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Title: Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations

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, C 18H 28N 2O) and ropivacaine (RVC, C 17H 26N 2O), in both their crystalline forms and complexed with water-soluble oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HP-β-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-β-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-β-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.

Authors:
 [1];  [2];  [3];  [4];  [1];  [5];  [6];  [7];  [8];  [9];  [10];  [11]
  1. Univ. of Copenhagen, Copenhagen (Denmark)
  2. Univ. of South Florida, Tampa, FL (United States); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Univ. of Copenhagen, Copenhagen (Denmark); Oxford Univ., Oxford (United Kingdom)
  4. Univ. of Copenhagen, Copenhagen (Denmark); Norwegian Univ. of Science and Technology (NTNU), Trondheim (Norway)
  5. Human and Natural Sciences Center Federal Univ. of ABC (UFABC), Santo Andre (Brazil)
  6. Univ. Paris-Saclay, Gif-sur-Yvette (France)
  7. Inst. of Materials (Italy); Inst. Laue-Langevin, Grenoble Cedex (France)
  8. Inst. Laue-Langevin, Grenoble Cedex (France)
  9. Chalmers Univ. of Technology, Goteborg (Sweden)
  10. State Univ. of Campinas (UNICAMP), Campinas (Brazil)
  11. Univ. of Copenhagen, Copenhagen (Denmark); European Spallation Source, Lund (Sweden)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Univ. of California, Oakland, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1563056
Alternate Identifier(s):
OSTI ID: 1413841; OSTI ID: 1543548
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
International Journal of Pharmaceutics
Additional Journal Information:
Journal Volume: 524; Journal Issue: 1-2; Journal ID: ISSN 0378-5173
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Pharmacology & Pharmacy; Local anesthetics; Bupivacaine; Ropivacaine; HP-β-cyclodextrin; Complexation; Inelastic neutron scattering

Citation Formats

Martins, Murillo L., Eckert, Juergen, Jacobsen, Henrik, dos Santos, Éverton C., Ignazzi, Rosanna, de Araujo, Daniele Ribeiro, Bellissent-Funel, Marie -Claire, Natali, Francesca, Koza, Michael Marek, Matic, Aleksander, de Paula, Eneida, and Bordallo, Heloisa N. Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations. United States: N. p., 2017. Web. doi:10.1016/j.ijpharm.2017.03.051.
Martins, Murillo L., Eckert, Juergen, Jacobsen, Henrik, dos Santos, Éverton C., Ignazzi, Rosanna, de Araujo, Daniele Ribeiro, Bellissent-Funel, Marie -Claire, Natali, Francesca, Koza, Michael Marek, Matic, Aleksander, de Paula, Eneida, & Bordallo, Heloisa N. Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations. United States. doi:10.1016/j.ijpharm.2017.03.051.
Martins, Murillo L., Eckert, Juergen, Jacobsen, Henrik, dos Santos, Éverton C., Ignazzi, Rosanna, de Araujo, Daniele Ribeiro, Bellissent-Funel, Marie -Claire, Natali, Francesca, Koza, Michael Marek, Matic, Aleksander, de Paula, Eneida, and Bordallo, Heloisa N. Fri . "Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations". United States. doi:10.1016/j.ijpharm.2017.03.051.
@article{osti_1563056,
title = {Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations},
author = {Martins, Murillo L. and Eckert, Juergen and Jacobsen, Henrik and dos Santos, Éverton C. and Ignazzi, Rosanna and de Araujo, Daniele Ribeiro and Bellissent-Funel, Marie -Claire and Natali, Francesca and Koza, Michael Marek and Matic, Aleksander and de Paula, Eneida and Bordallo, Heloisa N.},
abstractNote = {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-β-cyclodextrin (HP-β-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-β-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-β-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.},
doi = {10.1016/j.ijpharm.2017.03.051},
journal = {International Journal of Pharmaceutics},
number = 1-2,
volume = 524,
place = {United States},
year = {2017},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.ijpharm.2017.03.051

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