Title: Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations
Author: Rodrigues Da Silva, Gustavo H.; Ribeiro, Lígia N.M.; Mitsutake, Hery; Guilherme, Viviane A.; Castro, Simone R.; Poppi, Ronei J.; Breitkreitz, Márcia C.; De Paula, Eneida
Is part of: INTERNATIONAL JOURNAL OF PHARMACEUTICS, v. 529, p. 253 - 263
Citation: Rodrigues Da Silva, Gustavo H.; Ribeiro, Lígia N.M.; Mitsutake, Hery; Guilherme, Viviane A.; Castro, Simone R.; Poppi, Ronei J.; Breitkreitz, Márcia C.; De Paula, Eneida; Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations. INTERNATIONAL JOURNAL OF PHARMACEUTICS, v.529, p. 253-263, 2017
Abstract: Since potential changes in the dynamics and mobility of drugs upon complexation for delivery may affect their ultimate efficacy, we have investigated the dynamics of two local anesthetic molecules, bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O), in both their crystalline forms and complexed with water-soluble oligosaccharide 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The study was carried out by neutron scattering spectroscopy, along with thermal analysis, and density functional theory computation. Mean square displacements suggest that RVC may be less flexible in crystalline form than BVC, but both molecules exhibit very similar dynamics when confined in HP-beta-CD. The use of vibrational analysis by density functional theory (DFT) made possible the identification of molecular modes that are most affected in both molecules by insertion into HP-beta-CD, namely those of the piperidine rings and methyl groups. Nonetheless, the somewhat greater structure in the vibrational spectrum at room temperature of complexed RVC than that of BVC, suggests that the effects of complexation are more severe for the latter. This unique approach to the molecular level study of encapsulated drugs should lead to deeper understanding of their mobility and the respective release dynamics. (C) 2017 Elsevier B.V. All rights reserved.
Funding: Work by MLM was financed by the Science without Borders Program (grant number 205609/2014-7) and HJ partially funded by an internship grant offered by the Institute Laue-von-Langevin (ILL). ECS work was financed by the Norwegian Research Council (RCN) SYNKOYT Program (project number 228551). The work of RI was part of a student project and supported by collaboration between HNB and AM. EP acknowledges FAPESP (# 14/1447-5) grant. We acknowledge the support of the ILL in providing the neutron research facilities used in this work. This was financed by NMI3, CoNext and Danscatt. The thermoanalysis apparatus used in the work were financed by Carlsbergfondets (grants 2013_01_0589 and CF14-0230). This research also used resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. JE would also like to thank the Physics and Chemistry of Materials Group (T-1) at LANL for making computing resources available. HNB thanks Stephane Rols (ILL) for fruitful discussions concerning the analysis of the quasi-elastic data. We also thank Niels Vissing Holst for technical support on collection of X-ray diffraction data shown in data in brief.