| 1. |
- Tsapatsaris, Nikolaos, et al.
(författare)
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Polymorphic drugs examined with neutron spectroscopy: Is making more stable forms really that simple?
- 2013
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Ingår i: Chemical Physics. - : Elsevier BV. - 0301-0104. ; 427, s. 124-128
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Tidskriftsartikel (refereegranskat)abstract
- Understanding polymorphism in pharmaceutical ingredients is a long-standing challenge in formulation science. A well-known example is paracetamol, C8H9NO2. The marketed stable form I crystallizes with corrugated molecular layers. In contrast, form II, which is thermodynamically favorable at high pressures, has relatively planar layers that can slip over each other without difficulty, but is metastable at ambient conditions. By means of inelastic neutron scattering we demonstrated that the lattice modes of form II exhibit a sudden 1 meV energy shift at 300 K under a pressure of ca 0.4 GPa. Moreover, evidence of an increase of the vibrational energy in both polymorphs was found, which was accompanied, in form I, by an unexpectedly weak increase of the tunnel splitting. These results indicate an anisotropy of the potential surface probed by the methyl rotor, and are discussed in relation to the differences of the strength of the hydrogen bond environment for each polymorph. (C) 2013 Elsevier B. V. All rights reserved.
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| 2. |
- