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, 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.
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Universitetsparken 5 DK-2100, Copenhagen, Denmark. Electronic address: murillolongo@gmail.com.
authors.forename: Murillo L
authors.initials: ML
authors.lastname: Martins
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, United States; Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, United States.
authors.forename: Juergen
authors.initials: J
authors.lastname: Eckert
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Universitetsparken 5 DK-2100, Copenhagen, Denmark; Department of Physics, Oxford University, Oxford, OX1 3PU, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Jacobsen
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Universitetsparken 5 DK-2100, Copenhagen, Denmark; Department of Physics, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5 NO-7491, Trondheim, Norway.
authors.forename: Éverton C
authors.initials: ÉC
authors.lastname: Dos Santos
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Universitetsparken 5 DK-2100, Copenhagen, Denmark.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Ignazzi
authors.affiliation: Human and Natural Sciences Center Federal University of ABC (UFABC) 09210-170, Santo André, SP, Brazil.
authors.forename: Daniele Ribeiro
authors.initials: DR
authors.lastname: de Araujo
authors.affiliation: LLB, CEA, CNRS, Université Paris-Saclay, CEA Saclay, 91191-Gif-sur-Yvette, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Bellissent-Funel
authors.affiliation: Institute of Materials, Research National Council (CNR-IOM), Italy; Institut Laue-Langevin, 71 Avenue des Martyrs, CS 20156, Grenoble Cedex 9, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Natali
authors.affiliation: Institut Laue-Langevin, 71 Avenue des Martyrs, CS 20156, Grenoble Cedex 9, France.
authors.forename: Michael Marek
authors.initials: MM
authors.lastname: Koza
authors.affiliation: Department of Applied Physics, Chalmers University of Technology, SE-41296 Göteborg, Sweden.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Matic
authors.affiliation: Department of Biochemistry and Tissue Biology, State University of Campinas (UNICAMP) 13083-862, Campinas, SP, Brazil.
authors.forename: Eneida
authors.initials: E
authors.lastname: de Paula
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Universitetsparken 5 DK-2100, Copenhagen, Denmark; European Spallation Source ESS P.O. Box 176, SE-22100, Lund, Sweden.
authors.forename: Heloisa N
authors.initials: HN
authors.lastname: Bordallo
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry; D000577:Amides / Q000032:analysis*; D000779:Anesthetics, Local / Q000032:analysis*; D002045:Bupivacaine / Q000032:analysis*; D033363:Neutron Diffraction; D000077212:Ropivacaine; D013057:Spectrum Analysis; D047392:beta-Cyclodextrins
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077212:Ropivacaine; D002045:Bupivacaine
keywords: Bupivacaine; Complexation; HP-β-cyclodextrin; Inelastic neutron scattering; Local anesthetics; Ropivacaine