Browsing by Author "Invernizzi, Sergio"

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    Drug Salt Formation via Mechanochemistry: The Case Study of Vincamine
    (ACS Publications, 2012-11-27) Hasa, Dritan; Perissutti, Beatrice; Cepek, Cinzia; Bhardwaj, Sunil; Carlino, Elvio; Grassi, Mario; Invernizzi, Sergio; Voinovich, Dario
    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.
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    Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies
    (Springer, 2011-03-19) Hasa, Dritan; Voinovich, Dario; Perissutti, Beatrice; Grassi, Mario; Bonifacio, Alois; Sergo, Valter; Cepek, Cinzia; Chierotti, Michele R.; Gobetto, Roberto; Dall’Acqua, Stefano; Invernizzi, Sergio
    Purpose Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid. Methods The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solidstate characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine®). Results The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state. Conclusion From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.
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    Mechanochemically induced disordered structures of vincamine: The different mediation of two cross-linked polymers
    (Elsevier, 2012-06-18) Hasa, Dritan; Perissutti, Beatrice; Chierotti, Michele R.; Gobetto, Roberto; Grabnar, Iztok; Bonifacio, Alois; Dall’Acqua, Stefano; Invernizzi, Sergio; Voinovich, Dario
    The aims of this research were to prepare highly bioavailable binary cogrounds (vincamine–AcDiSol® or PVP-Cl) by means of a mechanochemical process and to study the mediation of each polymer in the induction of physical transformations of the drug. From a set of fifteen cogrounds for each crosslinked polymer, two samples were selected in each group on the basis of the AUC of in vitro dissolution profiles with the help of a statistical comparison. The chosen samples were analysed by means of TEM, XRPD, Raman-spectroscopy/imaging, SSNMR, also including the study of 1H spin–lattice relaxation times. The research encompassed in vivo oral absorption studies in rats, pharmacokinetic analysis and physical stability studies during 1 year. An intimate drug–polymer mixing was found in the coground samples with domain average dimensions smaller than 100A˚ ; this reflected in a remarkable enhancement of the in vitro and in vivo bioavailability. Different disordered states were detected in the coground samples as a function of cogrinding time and the type and amount of polymer used. Though both crosslinked polymers produced a remarkable enhancement of the oral bioavailability, coground systems based on AcDiSol® are preferable in terms of pharmacokinetic performance and physical stability.
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    Multidisciplinary Approach on Characterizing a Mechanochemically Activated Composite of Vinpocetine and Crospovidone
    (Wiley, 2010-09-13) Hasa, Dritan; Voinovich, Dario; Perissutti, Beatrice; Bonifacio, Alois; Grassi, Mario; Franceschinis, Erica; Dall'Acqua, Stefano; Speh, Manuela; Plavec, Janez; Invernizzi, Sergio
    Significant improvement of solubilization kinetics of poorly soluble vinpocetine was obtained through amechanochemical activation process in presence ofmicronized crospovidone. Drug-to-polymer weight ratio and milling time variables resulted to have statistically significant impacts on the activation of the product. The complete amorphization was obtained in the coground with the highest crospovidone contents (>80% wt), milled for the longest time (180 min). An ad hoc software was then used to calculate the dimensions of the drug crystallites in the samples on the basis of the calorimetric data. The thermal analyses were then accompanied and confirmed by an extensive solid-state characterization, performing X-ray diffraction, Raman imaging/spectroscopy, DRIFT, and SS-NMR spectroscopy, followed by laser diffraction and solubilization kinetics tests. All the analyses agreed on attesting the progressive loosing of crystalline structure of the drug when increasing milling time and amount of polymer in the formulations. This activated status of the drug, which resulted to be homogeneously distributed on the coground sample and stable for at least 1 year, was reflected on favorable solubilization kinetics. The in vivo studies on rats revealed that coground systems promoted a fivefold higher oral bioavailability enhancement in comparison to a commercial formulation (VimpocetinR 5mg Capsules, Pharma)