Drug Salt Formation Via Mechanochemistry: The Case Study of Vincamine
| العنوان: | Drug Salt Formation Via Mechanochemistry: The Case Study of Vincamine |
|---|---|
| المؤلفون: | Dritan Hasa, Cinzia Cepek, Dario Voinovich, Sunil Bhardwaj, Elvio Carlino, Beatrice Perissutti, Mario Grassi, Sergio Invernizzi |
| المساهمون: | Hasa, Dritan, Perissutti, Beatrice, Cepek, C., Bhardwaj, S., Carlino, E., Grassi, Mario, Invernizzi, Sergio, Voinovich, Dario |
| المصدر: | Molecular pharmaceutics (Online) 10 (2013): 211–224. doi:10.1021/mp300371f info:cnr-pdr/source/autori:Dritan Hasa, Beatrice Perissutti, Cinzia Cepek, Sunil Bhardwaj, Elvio Carlino, Mario Grassi, Sergio Invernizzi, Dario Voinovich/titolo:Drug Salt Formation Via Mechanochemistry: The Case Study of Vincamine/doi:10.1021%2Fmp300371f/rivista:Molecular pharmaceutics (Online)/anno:2013/pagina_da:211/pagina_a:224/intervallo_pagine:211–224/volume:10 |
| بيانات النشر: | American Chemical Society, Washington, D.C. , Stati Uniti d'America, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | vincamine salt/citrate, HRTEM, Chemistry, Pharmaceutical, Vincamine, Biological Availability, Pharmaceutical Science, Salt (chemistry), Pilot Projects, Nanotechnology, solid excipient, Citric Acid, Excipients, Rats, Sprague-Dawley, chemistry.chemical_compound, Drug Stability, X-Ray Diffraction, Mechanochemistry, Drug Discovery, medicine, XPS, Animals, Organic chemistry, mechanochemistry, solid state, bioequivalence, stability, Particle Size, Solubility, chemistry.chemical_classification, Photoelectron Spectroscopy, Rats, Solvent, Kinetics, chemistry, Yield (chemistry), Reagent, Solvents, Molecular Medicine, Salts, Citric acid, medicine.drug |
| الوصف: | The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. In the present research a salt of vincamine, a poorly bioavailable indole alkaloid derived from the leaves of Vinca minor L., was synthesized in the solid state by means of a mechanochemical process employing citric acid as a reagent. The mechanochemical process was adopted as a solvent-free alternative to classical citrate synthetic route that involves the use of solvents. Since the mechanochemical salification is little studied to date and presents the disadvantage of offering a low yield, in this work, the influence of three process and formulation variables on the percentage of vincamine citrate was studied. In particular, the time of mechanical treatment (in planetary mill Fritsch P5) and the amount of citric acid were varied in order to evaluate their effect on the yield of the process, and the introduction of a solid solvent, a common pharmaceutical excipient (sodium carboxymethylcellulose, NaCMC), was considered. Due to the complexity of the resulting samples’ matrix, an appropriate experimental design was employed to project the experimental trials and the influence of the three variables on the experimental response was estimated with the help of a statistical analysis. The experimental response, that is, the yield of the process corresponding to the percentage of vincamine in the protonated form, was unconventionally calculated by means of X-ray photoelectron spectroscopy analysis (XPS). Out of 16 samples, the one with the highest yield was the coground sample containing vincamine and citric acid in a 1:2 molar ratio, treated for 60 min in the presence of NaCMC. Under the above conditions the salification reaction was completed highlighting the importance of a proper selection of process and formulation variables of the mechanochemical salification, and emphasizing the crucial role of the solid solvent in facilitating the salification. The second step of the research encompassed the characterization of the citrate salt obtained by solid excipient assisted mechanochemical salification (SEAMS) in comparison with the vincamine citrate obtained by classical synthetic route. The samples were characterized by, besides XPS, high resolution transmission electron microscopy (HRTEM), X-ray powder diffraction (XRPD), in vitro solubilization kinetics and in vivo oral pilot study in rats. Finally, in order to monitor over time possible disproportionation phenomena, stability studies have been performed by repeating XPS analysis after 8 months. As expected, the the SEAMS-vincamine salt consisted of particles both crystalline and amorphous. The solubilization kinetics was superior to the corresponding salt probably thanks to the favorable presence of the hydrophilic excipient although the two salts were bioequivalent in rats after oral administration. Furthermore, no evidence of disporportionation phenomena in the SEAMSvincamine salt was found after storage. In conclusion, in the case of forming salts of poorly soluble drugs, the SEAMS process may be an interesting alternative to both classical synthetic routes, eliminating the need for solvent removal, and simple neat mechanochemical salification, overcoming the problem of limited process yield. |
| وصف الملف: | application/octet-stream; STAMPA |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9fedc4962f443eb414408adbef87ae0e https://publications.cnr.it/doc/207291 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9fedc4962f443eb414408adbef87ae0e |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |