ADMET and DMPK最新文献

{"title":"Schiff base metal complexes as emerging therapeutics against antimicrobial-resistant skin pathogens.","authors":"Parami Sinhapitiya, Samawansha Tennakoon, Isuri A D K Weeraratne","doi":"10.5599/admet.3214","DOIUrl":"10.5599/admet.3214","url":null,"abstract":"<p><strong>Background and purpose: </strong>The development of antimicrobial resistance reduces the efficacy of antimicrobial agents and poses a significant challenge to treat skin diseases. Many scientists, researchers, and pharmaceutical companies work diligently to investigate novel antimicrobial agents and discover alternatives to existing ones, aiming to address antimicrobial resistance. Within the broad field of metal complexes, Schiff base complexes occupy a prominent position, with structural versatility and significant biological properties that make them promising candidates for developing alternative drugs to combat the global crisis of antimicrobial resistance.</p><p><strong>Experimental approach: </strong>This paper reviewed the existing literature on how the structural features of some recently studied Schiff base ligands and their complexes influence the antibacterial and antifungal activities of these compounds against common skin pathogens, including <i>Candida albicans</i> sp., dermophytes, <i>Staphylococcus aureus</i> and <i>Streptococcus pyogenes</i>.</p><p><strong>Key results: </strong>The structural features, including the azomethine group (C=N), heteroatoms and substituents, in Schiff base compounds have been associated with interference with protein synthesis and the growth of bacterial and fungal cells. Schiff base compounds affect cell wall and cell membrane synthesis and inhibit enzymes essential to cell division and other cellular mechanisms. The chelation theory and the overtone's concept suggest that Schiff base metal complexes exhibit higher antibacterial and antifungal activities compared to Schiff base ligands.</p><p><strong>Conclusion: </strong>This review focuses on providing an overview of how the structural features of Schiff base compounds influence the antimicrobial properties of these compounds against <i>Candida albicans</i> sp., dermophytes, S<i>taphylococcus aureus</i> and <i>Streptococcus pyogenes</i>.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3214"},"PeriodicalIF":4.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory potential of plant-derived extracellular vesicles from <i>Solanum nigrum</i> L. integrated in gelatine-dopamine hydrogel on RAW 264.7 and MC3T3 cells.","authors":"Anggraini Barlian, Tasya Fediarisa, Aida Fitri Kamila, Noviana Vanawati, Yung-Hsin Cheng","doi":"10.5599/admet.3149","DOIUrl":"10.5599/admet.3149","url":null,"abstract":"<p><strong>Background and purpose: </strong>Plant-derived extracellular vesicles (PDEV) from <i>Solanum nigrum</i> L. fruit show promise as a cell-free regenerative and inflammatory therapy for bone defects due to their anti-inflammatory properties. However, challenges such as storage stability and targeted delivery efficiency remain in PDEV's applications. Strategies such as lyophilization and injectable hydrogel delivery systems offer potential solutions.</p><p><strong>Experimental approach: </strong>In this study, lyophilized PDEVs derived from <i>Solanum nigrum</i> L. berries were incorporated into a thermosensitive injectable gelatine-dopamine (Gel-Dop) hydrogel and evaluated by <i>in vitro</i> for their anti-inflammatory potential using MC3T3 pre-osteoblast cells and RAW 264.7 macrophage cells.</p><p><strong>Key results: </strong>The isolated PDEVs show a spherical morphology, an average size of approximately 132.6 nm, a polydispersity index of 0.197, and a protein concentration of 509 μg mL^-1. These PDEVs were efficiently internalized by MC3T3 and RAW 264.7 cells after 12 hours of incubation and showed no cytotoxic effects at concentrations up to 10 μg mL^-1. The release profile confirmed that the hydrogel effectively released the PDEVs, which remained non-toxic and were internalized by cells after 12 hours of incubation. Subsequently, treatment of lipopolysaccharide (LPS) stimulated MC3T3 and RAW 264.7 cells with PDEVs led to a reduction in IL-6 protein expression.</p><p><strong>Conclusion: </strong>These findings suggest that lyophilized PDEVs from <i>Solanum nigrum</i> L. berries, when incorporated into Gel-Dop hydrogel, hold promise for future development as an anti-inflammatory agent in bone therapy. This study is the first to characterize and incorporate lyophilized PDEVs from <i>Solanum nigrum</i> L. into thermosensitive injectable Gel-Dop hydrogel and demonstrate their anti-inflammatory potential through the suppression IL-6 expression in LPS-stimulated MC3T3 and RAW 264.7 cells.