume":"95","author":"Tatavarti","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.ejps.2013.08.040","article-title":"Compound selection for development\u2014Is salt formation the ultimate answer? Experiences with an extended concept of the \u201c100mg approach.\u201d","volume":"57","author":"Korn","year":"2014","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.addr.2007.05.010","article-title":"Salt formation to improve drug solubility","volume":"59","author":"Serajuddin","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chadha, R., Bhalla, Y., Vashisht, M.K., and Chadha, K. (2015). Cocrystallization in Nutraceuticals. Recrystallization in Materials Processing, InTech.","DOI":"10.5772\/59365"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.drudis.2007.01.006","article-title":"Designing a molecular delivery system within a preclinical timeframe","volume":"12","author":"Henck","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3524","DOI":"10.1021\/acs.cgd.8b00335","article-title":"Distinguishing Cocrystals from Simple Eutectic Mixtures: Phenolic Acids as Potential Pharmaceutical Coformers","volume":"18","author":"Cysewski","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/jps.20578","article-title":"Pharmaceutical Co-Crystals","volume":"95","author":"Vishweshwar","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111507","DOI":"10.1016\/j.molliq.2019.111507","article-title":"Thermodynamic analysis of the solubility and preferential solvation of sulfamerazine in (acetonitrile + water) cosolvent mixtures at different temperatures","volume":"293","author":"Ortiz","year":"2019","journal-title":"J. Mol. Liq."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"112361","DOI":"10.1016\/j.fluid.2019.112361","article-title":"Thermodynamic analysis and preferential solvation of sulfamethazine in acetonitrile + water cosolvent mixtures","volume":"505","author":"Ortiz","year":"2020","journal-title":"Fluid Phase Equilib."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7875","DOI":"10.1021\/jp712179w","article-title":"On the theory of solute solubility in mixed solvents","volume":"112","author":"Smith","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"32","DOI":"10.18433\/J3PP4K","article-title":"Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures","volume":"11","author":"Jouyban","year":"2008","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jouyban, A. (2010). Handbook of Solubility Data for Pharmaceuticals, CRC Press. [1st ed.].","DOI":"10.1201\/9781439804889"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11060","DOI":"10.1021\/cr300162p","article-title":"Deep Eutectic Solvents (DESs) and Their Applications","volume":"114","author":"Smith","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1104\/pp.111.178426","article-title":"Are natural deep eutectic solvents the missing link in understanding cellular metabolism and physiology?","volume":"156","author":"Choi","year":"2011","journal-title":"Plant Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.aca.2012.12.019","article-title":"Natural deep eutectic solvents as new potential media for green technology","volume":"766","author":"Dai","year":"2013","journal-title":"Anal. Chim. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.foodchem.2014.02.155","article-title":"Natural deep eutectic solvents providing enhanced stability of natural colorants from safflower (Carthamus tinctorius)","volume":"159","author":"Dai","year":"2014","journal-title":"Food Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.trac.2015.11.006","article-title":"Natural designer solvents for greening analytical chemistry","volume":"76","author":"Espino","year":"2016","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6454","DOI":"10.1002\/ange.201001561","article-title":"DNA and RNA in Anhydrous Media: Duplex, Triplex, and G-Quadruplex Secondary Structures in a Deep Eutectic Solvent","volume":"122","author":"Mamajanov","year":"2010","journal-title":"Angew. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1021\/sc500096j","article-title":"Natural Deep Eutectic Solvents\u2014Solvents for the 21st Century","volume":"2","author":"Paiva","year":"2014","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1002\/anie.200905212","article-title":"Bacteria Incorporation in Deep-eutectic Solvents through Freeze-Drying","volume":"49","author":"Ferrer","year":"2010","journal-title":"Angew. Chemie Int. Ed."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1039\/c2gc35660k","article-title":"New natural and renewable low transition temperature mixtures (LTTMs): Screening as solvents for lignocellulosic biomass processing","volume":"14","author":"Francisco","year":"2012","journal-title":"Green Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1039\/c3gc40899j","article-title":"Evaluation of deep eutectic solvent\u2013water binary mixtures for lipase-catalyzed lipophilization of phenolic acids","volume":"15","author":"Durand","year":"2013","journal-title":"Green Chem."