{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:05:46Z","timestamp":1784005546067,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"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>Background\/Objectives: Cyclodextrin-based ternary systems are widely used to improve the solubility of poorly soluble drugs. Amino acids such as L-arginine may further increase dissolved drug concentrations and reduce precipitation under physiologically relevant conditions. In many systems, apparent solubility enhancement is influenced simultaneously by drug ionization, inclusion complex formation, multicomponent interactions, and solid\u2013liquid equilibria. This study presents a physicochemical modeling approach for analyzing pH-dependent solubility enhancement and precipitation behavior in drug\u2013cyclodextrin\u2013L-arginine systems. Methods: The model combines acid\u2013base equilibria, binary inclusion complexation, ternary association, and explicit solid-phase partitioning within a unified mass-balance treatment. The approach was applied to representative ternary systems containing repaglinide, sulfadiazine, cefixime, and meloxicam. Results: Quantitative comparison with published phase-solubility data for the repaglinide\u2013HP\u03b2CD\u2013L-arginine system confirmed the numerical consistency of the model. The calculated profiles showed that enhanced solubilization and reduced precipitation occur only within specific pH regions determined by coupled equilibrium effects. For cefixime and meloxicam, the calculations were interpreted as predictive applications because directly comparable validation datasets were not available. Outside the favorable pH regions, a substantial fraction of the drug remained in the solid phase. Conclusions: These observations support the importance of pH and multicomponent interactions in controlling formulation performance in cyclodextrin-containing systems. The obtained profiles may support preliminary optimization of formulation pH and excipient composition before experimental screening.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070834","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T16:16:44Z","timestamp":1783613804000},"page":"834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predicting pH-Dependent Solubility Enhancement and Precipitation Suppression in Drug\u2013Cyclodextrin\u2013Arginine Formulations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-9091","authenticated-orcid":false,"given":"Natalia","family":"Bolocan","sequence":"first","affiliation":[{"name":"Institute of Chemistry, Moldova State University, MD-2028 Chisinau, Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2536-6706","authenticated-orcid":false,"given":"Igor","family":"Povar","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Moldova State University, MD-2028 Chisinau, Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6797-9725","authenticated-orcid":false,"given":"Alina Catrinel","family":"Ion","sequence":"additional","affiliation":[{"name":"Faculty of Applied Chemistry and Materials Science, University POLITEHNICA of Bucharest, 011061 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3166-1931","authenticated-orcid":false,"given":"Oxana","family":"Spinu","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Moldova State University, MD-2028 Chisinau, Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1023\/A:1016212804288","article-title":"A Theoretical Basis for a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability","volume":"12","author":"Amidon","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1056-8719(00)00107-6","article-title":"Drug-like Properties and the Causes of Poor Solubility and Poor Permeability","volume":"44","author":"Lipinski","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2006.10.044","article-title":"Cyclodextrins and Their Pharmaceutical Applications","volume":"329","author":"Loftsson","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ijpharm.2005.05.042","article-title":"Evaluation of Cyclodextrin Solubilization of Drugs","volume":"302","author":"Loftsson","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_6","first-page":"117","article-title":"Phase-Solubility Techniques","volume":"4","author":"Higuchi","year":"1965","journal-title":"Adv. Anal. Chem. Instrum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jpba.2015.01.058","article-title":"Analytical Techniques for Characterization of Cyclodextrin Complexes in the Solid State: A Review","volume":"113","author":"Mura","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s10847-015-0559-y","article-title":"Influence of auxiliary agents on solubility and dissolution profile of repaglinide with hydroxypropyl-\u03b2-cyclodextrin: Inclusion complex formation and its solid-state characterization","volume":"83","author":"Vakani","year":"2015","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"167","DOI":"10.30827\/ars.v57i4.5561","article-title":"Studies of Ternary Systems of Sulfadiazine with \u03b2-Cyclodextrin and Amino Acids","volume":"57","author":"Delrivo","year":"2016","journal-title":"Ars Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.carbpol.2013.07.070","article-title":"Physicochemical and Molecular Modeling Studies of Cefixime\u2013L-Arginine\u2013Cyclodextrin Ternary Inclusion Compounds","volume":"98","author":"Jadhav","year":"2013","journal-title":"Carbohydr. Polym."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2478\/v10007-008-0029-9","article-title":"Characterization of Ternary Complexes of Meloxicam-HP\u03b2CD and PVP or L-Arginine Prepared by the Spray-Drying Technique","volume":"58","author":"Mortada","year":"2008","journal-title":"Acta Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/0039-9140(91)80293-9","article-title":"Microscopic acid\u2013base equilibria of arginine","volume":"38","year":"1991","journal-title":"Talanta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1002\/pro.2647","article-title":"Arginine: Its pKa value revisited","volume":"24","author":"Fitch","year":"2015","journal-title":"Protein Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"117868","DOI":"10.1016\/j.carbpol.2021.117868","article-title":"Comparative chemical examination of inclusion complexes formed with \u03b2-cyclodextrin derivatives and basic amino acids","volume":"262","author":"Esmaeilpour","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lucero-Borja, D., Ruiz, R., Fuguet, E., and R\u00e0fols, C. (2025). Influence of Ionization and the Addition of Cyclodextrins and Hydrophilic Excipients on the Solubility of Benzthiazide, Isoxicam, and Piroxicam. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17050571"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"K\u00e1d\u00e1r, S., Csics\u00e1k, D., T\u0151zs\u00e9r, P., Farkas, A., P\u00e1lla, T., Mirzahosseini, A., T\u00f3th, B., T\u00f3th, G., Fiser, B., and Horv\u00e1th, P. (2022). Understanding the pH Dependence of Supersaturation of Telmisartan. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081635"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zafar, A., Alruwaili, N.K., Imam, S.S., Alsaidan, O.A., Alkholifi, F.K., Alharbi, K.S., Mostafa, E.M., Alanazi, A.S., Gilani, S.J., and Musa, A. (2021). Formulation of Genistein-HP \u03b2 cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13121997"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101123","DOI":"10.1016\/j.ceja.2026.101123","article-title":"Toward a Thermodynamic Framework for Identifying and Quantifying Chemical Synergism in Heterogeneous Systems","volume":"26","author":"Bolocan","year":"2026","journal-title":"Chem. Eng. J. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100418","DOI":"10.1016\/j.fochms.2026.100418","article-title":"Commentary: Molecular Mechanisms of True and Apparent Antioxidant Synergism in Foods","volume":"12","author":"Bolocan","year":"2026","journal-title":"Food Chem. Mol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100825","DOI":"10.1016\/j.ceja.2025.100825","article-title":"Forecasting Chemical Synergism and Antagonism by Thermodynamic Analysis of Complex Equilibria in Metal Solvent Extraction","volume":"23","author":"Povar","year":"2025","journal-title":"Chem. Eng. J. Adv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1016\/j.carbpol.2011.10.025","article-title":"Interaction of sulfadiazine with cyclodextrins in aqueous solution and solid state","volume":"87","author":"Delrivo","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s10337-011-2013-7","article-title":"Determination of pKa values of cefdinir and cefixime by LC and spectrophotometric methods and their analysis in pharmaceutical dosage forms","volume":"73","author":"Sanli","year":"2011","journal-title":"Chromatographia"},{"key":"ref_23","unstructured":"Abdo, A.M. (2003). Parameters Influencing Complexation of Some Acidic Drugs in Aqueous Cyclodextrin Solutions. [Ph.D. Thesis, Lancaster University]."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1080\/10837450.2024.2417766","article-title":"Meloxicam-amino acids salts\/ion pair complexes with advanced solubility, dissolution, and gastric safety","volume":"29","author":"Abdelkader","year":"2024","journal-title":"Pharm. Dev. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1590\/S1984-82502009000100008","article-title":"Dissolution test optimization for meloxicam in the tablet pharmaceutical form","volume":"45","author":"Oliveira","year":"2009","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cirri, M., Mennini, N., Nerli, G., Rubia, J., Casalone, E., Melani, F., Maestrelli, F., and Mura, P. (2021). Combined use of cyclodextrins and amino acids for the development of cefixime oral solutions for pediatric use. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111923"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2478\/v10007-010-0020-0","article-title":"Formulation of meloxicam gel for topical application: In vitro and in vivo evaluation","volume":"60","author":"Bachhav","year":"2010","journal-title":"Acta Pharm."},{"key":"ref_28","first-page":"1367","article-title":"MCM-41 for meloxicam dissolution improvement: In vitro release and in vivo bioavailability studies","volume":"26","author":"Hassan","year":"2015","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_29","unstructured":"Butler, J.N. (1998). Ionic Equilibrium: Solubility and pH Calculations, Wiley."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1515\/tsd-2022-2473","article-title":"Thermodynamics of Complex Equilibria in Surfactant Mixtures","volume":"59","author":"Povar","year":"2022","journal-title":"Tenside Surfactants Deterg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1139\/cjc-2018-0446","article-title":"Copper(I) Speciation in Ammonium Thiosulfate Systems","volume":"97","author":"Povar","year":"2019","journal-title":"Can. J. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1080\/07366299.2014.951284","article-title":"Acid\u2013Base Buffer Properties of Heterogeneous Extraction Systems","volume":"33","author":"Povar","year":"2015","journal-title":"Solvent Extr. Ion Exch."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1139\/cjc-2012-0412","article-title":"Synergic Effects in Mo(VI)\u2013Hydroxy Ligand\u2013KClO3 Systems","volume":"91","author":"Povar","year":"2013","journal-title":"Can. J. Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T04:26:13Z","timestamp":1784003173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pharmaceutics18070834"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18070834","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}