Sahar Nasrallah, Alexander Wendler, Sebastian A Hallweger, Gregor Kieslich, Mirjana Minceva
{"title":"通过水亲和性来阐明有效药物成分的溶解度增强：以局部麻醉剂为例。","authors":"Sahar Nasrallah, Alexander Wendler, Sebastian A Hallweger, Gregor Kieslich, Mirjana Minceva","doi":"10.1021/acs.molpharmaceut.5c00628","DOIUrl":null,"url":null,"abstract":"<p><p>Hydrotropy has emerged as a promising approach to enhance the solubility and the availability of hydrophobic active pharmaceutical ingredients (APIs). To understand the hydrotropic effect on API solubility, it is crucial to investigate the molecular interactions and phase behavior in the API-hydrotrope-water system. The solid-liquid equilibrium (SLE) phase diagram of the ternary system aids in quantifying the hydrotropic effect and can guide the selection of an effective hydrotrope and its concentration. However, experimental determination of the complete SLE phase diagram at different temperatures is challenging and labor-intensive. This study introduces a thermodynamic-based method for selecting hydrotropes to enhance the solubility of APIs in water, considering API-hydrotrope, API-water, and hydrotrope-water interactions. The approach was demonstrated using three APIs, lidocaine, procaine, and benzocaine, and three hydrotropes, nicotinamide, caffeine, and urea. The SLE phase diagram of the ternary API-hydrotrope-water systems was predicted using the melting properties of the system components and their activity coefficients in the liquid solution, calculated with the nonrandom two-liquid (NRTL) model. The NRTL model binary interaction parameters were obtained from experimental SLE data for API-hydrotrope, API-water, and hydrotrope-water binary systems. The predicted SLE diagrams of the ternary API-hydrotrope-water systems revealed that the studied systems are eutectic systems with maximum API solubility at the eutectic point. Moreover, the thermodynamic analysis has shown that an efficient hydrotrope strongly interacts with API and water, with nicotinamide yielding the highest API solubility enhancement for the studied systems. This study highlights the potential of thermodynamic modeling in guiding the selection of hydrotropes and their concentrations to achieve the targeted API solubility in water.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Elucidating the Solubility Enhancement of Active Pharmaceutical Ingredients through Hydrotropy: A Case of Local Anesthetics.\",\"authors\":\"Sahar Nasrallah, Alexander Wendler, Sebastian A Hallweger, Gregor Kieslich, Mirjana Minceva\",\"doi\":\"10.1021/acs.molpharmaceut.5c00628\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hydrotropy has emerged as a promising approach to enhance the solubility and the availability of hydrophobic active pharmaceutical ingredients (APIs). To understand the hydrotropic effect on API solubility, it is crucial to investigate the molecular interactions and phase behavior in the API-hydrotrope-water system. The solid-liquid equilibrium (SLE) phase diagram of the ternary system aids in quantifying the hydrotropic effect and can guide the selection of an effective hydrotrope and its concentration. However, experimental determination of the complete SLE phase diagram at different temperatures is challenging and labor-intensive. This study introduces a thermodynamic-based method for selecting hydrotropes to enhance the solubility of APIs in water, considering API-hydrotrope, API-water, and hydrotrope-water interactions. The approach was demonstrated using three APIs, lidocaine, procaine, and benzocaine, and three hydrotropes, nicotinamide, caffeine, and urea. The SLE phase diagram of the ternary API-hydrotrope-water systems was predicted using the melting properties of the system components and their activity coefficients in the liquid solution, calculated with the nonrandom two-liquid (NRTL) model. The NRTL model binary interaction parameters were obtained from experimental SLE data for API-hydrotrope, API-water, and hydrotrope-water binary systems. The predicted SLE diagrams of the ternary API-hydrotrope-water systems revealed that the studied systems are eutectic systems with maximum API solubility at the eutectic point. Moreover, the thermodynamic analysis has shown that an efficient hydrotrope strongly interacts with API and water, with nicotinamide yielding the highest API solubility enhancement for the studied systems. 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Elucidating the Solubility Enhancement of Active Pharmaceutical Ingredients through Hydrotropy: A Case of Local Anesthetics.
Hydrotropy has emerged as a promising approach to enhance the solubility and the availability of hydrophobic active pharmaceutical ingredients (APIs). To understand the hydrotropic effect on API solubility, it is crucial to investigate the molecular interactions and phase behavior in the API-hydrotrope-water system. The solid-liquid equilibrium (SLE) phase diagram of the ternary system aids in quantifying the hydrotropic effect and can guide the selection of an effective hydrotrope and its concentration. However, experimental determination of the complete SLE phase diagram at different temperatures is challenging and labor-intensive. This study introduces a thermodynamic-based method for selecting hydrotropes to enhance the solubility of APIs in water, considering API-hydrotrope, API-water, and hydrotrope-water interactions. The approach was demonstrated using three APIs, lidocaine, procaine, and benzocaine, and three hydrotropes, nicotinamide, caffeine, and urea. The SLE phase diagram of the ternary API-hydrotrope-water systems was predicted using the melting properties of the system components and their activity coefficients in the liquid solution, calculated with the nonrandom two-liquid (NRTL) model. The NRTL model binary interaction parameters were obtained from experimental SLE data for API-hydrotrope, API-water, and hydrotrope-water binary systems. The predicted SLE diagrams of the ternary API-hydrotrope-water systems revealed that the studied systems are eutectic systems with maximum API solubility at the eutectic point. Moreover, the thermodynamic analysis has shown that an efficient hydrotrope strongly interacts with API and water, with nicotinamide yielding the highest API solubility enhancement for the studied systems. This study highlights the potential of thermodynamic modeling in guiding the selection of hydrotropes and their concentrations to achieve the targeted API solubility in water.
期刊介绍：
Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development.
Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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