European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Peptide-loaded chitosan nanoparticles improve mitochondrial and cognitive functions via inhibition of Aβ-ABAD interaction in Alzheimer’s disease","authors":"Yomna A. Youssef ,&nbsp;Salma N. Tammam ,&nbsp;Basma M. Elshenawy ,&nbsp;Shaista Ilyas ,&nbsp;Alaa A. Gad ,&nbsp;Karin S. Farag ,&nbsp;Sanjay Mathur ,&nbsp;Reham M. Abdel-Kader","doi":"10.1016/j.ejpb.2025.114778","DOIUrl":"10.1016/j.ejpb.2025.114778","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most prevalent form of dementia. Mitochondrial dysfunction is recognized among the earliest pathological events in AD, and is closely-linked with the accumulation of amyloid-beta (Aβ) plaques which is a well-established hallmark of AD. The interplay between the two converges on the interaction of Aβ with the mitochondrial enzyme Aβ-binding alcohol dehydrogenase (ABAD), and the formation of Aβ-ABAD complex. This leads to the suppression of the normal function of ABAD, and elicits a number of detrimental events such as the excessive generation of reactive oxygen species (ROS) resulting in apoptosis of neuronal cells. To intercept the Aβ-ABAD interaction, a decoy peptide (DP) was employed, and was loaded into polymeric chitosan nanoparticles (CSNPs) for efficient delivery across the blood–brain barrier (BBB). <em>In vivo</em> studies on control and neuroinflammatory mouse models confirmed that NPs of the smaller size (SNPs; 59 ± 6 nm) accumulated in the brain with minimal off-target delivery. Unlike free DP, DP-loaded SNPs significantly improved cognitive functions as depicted by the modified Y-maze test. The DP also had protective effects on the mitochondria that were associated with a decrease in Aβ, an increase in ATP and a normalization in SOD activity. Additionally, the restoration of ABAD normal function was reflected by elevated estradiol levels. These findings indicate that the inhibition of Aβ-ABAD complex ameliorates Aβ-induced toxicity in AD, consequently enhancing both mitochondrial and cognitive functions.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114778"},"PeriodicalIF":4.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of polysorbate 80 oxidation: Acetate and Fe(III) mediated near UV and visible light degradation enhanced by free fatty acids","authors":"Yaqi Wu ,&nbsp;David Richards ,&nbsp;Yilue Zhang ,&nbsp;Lin Zhang ,&nbsp;Steve W. Dodd ,&nbsp;Christian Schöneich","doi":"10.1016/j.ejpb.2025.114763","DOIUrl":"10.1016/j.ejpb.2025.114763","url":null,"abstract":"<div><div>Polysorbate 80 (PS80) is a widely used nonionic surfactant in biopharmaceutical formulations. PS80 is prone to chemical degradation, potentially resulting in loss of surfactant properties essential for the stability of pharmaceutical formulations. A deep understanding of PS80 stability is critical to maintaining drug efficacy and safety. While general mechanisms of oxidation are known, specific mechanistic information on the initiation of PS80 oxidation in formulations is lacking. Here, we report on novel mechanisms of photo-degradation of PS80 in pharmaceutical buffers such as acetate, succinate, and adipate, containing Fe(III). Photo-degradation was monitored by fluorescence micelle assay (FMA) and mass spectrometry (MS). The mechanistic investigation suggests an <em>intra</em>-micellar PS80 photo-degradation mechanism, wherein buffer-derived carbon-centered radicals, generated from light-induced ligand-to-metal-charge-transfer (LMCT) and decomposition of Fe(III)-carboxylate complexes, enter the PS80 micelles and initiate degradation. Critical for the extent of photo-degradation is the presence of small levels of free fatty acids (FFAs), such as can be present in commercial multi-compendial PS80, facilitating the access of radicals into micelles via complexing with Fe(III) on the micelle surface.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114763"},"PeriodicalIF":4.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A questionnaire survey on the barriers regarding pharmaceutical excipients during pediatric drug development","authors":"Jumpei Saito,&nbsp;Hidefumi Nakamura,&nbsp;Miki Akabane,&nbsp;Akimasa Yamatani","doi":"10.1016/j.ejpb.2025.114775","DOIUrl":"10.1016/j.ejpb.2025.114775","url":null,"abstract":"<div><div>It is unclear whether there have been any problems caused by excipients in the development of pediatric drugs. In this study, we investigated the current issues caused by excipients in developing pediatric formulations. The current issues and challenges related to excipients in pediatric drug development and the sources of information on excipients were investigated through a questionnaire sent to the 38 pharmaceutical companies that are members of the Japan Pharmaceutical Manufacturers Association. Twelve pharmaceutical companies with experience in developing pediatric formulations faced difficulties due to uncertain information on the suitability of excipients for pediatrics, and four companies faced difficulties due to different regulations on excipients in different countries. Uncertainty about the maximum acceptable dose and regulatory differences between countries were also cited as barriers. Regarding excipient databases, the United States Food and Drug Administration Inactive Ingredients Database and the European Safety and Toxicity of Excipients for Paediatrics database have been used for national and international pediatric drug development. The drawbacks of both international databases were the lack of information on excipients commonly used in Japan and the historically used maximum dose for each excipient. Future improvements in database information and clarification and standardization of the excipient regulatory process will be required.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114775"},"PeriodicalIF":4.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-embedding of curcumin and gold nanoparticles with ZIF-8 nanoparticles for the treatment of liver cancer and its impact on metabolomics","authors":"Xiaohui Wang ,&nbsp;Lin Zhou ,&nbsp;Yingying Shi ,&nbsp;Wang Wang ,&nbsp;Peng Li ,&nbsp;Rui Cui ,&nbsp;Yajuan Wu ,&nbsp;Feng Wang ,&nbsp;Qiuzheng Du","doi":"10.1016/j.ejpb.2025.114773","DOIUrl":"10.1016/j.ejpb.2025.114773","url":null,"abstract":"<div><div>The mortality rate of primary liver malignant tumors is very high. Curcumin (Cur) is one of the most commonly used drugs for the treatment of liver cancer. However, due to its low bioavailability, nano-drug delivery systems are rapidly developing. Zeolitic imidazolate framework-8 (ZIF-8), is pH-sensitive and biodegradable in acidic environments, providing a very suitable platform for drug delivery. Here, the anti-tumor properties of Cur and the anti-inflammatory properties of gold nanoparticles (Au NPs) were integrated and encapsulated in ZIF-8 material to prepare a composite drug delivery system (Cur/Au@ZIF-8). The prepared materials were characterized by scanning electron microscopy and elemental analysis, transmission electron microscopy, and powder X-ray diffraction. The drug loading efficiency of Cur in this delivery system reached 47.16 %. The drug release curve showed that the release rate of Cur/Au@ZIF-8 was faster at pH 5.5, with a release rate of 72.34 %. Ultrasound-guided in situ liver cancer models were constructed in SD rats to investigate the <em>in vivo</em> anti-tumor effects of Cur/Au@ZIF-8 and its impact on the metabolomics of tumor-bearing rats before and after treatment. <em>In vivo</em> results indicated that Cur/Au@ZIF-8 showed better anti-tumor effects, with a tumor inhibition rate of 46.81 %. After treatment, 26 key differential metabolites (p &lt; 0.05) were identified from expression patterns and metabolic pathways, which were mainly related to fatty acid metabolism. This treatment strategy provides a reference for future cancer treatment and mechanism exploration.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114773"},"PeriodicalIF":4.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-Hydroxypropyl-β-cyclodextrin, solubiliser in a novel dantrolene formulation: Its binding affinities to clinical compounds that may be used during anaesthesia or management of malignant hyperthermia","authors":"Richard H. Ng Kwet Shing ,&nbsp;David J. Wright ,&nbsp;Sandeep Pal ,&nbsp;Samuel L. Smith ,&nbsp;Lucy B. Clayton ,&nbsp;Jonathan G. Bilmen","doi":"10.1016/j.ejpb.2025.114765","DOIUrl":"10.1016/j.ejpb.2025.114765","url":null,"abstract":"<div><div>2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is used as an excipient to improve the solubility of the highly lipophilic drug dantrolene in a novel formulation, NPJ5008. Dantrolene acts as an antidote for life-threatening anaesthesia-associated malignant hyperthermia (MH) crises and intervention speed is essential to minimise morbidity. NPJ5008 can be prepared and administered substantially faster than DANTRIUM IV in a smaller volume of fluid. Like other cyclodextrins in clinical use, HP-β-CD forms inclusion complexes with lipophilic molecules. The potential of HP-β-CD to unintentionally interact <em>in vivo</em> with other drugs administered during anaesthesia or an MH emergency was assessed. An <em>in silico</em> predictive model of HP-β-CD binding was built from published data using LigPrep/Glide and GROMACS for molecular dynamic simulations to generate data for binding free energy calculations, performed with the molecular mechanics Poisson–Boltzmann surface area method using a thermodynamic cycle. Docking of &gt;70 anaesthesia-relevant compounds with HP-β-CD was evaluated and 10 compounds were predicted to bind HP-β-CD using a cut-off of −4 kcal mol⁻¹. <em>In vitro</em> isothermal titration calorimetry (37 °C, pH 7) was also used to determine the enthalpy of interaction of HP-β-CD with 18 of the most clinically relevant compounds, including rocuronium, vecuronium and remifentanyl (the strongest predicted binder from the <em>in silico</em> work). All had low injection heats with assay parameters of 1500 µM test compound and 50 µM HP-β-CD, i.e. there was no discernible binding to HP-β-CD. Thus, the HP-β-CD component of NPJ5008 is unlikely to interfere with other drugs clinically relevant in MH.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114765"},"PeriodicalIF":4.4,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FcRn-targeted Pluronic F127-Poly (L-lactic Acid) polymersomes for oral insulin delivery","authors":"Pin Pin Ma,&nbsp;Zi Ling Li,&nbsp;Hong Xia Gao,&nbsp;Xiang Yuan Xiong","doi":"10.1016/j.ejpb.2025.114761","DOIUrl":"10.1016/j.ejpb.2025.114761","url":null,"abstract":"<div><div>The intestinal epithelium barrier is one of the main factors limiting the bioavailability of oral insulin delivery systems. Neonatal Fc (fragment crystallizable) receptor (FcRn) is highly expressed in the intestinal epithelium, which can bind specifically to the Fc fragments of IgG in a pH-dependent manner and thus improve the transepithelial transport of carriers modified by IgG Fc or Fc domain-binding peptides (FcBP) ligand. Thus, FcBP ligand was attached to Pluronic F127-polylactic acid polymersomes by using the biotin-avidin bridging technology to obtain FcRn-targeted FcBP-F127-PLA polymersomes. Insulin (INS) was loaded successfully into FcBP-F127-PLA with the loading efficiency of 12.01 %. The transepithelial transport experiments on Caco-2 cells using Coumarin-6 (C-6) as a fluorescence probe showed that the cumulative permeability percentage and apparent permeability coefficient (Papp) of the<!--> <!-->FcBP-F127-PLA/C-6 group was 1.7 and 1.8 times that of PLA-F127-PLA/C-6 group after 2 h of incubation, respectively. FcBP ligand density of FcBP-F127-PLA played a role on their transepithelial transport ability and 10%FcBP-F127-PLA with 10 % FcBP molar content was found to be the best. The in vivo hypoglycemic results showed that the relative pharmacological bioavailability (PA_R%) of the<!--> <!-->oral 10%FcBP-F127-PLA/INS group was 43.6 %, which was 1.27 times that of the PLA-F127-PLA/INS group. Therefore, FcBP-F127-PLA polymersomes could be a promising carrier of the oral insulin delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114761"},"PeriodicalIF":4.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impurity profiling of PEGylated myristoyl diglyceride, DMG-PEG 2000, a functional excipient used in mRNA lipid nanoparticle formulations","authors":"Benedikt Sperber ,&nbsp;Marcus Gutmann ,&nbsp;Josef Kehrein ,&nbsp;Tessa Lühmann ,&nbsp;Ulrike Holzgrabe ,&nbsp;Lorenz Meinel","doi":"10.1016/j.ejpb.2025.114762","DOIUrl":"10.1016/j.ejpb.2025.114762","url":null,"abstract":"<div><div>Lipid nanoparticles have gained significant attention during the COVID-19 pandemic, particularly due to their role in mRNA vaccine delivery. However, their rapid advancement has outpaced the development of established harmonized protocols for the quality control of the various excipients. In this study, we focused on the “stealth” lipopolymer 1,2-dimyristoyl-<em>rac</em>-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), a critical excipient used in Moderna’s Spikevax® mRNA vaccine. We investigated different commercial batches of DMG-PEG 2000 for impurities originating from both synthesis and degradation. Synthesis-related impurities include free glycerol and fatty acids of varying chain lengths, while degradation products result from single or double hydrolysis reactions. These synthetic and degradation-related impurities were primarily analyzed using an optimized high-performance liquid chromatography method with a charged aerosol detector (HPLC-CAD). Applying this validated method, a high purity of commercially available DMG-PEG 2000 was revealed, with every batch investigated exceeding a purity of 98.5%. In addition, gas chromatography (GC), HPLC with an evaporative light scattering detector (HPLC-ELSD), and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry were employed for comparative purposes and to enable further characterization. Based on these analyses, we developed a streamlined and robust impurity profiling protocol that (i) provides essential insight into the impurity profile of DMG-PEG 2000 in marketed products and (ii) may facilitate more decentralized and standardized validation processes in the future. The analytical approach presented here may also serve as a foundation for a future pharmacopeial monograph proposal for DMG-PEG 2000.