},{"key":"ref_59","first-page":"120","article-title":"Novel lactic acid-based natural deep eutectic solvents: Efficiency in the ultrasound-assisted extraction of antioxidant polyphenols from common native Greek medicinal plants","volume":"3","author":"Bakirtzi","year":"2016","journal-title":"J. Appl. Res. Med. Aromat. Plants"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s002280000197","article-title":"Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers","volume":"56","author":"Erlund","year":"2000","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.lwt.2016.05.037","article-title":"Natural deep eutectic solvents as beneficial extractants for enhancement of plant extracts bioactivity","volume":"73","year":"2016","journal-title":"LWT Food Sci. Technol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.addr.2007.05.005","article-title":"Computational approaches to determine drug solubility","volume":"59","author":"Faller","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6174","DOI":"10.1039\/C5CP00288E","article-title":"A review of methods for the calculation of solution free energies and the modelling of systems in solution","volume":"17","author":"Skyner","year":"2015","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1023\/A:1014224900524","article-title":"Experimental and computational screening models for prediction of aqueous drug solubility","volume":"19","author":"Norinder","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/aic.690140124","article-title":"Local compositions in thermodynamic excess functions for liquid mixtures","volume":"14","author":"Renon","year":"1968","journal-title":"AIChE J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1021\/ja01056a002","article-title":"Vapor-Liquid Equilibrium. XI. A New Expression for the Excess Free Energy of Mixing","volume":"86","author":"Wilson","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1006\/jcht.1998.0424","article-title":"Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL-aspartate in water from T = (278 to 348) K","volume":"31","author":"Apelblat","year":"1999","journal-title":"J. Chem. Thermodyn."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jct.2014.03.013","article-title":"(Solid + liquid) solubility of organic compounds in organic solvents\u2014Correlation and extrapolation","volume":"76","author":"Rasmuson","year":"2014","journal-title":"J. Chem. Thermodyn."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1021\/j100446a008","article-title":"Solvent activity along a saturation line and solubility of hydrogen-bonding solids","volume":"84","author":"Buchowski","year":"1980","journal-title":"J. Phys. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1021\/ci000338c","article-title":"Prediction of drug solubility by the general solubility equation (GSE)","volume":"41","author":"Ran","year":"2001","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13065-015-0085-4","article-title":"Predicting Abraham model solvent coefficients","volume":"9","author":"Bradley","year":"2015","journal-title":"Chem. Cent. J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0378-3812(00)00357-5","article-title":"COSMO-RS: A novel and efficient method for the a priori prediction of thermophysical data of liquids","volume":"172","author":"Klamt","year":"2000","journal-title":"Fluid Phase Equilib."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/aic.690480220","article-title":"Fast solvent screening via quantum chemistry: COSMO-RS approach","volume":"48","author":"Eckert","year":"2002","journal-title":"AIChE J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"114266","DOI":"10.1016\/j.molliq.2020.114266","article-title":"Enhancement of biomolecules solubility in aqueous media using designer solvents as additives: An experimental and COSMO-based models\u2019 approach","volume":"318","author":"Oliveira","year":"2020","journal-title":"J. Mol. Liq."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zhu, R., and Lei, Z. (2021). COSMO-based models for predicting the gas solubility in polymers. Green Energy Environ.","DOI":"10.1016\/j.gee.2021.03.009"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cherd.2017.04.015","article-title":"Screening of ionic liquids for efficient extraction of methylxanthines using COSMO-RS methodology","volume":"122","author":"Cysewski","year":"2017","journal-title":"Chem. Eng. Res. Des."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"115387","DOI":"10.1016\/j.molliq.2021.115387","article-title":"COSMO-RS based screening of ionic liquids for extraction of phenolic compounds from aqueous media","volume":"328","author":"Khan","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.molliq.2018.07.111","article-title":"COSMO-RS screening for ionic liquid to be applied in extraction of 2-phenylethanol from aqueous solutions","volume":"271","year":"2018","journal-title":"J. Mol. Liq."