Paola Disisto , Laura Baraldi , Luca Fornasari , Irene Bassanetti , Valentina Mileo , Francesco Castagnini , Francesca Ferlenghi , Pietro Franceschi , Alessia Bacchi , Luciano Marchiò
{"title":"有机酸反离子在调节普鲁卡因盐的体外溶出和渗透性中的作用","authors":"Paola Disisto , Laura Baraldi , Luca Fornasari , Irene Bassanetti , Valentina Mileo , Francesco Castagnini , Francesca Ferlenghi , Pietro Franceschi , Alessia Bacchi , Luciano Marchiò","doi":"10.1016/j.ejpb.2025.114758","DOIUrl":null,"url":null,"abstract":"<div><div>Procaine, a widely used local anesthetic, suffers from slow onset and rapid degradation into <em>para</em>-aminobenzoic acid and diethylaminoethanol, resulting in a brief half-life and short duration of action. In this study, we investigate salification in order to modify dissolution rate and permeability without altering the chemical structure or using complex formulations. Six procaine salts with carboxylic acids and four with sulfonic acids were prepared and systematically evaluated in comparison with procaine hydrochloride, focusing on their <em>in-vitro</em> pharmacokinetic properties in two physiological conditions at pH 4.5 and 7.4. Dissolution rate studies showed that all procaine salts achieved complete dissolution within 30 min, while procaine reached 75 % dissolution and remained partially undissolved even after 2 h. In addition, permeability studies revealed a range of permeation values among the different procaine salts, in which sulfonate anions significantly improved the permeability of procaine by approximately 40 % to 70 %. Furthermore, a correlation between permeability and lipophilicity descriptors was assessed, with particular attention to ion pair stability, the lipophilicity of the counterion and the lipophilicity of procaine in its neutral form. Notably, salts with higher permeability, primarily sulfonates, exhibited less stable ion pairs, contributing to a more effective drug diffusion and a potential for faster onset and absorption of procaine. On the other side, carboxylic acids tend to confer a higher ion pair stability, inhibiting the membrane permeation. Our findings support the canonical model of passive permeability, suggesting that the neutral form of the drug can form in response to local environmental conditions near the membrane or within the transmembrane compartment. In this context, both the neutral form and the ion pair could contribute and play a role as a part of the equilibrium of partitioning across the membrane.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"213 ","pages":"Article 114758"},"PeriodicalIF":4.3000,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The role of organic acid counterions in modulating the in-vitro dissolution and permeability profiles of procaine salts\",\"authors\":\"Paola Disisto , Laura Baraldi , Luca Fornasari , Irene Bassanetti , Valentina Mileo , Francesco Castagnini , Francesca Ferlenghi , Pietro Franceschi , Alessia Bacchi , Luciano Marchiò\",\"doi\":\"10.1016/j.ejpb.2025.114758\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Procaine, a widely used local anesthetic, suffers from slow onset and rapid degradation into <em>para</em>-aminobenzoic acid and diethylaminoethanol, resulting in a brief half-life and short duration of action. In this study, we investigate salification in order to modify dissolution rate and permeability without altering the chemical structure or using complex formulations. Six procaine salts with carboxylic acids and four with sulfonic acids were prepared and systematically evaluated in comparison with procaine hydrochloride, focusing on their <em>in-vitro</em> pharmacokinetic properties in two physiological conditions at pH 4.5 and 7.4. Dissolution rate studies showed that all procaine salts achieved complete dissolution within 30 min, while procaine reached 75 % dissolution and remained partially undissolved even after 2 h. In addition, permeability studies revealed a range of permeation values among the different procaine salts, in which sulfonate anions significantly improved the permeability of procaine by approximately 40 % to 70 %. Furthermore, a correlation between permeability and lipophilicity descriptors was assessed, with particular attention to ion pair stability, the lipophilicity of the counterion and the lipophilicity of procaine in its neutral form. Notably, salts with higher permeability, primarily sulfonates, exhibited less stable ion pairs, contributing to a more effective drug diffusion and a potential for faster onset and absorption of procaine. On the other side, carboxylic acids tend to confer a higher ion pair stability, inhibiting the membrane permeation. Our findings support the canonical model of passive permeability, suggesting that the neutral form of the drug can form in response to local environmental conditions near the membrane or within the transmembrane compartment. In this context, both the neutral form and the ion pair could contribute and play a role as a part of the equilibrium of partitioning across the membrane.</div></div>\",\"PeriodicalId\":12024,\"journal\":{\"name\":\"European Journal of Pharmaceutics and Biopharmaceutics\",\"volume\":\"213 \",\"pages\":\"Article 114758\"},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2025-05-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Pharmaceutics and Biopharmaceutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0939641125001353\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutics and Biopharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0939641125001353","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
The role of organic acid counterions in modulating the in-vitro dissolution and permeability profiles of procaine salts
Procaine, a widely used local anesthetic, suffers from slow onset and rapid degradation into para-aminobenzoic acid and diethylaminoethanol, resulting in a brief half-life and short duration of action. In this study, we investigate salification in order to modify dissolution rate and permeability without altering the chemical structure or using complex formulations. Six procaine salts with carboxylic acids and four with sulfonic acids were prepared and systematically evaluated in comparison with procaine hydrochloride, focusing on their in-vitro pharmacokinetic properties in two physiological conditions at pH 4.5 and 7.4. Dissolution rate studies showed that all procaine salts achieved complete dissolution within 30 min, while procaine reached 75 % dissolution and remained partially undissolved even after 2 h. In addition, permeability studies revealed a range of permeation values among the different procaine salts, in which sulfonate anions significantly improved the permeability of procaine by approximately 40 % to 70 %. Furthermore, a correlation between permeability and lipophilicity descriptors was assessed, with particular attention to ion pair stability, the lipophilicity of the counterion and the lipophilicity of procaine in its neutral form. Notably, salts with higher permeability, primarily sulfonates, exhibited less stable ion pairs, contributing to a more effective drug diffusion and a potential for faster onset and absorption of procaine. On the other side, carboxylic acids tend to confer a higher ion pair stability, inhibiting the membrane permeation. Our findings support the canonical model of passive permeability, suggesting that the neutral form of the drug can form in response to local environmental conditions near the membrane or within the transmembrane compartment. In this context, both the neutral form and the ion pair could contribute and play a role as a part of the equilibrium of partitioning across the membrane.
期刊介绍:
The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics.
Topics covered include for example:
Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids)
Aspects of manufacturing process design
Biomedical aspects of drug product design
Strategies and formulations for controlled drug transport across biological barriers
Physicochemical aspects of drug product development
Novel excipients for drug product design
Drug delivery and controlled release systems for systemic and local applications
Nanomaterials for therapeutic and diagnostic purposes
Advanced therapy medicinal products
Medical devices supporting a distinct pharmacological effect.