Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility Through Local Methyl Dynamics Full article
Journal |
Molecular Pharmaceutics
ISSN: 1543-8384 , E-ISSN: 1543-8392 |
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Output data | Year: 2014, Volume: 11, Number: 3, Pages: 1032-1041 Pages count : 10 DOI: 10.1021/mp400707m | ||||||||||||||||
Tags | molecular drugs; polymorphism; inelastic neutron scattering; methyl rotation; hydrogen bonding; DFT calculations | ||||||||||||||||
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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.
Cite:
Tsapatsaris N.
, Kolesov B.A.
, Fischer J.
, Boldyreva E.V.
, Daemen L.
, Eckert J.
, Bordallo H.N.
Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility Through Local Methyl Dynamics
Molecular Pharmaceutics. 2014. V.11. N3. P.1032-1041. DOI: 10.1021/mp400707m WOS Scopus РИНЦ
Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility Through Local Methyl Dynamics
Molecular Pharmaceutics. 2014. V.11. N3. P.1032-1041. DOI: 10.1021/mp400707m WOS Scopus РИНЦ
Dates:
Submitted: | Nov 25, 2013 |
Accepted: | Feb 7, 2014 |
Published online: | Feb 19, 2014 |
Published print: | Mar 3, 2014 |
Identifiers:
Web of science | WOS:000332348600036 |
Scopus | 2-s2.0-84901742839 |
Elibrary | 24049820 |
Chemical Abstracts | 2014:208329 |
Chemical Abstracts (print) | 160:317504 |
OpenAlex | W2050621986 |