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3149"},"PeriodicalIF":4.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In silico</i> based exploration of natural and synthetic antidiabetic compounds: A comprehensive review of computational approaches.","authors":"Ahmad Fariz Maulana, Sriwidodo Sriwidodo, Iman Permana Maksum, Yaya Rukayadi","doi":"10.5599/admet.3070","DOIUrl":"10.5599/admet.3070","url":null,"abstract":"<p><strong>Background and purpose: </strong>Diabetes mellitus type 2 is a global health issue marked by hyperglycemia and metabolic dysfunction. Despite progress, discovering safe and effective antidiabetic agents remains crucial. This review highlights integrated In Silico, In Vitro, and <i>in vivo</i> methods for identifying novel antidiabetic compounds from natural and synthetic origins.</p><p><strong>Experimental approach: </strong>Computational tools including molecular docking, molecular dynamics, and ADMET prediction identified inhibitors targeting DPP-IV, α-glucosidase, and PPAR. Promising compounds underwent <i>in vitro</i> enzymatic and cellular assays, followed by <i>in vivo</i> efficacy tests in diabetic animal models assessing glucose levels, biochemical markers, and tissue histopathology.</p><p><strong>Key results: </strong>Integrated computational and experimental approaches effectively pinpointed compounds with strong target binding, enzyme inhibition, and positive cellular effects. <i>In vivo</i> data showed significant glucose reduction, enhanced insulin response, and pancreatic protection. ADMET analysis further supported their drug-likeness and safety profiles.</p><p><strong>Conclusion: </strong>Combining computational screening with biological validations forms a cost-effective pipeline for antidiabetic drug discovery. Multi-disciplinary integration increases lead identification success, guiding future refinement of <i>in silico</i> models and expanded <i>in vivo</i> studies to accelerate novel diabetes therapeutic development.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3070"},"PeriodicalIF":4.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rosanoid diterpenoids: structural diversity, classification and biological activities.","authors":"Sabrin R M Ibrahim, Hani Z Asfour, Gamal A Mohamed, Nabil A Alhakamy, Hossam M Abdallah, Hagar M Mohamed","doi":"10.5599/admet.3165","DOIUrl":"10.5599/admet.3165","url":null,"abstract":"<p><strong>Background and purpose: </strong>Rosanoid diterpenoids, including ent-rosane and rosane diterpenoids, are structurally unique and bioactive subclass diterpenes characterized by a tricyclic carbon skeleton. This work aims to provide a comprehensive review of the literature on these diterpenoids from 1975. to September 2025., including their occurrence, structural diversity, and biological activities.</p><p><strong>Approach: </strong>An extensive literature search was conducted through scientific databases (ScienceDirect, PubMed, Scopus, Web of Science, and Google Scholar) and publishers' webpages (Elsevier, Wiley, ACS, RSC, Taylor & Francis, Springer, Bentham, Thieme, and MDPI), covering reports from 1975 to September 2025.</p><p><strong>Key results: </strong>Rosanoid diterpenoids have been isolated from various natural sources, including fungi, liverworts, and higher plant families such as <i>Euphorbiaceae, Lamiaceae, Alismataceae, Asteraceae, Velloziaceae, and Celastraceae</i>. They are predominantly found in <i>Euphorbia</i> species, revealing their chemotaxonomic relevance to the <i>Euphorbiaceae</i> family. These compounds exhibit extensive structural diversity, encompassing a broad spectrum of biological activities, including anti-inflammatory, antimicrobial, antiviral, cytotoxic, enzyme-inhibitory, neuroactive, and anti-adipogenic effects.</p><p><strong>Conclusion: </strong>The reported findings highlight the chemical variability and pharmacological potential of rosanoid diterpenoids, making them promising building blocks for future drug discovery and natural product development. However, further studies are warranted to explore their pharmacokinetics, mechanisms of action, safety profiles, and biosynthetic pathways.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3165"},"PeriodicalIF":4.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into drug resistance in <i>Leishmania</i>: Mechanisms, therapeutics, and clinical case studies.","authors":"Gajala Deethamvali Ghousepeer, Mansi Rani, Aman Kumar, Shubhankar Kumar Singh, Anjali Priyadarshini, Elcio Leal, Shailja Singh, V Samuel Raj, Subhajit Basu, Ramendra Pati Pandey","doi":"10.5599/admet.2992","DOIUrl":"10.5599/admet.2992","url":null,"abstract":"<p><strong>Background and purpose: </strong>Leishmaniasis, a neglected tropical disease caused by the protozoan parasite <i>Leishmania</i>, remains a significant public health concern in endemic regions. The disease manifests in various forms, including cutaneous, mucocutaneous, and visceral leishmaniasis, each associated with specific <i>Leishmania</i> species and influenced by host immune responses. Over the past few decades, treatment for leishmaniasis has relied on a limited range of drugs, including pentavalent antimonials, amphotericin B formulations, miltefosine, and paromomycin. However, widespread drug resistance, particularly in visceral leishmaniasis, has severely compromised treatment efficacy, leading to rising cases of treatment failure. This review aims to provide a comprehensive understanding of the mechanisms underlying drug resistance in leishmaniasis and to highlight the factors that contribute to its development.</p><p><strong>Experimental approach: </strong>The study synthesizes existing literature on resistance mechanisms among anti-leishmanial drugs, focusing on changes in parasite uptake and efflux, intracellular sequestration, and modulation of stress responses. It also examines the impact of environmental factors, such as arsenic exposure in endemic regions, and reviews recent molecular and genomic studies that have identified resistance-associated markers.</p><p><strong>Conclusion: </strong>The review underscores the urgent need for innovative therapeutic strategies and highlights the importance of an integrated approach to combat drug resistance through enhanced surveillance, molecular insights, and global collaboration.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"2992"},"PeriodicalIF":4.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-infective macrozones: design, biological evaluation and structure-activity relationships.","authors":"Tomislav Jednačak, Višnja Stepanić, Iva Habinovec, Ivana Mikulandra, Kristina Smokrović, Hana Čipčić Paljetak, Mirjana Bukvić, Jelena Parlov Vuković, Ivan Grgičević, Leda Divjak, Klaus Zangger, Predrag Novak","doi":"10.5599/admet.3139","DOIUrl":"10.5599/admet.3139","url":null,"abstract":"<p><strong>Background and purpose: </strong>To discover novel compounds active against sensitive and resistant bacterial strains, a series of novel azithromycin-thiosemicarbazone conjugates, the macrozones, have been synthesized and their biological activity evaluated with corresponding (quantitative) structure-activity relationship ((Q)SAR) analyses conducted.</p><p><strong>Experimental approach: </strong>A systematic variation of thiosemicarbazone side-chains and coupling at positions 4\"-, 3-, and 9a of the azithromycin scaffold has resulted in a novel class of bacterial ribosome inhibitors.</p><p><strong>Key results: </strong>Compared to azithromycin, the activity of 4\"-macrozones has shown the greatest improvements against efflux-resistant <i>S. pneumoniae</i> and <i>S. aureus</i>, as well as very good activity of 4\" derivatives against <i>E. faecalis</i>. QSAR calculations indicate that the antibacterial activity of macrozones is primarily determined by the position of the thiosemicarbazone side chain. Among the conjugated derivatives, the 4\"-substituted macrozones exhibit the highest overall activity against a range of sensitive and efflux-resistant Gram-positive bacteria, as well as against Gram-negative <i>E. coli</i> strains, while those substituted at 9a- and 3- positions are found to be less potent. The antibacterial activity of macrozones is favourably influenced by larger fractions of their cationic and zwitterionic forms, their capacity for hydrogen bond formation, and the extension of π-electron delocalization involving the thiosemicarbazone moiety.</p><p><strong>Conclusion: </strong>The results obtained provide a sound basis for guiding further medicinal chemistry efforts toward the discovery of more potent macrolide anti-infectives, with particular emphasis on resistant bacteria that pose a serious threat to human health.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3139"},"PeriodicalIF":4.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel stirring method for small-scale dissolution test: Rotating vessel method.","authors":"Shiori Ishida, Samuel Lee, Balint Sinko, Karl Box, Kiyohiko Sugano","doi":"10.5599/admet.3136","DOIUrl":"10.5599/admet.3136","url":null,"abstract":"<p><strong>Background and purpose: </strong>In the compendial dissolution test, the overhead rotating paddle method (ORP) has been used for stirring, whereas the magnetic stirring bar method (MSB) has been employed for small-scale dissolution tests, such as the μDISS Profiler^TM (μDISS). Previous reports have indicated that differences exist in the precipitation profiles of a drug between ORP and MSB, because the latter causes contact-induced nucleation. However, it has been difficult to use an ORP and an <i>in situ</i> UV probe simultaneously in μDISS. In this study, a novel stirring method, the rotating vessel method (RV), was developed for μDISS. The dissolution and precipitation profiles of model drugs in RV-μDISS were then compared with those in MSB-μDISS, as well as with the results of conventional dissolution tests using an ORP.</p><p><strong>Experimental approach: </strong>In RV-μDISS, a small paddle (approximately 1/4 of the conventional paddle) was fixed to the UV probe, and the glass vessel was rotated to produce a flow pattern similar to that of ORP. The dissolution and bulk-phase precipitation tests were performed for ibuprofen sodium (IBU Na) and carbamazepine (CBZ), respectively, using RV-μDISS and MSB-μDISS, as well as ORP with the conventional vessel (500 mL, for IBU Na) (CV) or the mini-vessel (50 mL, for CBZ) (MV).</p><p><strong>Key results: </strong>The dissolution rate of IBU Na was similar in all methods. Rapid precipitation of crystalline IBU free acid was observed in the MSB-μDISS method. In contrast, no crystalline precipitation was observed in RV-μDISS and ORP-CV, and the drug phase-separated as a liquid (oil) phase (liquid-liquid phase separation). The precipitation rate of CBZ in RV-μDISS was similar to that in ORP-MV, but slower than that in MSB-μDISS.</p><p><strong>Conclusion: </strong>The precipitation profile in RV-μDISS was close to those in ORP-CV and ORP-MV. RV-μDISS would be a useful tool for the assessment of the precipitation profiles of drugs.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3136"},"PeriodicalIF":4.3,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Injectable hydrogels for bone regeneration: mechanical reinforcement strategies using nanoparticles and nanofibers.","authors":"Morteza Mirzagoli, Fariba Ganji, Lobat Tayebi","doi":"10.5599/admet.3037","DOIUrl":"10.5599/admet.3037","url":null,"abstract":"<p><strong>Background and purpose: </strong>The growing demand for bone regeneration following severe injuries highlights the importance of scaffolds in bone tissue engineering (BTE). Injectable hydrogels have emerged as promising candidates because their properties closely mimic the native extracellular matrix (ECM). However, their limited mechanical strength and structural instability restrict their practical application.</p><p><strong>Approach: </strong>This review summarizes recent strategies for reinforcing in situ-forming injectable hydrogels to improve their mechanical performance for bone regeneration. Particular emphasis is placed on nanomaterial-based strategies, including the incorporation of nanoparticles and nanofibers, and their ability to enhance the physical properties of polymeric networks.</p><p><strong>Key results: </strong>Evidence from recent studies demonstrates that reinforcing hydrogels with nano-scaled materials creates interconnected networks that improve load-bearing capacity, stability, and resistance to deformation. These reinforced systems retain the inherent advantages of injectable hydrogels-biocompatibility, biodegradability, permeability to oxygen and nutrients, and drug delivery capability-while addressing their mechanical shortcomings.</p><p><strong>Conclusion: </strong>Nanomaterial-based reinforcement offers a versatile approach to overcoming the limitations of injectable hydrogels in BTE. By providing improved structural integrity alongside biological functionality, these advanced systems broaden the potential of injectable hydrogels for clinical translation. Future work should focus on optimizing reinforcement strategies to balance mechanical enhancement with safety, manufacturability, and regulatory considerations.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3037"},"PeriodicalIF":4.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential effect of nanoformulated iota carrageenan in Aβ1-42 disaggregation: an <i>in vitro</i>, <i>in vivo</i> and <i>in silico</i> study.","authors":"Saranya Udayakumar, Sanjay Kisan Metkar, Koyeli Girigoswami, Agnishwar Girigoswami","doi":"10.5599/admet.3122","DOIUrl":"10.5599/admet.3122","url":null,"abstract":"<p><strong>Background and purpose: </strong>Alzheimer's disease is the primary contributor to neurodegenerative conditions. These pathologies are identified by the deposition of β-amyloid peptide within brain regions. It develops insoluble fibrils known as senile plaques. These plaques are associated with synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Hence, the degradation and elimination of β-amyloid peptide fibrils from the body are viable therapeutic approaches for managing Alzheimer's disease.</p><p><strong>Experimental approach: </strong>In the current study, liposomal nanoformulated iota carrageenan was synthesized and characterized using different photophysical tools. The nanoformulated iota carrageenan effectively degraded β-amyloid peptide 1-42, with 45.5 % reduction confirmed by Thioflavin T fluorescence assay. This activity was further supported by turbidity and dynamic light scattering analysis.</p><p><strong>Key results: </strong>The biocompatibility of nanoformulated iota carrageenan and its degraded β-amyloid peptide was determined using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), live/dead cell assay on PC12 cells. Structural disintegration of the β-amyloid peptide fibrils was validated through atomic force microscopy, revealing a significant reduction in fibrillar morphology. <i>In silico</i> studies also evidenced the interaction between the β-amyloid peptide and nanoformulated iota carrageenan. In addition, the neuroprotective potential of nanoformulated iota carrageenan, as evidenced by nanoformulated iota carrageenan-treated β-amyloid peptide, was supported by neurite outgrowth studies. These studies showed that differentiated PC12 cells exhibited larger neurite growth with extensive branching, indicating the reversal of β-amyloid peptide-induced neurotoxicity. CAM assay demonstrated enhanced blood vessel formation in chick embryos treated with nanoformulated iota carrageenan and its β-amyloid peptide-degraded group.</p><p><strong>Conclusion: </strong>These findings suggest that nanoformulated iota carrageenan holds potential and has nontoxic therapeutic effects for Alzheimer's disease. Additional <i>in vivo</i> validation is required in future investigations.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3122"},"PeriodicalIF":4.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imipramine solubility-pH profiles: self-aggregation <i>vs.</i> common-ion effect.","authors":"Olivera S Marković, Miloš P Pešić, Alex Avdeef, Abu T M Serajuddin, Tatjana Ž Verbić","doi":"10.5599/admet.3128","DOIUrl":"10.5599/admet.3128","url":null,"abstract":"<p><strong>Background and purpose: </strong>The pH-dependent solubility of imipramine, a tricyclic antidepressant, and its hydrochloride salt was investigated in phosphate buffers and chloride-containing aqueous media using the pH-ramp shake-flask method. It was reported that aggregation of imipramine in acidic media and its partial degradation in alkaline media complicate the determination of its solubility. This was further investigated with modified methods.</p><p><strong>Experimental approach: </strong>For imipramine solubility studies, the computer program <i>p</i>DISOL-X was used to design experiments, process data, and refine the equilibrium constants. Isolated solid precipitates under various conditions were characterized using thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analysis. The critical micelle concentration of imipramine hydrochloride was determined in 0.10 mol L^-1 NaH₂PO₄ and in 0.15 mol L^-1 NaCl by conductometric titrations.</p><p><strong>Key results: </strong>A detailed analysis of imipramine pH-solubility profiles reveals complex equilibria in the aqueous phase, as well as various solid-phase transformations. Intrinsic solubility of imipramine, solubility products of imipramine hydrochloride and imipramine phosphate salts, and aggregation constants (trimer, heptamer, and cationic complex with phosphate ions) were determined. Solid state characterization results are in accordance with pDISOL-X analysis.</p><p><strong>Conclusion: </strong>These findings, along with our previous solubility studies of desipramine and nortriptyline, suggest that even subtle structural variations can lead to significant differences in the aqueous media behaviour of tricyclic antidepressants. This type of information can be valuable in the early stages of drug discovery, in formulation optimization experiments, as well as in <i>in vitro</i> and <i>in vivo</i> studies.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3128"},"PeriodicalIF":4.3,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}