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"214 ","pages":"Article 114762"},"PeriodicalIF":4.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bactericidal synergism between phage and antibiotics: A combination strategy to target multidrug-resistant Klebsiella pneumoniae in vitro and in vivo","authors":"Shuxian Wang ,&nbsp;Wenqi Fan ,&nbsp;Rulin Jin ,&nbsp;Weiqing Lan ,&nbsp;Yong Zhao ,&nbsp;Xiaohong Sun","doi":"10.1016/j.ejpb.2025.114759","DOIUrl":"10.1016/j.ejpb.2025.114759","url":null,"abstract":"<div><div>Bacteriophages have reemerged to potentially replace or complement the role of antibiotics, as bacterial viruses have the ability to inactivate pathogens. However, certain intrinsic limitations of phages overshadow their clinical application, particularly their narrow host spectrum and rapid development of resistance upon treatment. This study aimed to explore the synergistic antimicrobial effect of phage combined with antibiotics against <em>Klebsiella pneumoniae</em>. The time-killing experiments <em>in vitro</em> showed that phage and gentamicin combination displayed synergistic bactericidal activity, leading to a reduction in the minimum inhibitory concentration of gentamicin. Furthermore, the phage HS106/gentamicin combination significantly inhibited biofilm formation and eliminated mature biofilms. On the other hand, phage treatment for 2 h before gentamicin treatment produced better synergistic inhibitory effect. The use of phage followed by gentamicin can effectively inhibit the efflux effect. Surprisingly, the phage HS106/gentamicin combination still exhibited antimicrobial activity against phage-resistant mutants and double-resistant mutants. Finally, the phage HS106/gentamicin combination significantly increased the survival rate of zebrafish infected with <em>K. pneumoniae</em>, indicating its excellent bactericidal activity <em>in vivo</em>. Overall, the phage HS106/gentamicin combination may provide a promising approach for treating infections caused by high-level multidrug-resistant <em>K. pneumoniae</em>.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"213 ","pages":"Article 114759"},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and evaluation of celecoxib lyophilized orally disintegrating tablets with high bioavailability","authors":"Shuai Sun ,&nbsp;Mengjun Wang ,&nbsp;Jin Chen ,&nbsp;Xiaoli Ju ,&nbsp;Furong Zhang ,&nbsp;Meilin He ,&nbsp;Dongfang Cheng ,&nbsp;Shumeng Kong","doi":"10.1016/j.ejpb.2025.114756","DOIUrl":"10.1016/j.ejpb.2025.114756","url":null,"abstract":"<div><div>This study aimed to develop industrially feasible nano-lyophilized orally disintegrating tablets of celecoxib with high bioavailability and rapid onset of action. Nano-lyophilized orally disintegrating tablets were prepared using a media milling method combined with freeze-drying technology, in which the particle size of celecoxib was at the nanoscale. Single-factor experimental design and Box–Behnken statistical experimental design optimized the process and formulation. The optimized formulation contained 49.5 % celecoxib, 11.3 % PVP K30, 2.6 % SDS and 36.6 % mannitol. The tablets disintegrated within 5 s, with an average drug particle size of 351 nm after dispersion. The solubility of celecoxib increased significantly across all tested pH levels. In vitro release studies demonstrated that over 90 % of celecoxib was released from the tablets within 3 min. In vivo studies in rats and beagle dogs showed relative bioavailabilities of 155 % and 292 %, respectively, compared to Celebrex®, and tmax was reduced by 25.5 % and 33.5 %. The study successfully developed a nanotechnology-based lyophilized orally disintegrating tablet of celecoxib with enhanced bioavailability, offering a promising approach for low-dose NSAID formulations.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"213 ","pages":"Article 114756"},"PeriodicalIF":4.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of organic acid counterions in modulating the in-vitro dissolution and permeability profiles of procaine salts","authors":"Paola Disisto ,&nbsp;Laura Baraldi ,&nbsp;Luca Fornasari ,&nbsp;Irene Bassanetti ,&nbsp;Valentina Mileo ,&nbsp;Francesco Castagnini ,&nbsp;Francesca Ferlenghi ,&nbsp;Pietro Franceschi ,&nbsp;Alessia Bacchi ,&nbsp;Luciano Marchiò","doi":"10.1016/j.ejpb.2025.114758","DOIUrl":"10.1016/j.ejpb.2025.114758","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":4.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}