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Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility through Local Methyl Dynamics.

Tsapatsaris, Nikolaos LU ; Kolesov, Boris A; Fischer, Jennifer; Boldyreva, Elena V; Daemen, Luke; Eckert, Juergen and Bordallo, Heloisa (2014) In Molecular Pharmaceutics 11(3). p.1032-1041
Abstract
This study focuses on the interplay of molecular flexibility and hydrogen bonding manifested in the monoclinic (form I) and orthorhombic (form II) polymorphs of paracetamol. By means of incoherent inelastic neutron scattering and density functional theory calculations, the relaxation processes related to the methyl side-group reorientation were analyzed in detail. Our computational study demonstrates the importance of considering quantum effects to explain how methyl reorientations and subtle conformational changes of the molecule are intertwined. Indeed, by analyzing the quasi elastic signal of the neutron data, we were able to show a unique and complex motional flexibility in form II, reflected by a coupling between the methyl and the... (More)
This study focuses on the interplay of molecular flexibility and hydrogen bonding manifested in the monoclinic (form I) and orthorhombic (form II) polymorphs of paracetamol. By means of incoherent inelastic neutron scattering and density functional theory calculations, the relaxation processes related to the methyl side-group reorientation were analyzed in detail. Our computational study demonstrates the importance of considering quantum effects to explain how methyl reorientations and subtle conformational changes of the molecule are intertwined. Indeed, by analyzing the quasi elastic signal of the neutron data, we were able to show a unique and complex motional flexibility in form II, reflected by a coupling between the methyl and the phenyl reorientation. This is associated with a higher energy barrier of the methyl rotation and a lower Gibbs free energy when compared to form I. We put forward the idea that correlating solubility and molecular flexibility, through the relation between pKa and methyl rotation activation energy, might bring new insights to understanding and predicting drug bioavailability. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Pharmaceutics
volume
11
issue
3
pages
1032 - 1041
publisher
The American Chemical Society
external identifiers
  • pmid:24506163
  • wos:000332348600036
  • scopus:84901742839
ISSN
1543-8392
DOI
10.1021/mp400707m
language
English
LU publication?
yes
id
f66bc4c7-2c93-400d-ac3e-c3b0ae1e63b5 (old id 4335390)
date added to LUP
2014-03-11 12:31:10
date last changed
2017-11-12 03:01:16
@article{f66bc4c7-2c93-400d-ac3e-c3b0ae1e63b5,
  abstract     = {This study focuses on the interplay of molecular flexibility and hydrogen bonding manifested in the monoclinic (form I) and orthorhombic (form II) polymorphs of paracetamol. By means of incoherent inelastic neutron scattering and density functional theory calculations, the relaxation processes related to the methyl side-group reorientation were analyzed in detail. Our computational study demonstrates the importance of considering quantum effects to explain how methyl reorientations and subtle conformational changes of the molecule are intertwined. Indeed, by analyzing the quasi elastic signal of the neutron data, we were able to show a unique and complex motional flexibility in form II, reflected by a coupling between the methyl and the phenyl reorientation. This is associated with a higher energy barrier of the methyl rotation and a lower Gibbs free energy when compared to form I. We put forward the idea that correlating solubility and molecular flexibility, through the relation between pKa and methyl rotation activation energy, might bring new insights to understanding and predicting drug bioavailability.},
  author       = {Tsapatsaris, Nikolaos and Kolesov, Boris A and Fischer, Jennifer and Boldyreva, Elena V and Daemen, Luke and Eckert, Juergen and Bordallo, Heloisa},
  issn         = {1543-8392},
  language     = {eng},
  number       = {3},
  pages        = {1032--1041},
  publisher    = {The American Chemical Society},
  series       = {Molecular Pharmaceutics},
  title        = {Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility through Local Methyl Dynamics.},
  url          = {http://dx.doi.org/10.1021/mp400707m},
  volume       = {11},
  year         = {2014},
}