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

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.

Crystal structure of two paracetamol polymorphs at 20 K: A search for the “structure-property” relationship

“…Thus, alterations in the Raman spectra below 100 K are not directly associated with a change in the time and space averaged orientation of the methyl group, which was found from the single crystal XRD data. The location of hydrogen atoms from the residual electron density maps during the common single crystal XRD study does not reveal the possible changes in the (2) dynamics of the methyl groups and their disordering, which were observed in the Raman spectroscopic investigations [15] and also in the inelastic neutron scattering [22,23]. The reasons for the discrepancies in the results obtained by different methods require an additional special investigation.…”

From BASIS to MIRACLES: Benchmarking and perspectives for high-resolution neutron spectroscopy at the ESS

“…McStas 2.0, was used for the simulations and executed on the Data Management and Software Centre (DMSC) at the Niels Bohr Institute in the University of Copenhagen. This allowed the collection of sufficient simulation statistics, using 10 12 neutron trajectories over a wavelength range of λ = 0.5-30Å, within 24 hours. In addition, an identical virtual instrument setup was developed in VITESS 3.1.…”

“…Being part of the unique scientific ecosystem of the ESS, MIRACLES will help open up new scientific horizons. For example, water dynamics that can be probed by quasi-elastic neutron scattering (QENS) on the 1 ps-1 ns timescale play an important role in drug release characteristics and molecular conformation, of novel injectable drug delivery media made from thermoresponsive polymer micro-capsules [7,8] or widely used analgesics [9][10][11]. Moreover, using MIRACLES it will be possible to effectively probe the multiple energy states of water held by?…”

Bis(paracetamol) pyridine – a new elusive paracetamol solvate: from modeling the phase diagram to successful single-crystal growth and structure–property relations

“…In such cases, the multicomponent crystals can be obtained under non-equilibrium conditions only, such as rapid precipitation by anti-solvents, spray-drying, or by co-grinding 5,[29][30][31][32][33][34][35][36] . Phase diagrams are helpful to optimize co-crystallisation conditions, to 55 obtain co-crystals from the melt or solution, or by spray-drying [38][39][40][41][42] . Careful preliminary studies of the phase diagrams in such systems are required in order to reliably control the crystallisation 50 process.…”