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Song, Z., Wang, J., and Sundmacher, K. (2021). Evaluation of COSMO-RS for solid\u2013liquid equilibria prediction of binary eutectic solvent systems. Green Energy Environ.","DOI":"10.1016\/j.gee.2020.11.020"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"106032","DOI":"10.1016\/j.jct.2019.106032","article-title":"Evaluation of COSMO-RS model for the LLE prediction of benzene plus cyclohexane plus ionic liquid system","volume":"145","author":"Dezhang","year":"2020","journal-title":"J. Chem. Thermodyn."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jct.2016.01.008","article-title":"Isobaric VLE of the mixture {1,8-cineole + ethanol}. EOS analysis and COSMO-RS modeling","volume":"97","author":"Torcal","year":"2016","journal-title":"J. Chem. Thermodyn."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1080\/00268970903313667","article-title":"Towards a first principles prediction of pKa: COSMO-RS and the cluster-continuum approach","volume":"108","author":"Eckert","year":"2010","journal-title":"Mol. Phys."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1021\/j100007a062","article-title":"Conductor-like screening model for real solvents: A new approach to the quantitative calculation of solvation phenomena","volume":"99","author":"Klamt","year":"1995","journal-title":"J. Phys. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5074","DOI":"10.1021\/jp980017s","article-title":"Refinement and parametrization of COSMO-RS","volume":"102","author":"Klamt","year":"1998","journal-title":"J. Phys. Chem. A"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"154104","DOI":"10.1063\/1.3382344","article-title":"A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu","volume":"132","author":"Grimme","year":"2010","journal-title":"J. Chem. Phys."},{"key":"ref_86","unstructured":"COSMOtherm (2020). Version 20.0.0, Revision 5273M, Dassault Syst\u00e8mes, Biovia."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.fluid.2014.08.030","article-title":"Consideration of dimerization for property prediction with COSMO-RS-DARE","volume":"382","author":"Sachsenhauser","year":"2014","journal-title":"Fluid Phase Equilib."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"111163","DOI":"10.1016\/j.molliq.2019.111163","article-title":"Prediction of ethenzamide solubility in organic solvents by explicit inclusions of intermolecular interactions within the framework of COSMO-RS-DARE","volume":"290","author":"Cysewski","year":"2019","journal-title":"J. Mol. Liq."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1021\/ci5004224","article-title":"Topology of the Interactions Pattern in Pharmaceutically Relevant Polymorphs of Methylxanthines (Caffeine, Theobromine, and Theophiline): Combined Experimental (1H\u201314N Nuclear Quadrupole Double Resonance) and Computational (DFT and Hirshfeld-Based) Study","volume":"54","author":"Olejniczak","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1107\/S0108270198009469","article-title":"Methylxanthines. II. Anhydrous Theobromine","volume":"54","author":"Ford","year":"1998","journal-title":"Acta Crystallogr. Sect. C"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Edwards, H.G.M., Lawson, E., de Matas, M., Shields, L., and York, P. (1997). Metamorphosis of caffeine hydrate and anhydrous caffeine. J. Chem. Soc. Perkin Trans. 2, 1985\u20131990.","DOI":"10.1039\/a702041d"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0378-5173(95)04466-3","article-title":"Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. Theophylline","volume":"135","author":"Zhu","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s12039-014-0707-8","article-title":"Salts and Co-crystals of Theobromine and their phase transformations in water","volume":"126","author":"Sanphui","year":"2014","journal-title":"J. Chem. Sci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1021\/acs.jced.7b00065","article-title":"Measurement and Correlation of Solubility of Theobromine, Theophylline, and Caffeine in Water and Organic Solvents at Various Temperatures","volume":"62","author":"Zhong","year":"2017","journal-title":"J. Chem. Eng. Data"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1021\/je9900171","article-title":"Density, viscosity, and refractive index for binary systems of n-C16 and four nonlinear alkanes at 298.15 K","volume":"44","author":"Fermeglia","year":"1999","journal-title":"J. Chem. Eng. Data"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1021\/ie50458a036","article-title":"Algebraic Representation of Thermodynamic Properties and the Classification of Solutions","volume":"40","author":"Redlich","year":"1948","journal-title":"Ind. Eng. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Acree, W.E. (2012). Experimental and Computational Methods Pertaining to Drug Solubility. Toxicity and Drug Testing, InTech.","DOI":"10.5772\/1976"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:30Z","timestamp":1760164410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":97,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["pharmaceutics13081118"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13081118","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]}}}