TY - JOUR
T1 - Polymorphism of paracetamol
T2 - a new understanding of molecular flexibility through local methyl dynamics
AU - Tsapatsaris, Nikolaos
AU - Kolesov, Boris A.
AU - Fischer, Jennifer
AU - Boldyreva, Elena V.
AU - Daemen, Luke
AU - Eckert, Juergen
AU - Bordallo, Heloisa N.
PY - 2014/3/3
Y1 - 2014/3/3
N2 - 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.
AB - 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.
U2 - 10.1021/mp400707m
DO - 10.1021/mp400707m
M3 - Journal article
C2 - 24506163
SN - 1543-8384
VL - 11
SP - 1032
EP - 1041
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 3
ER -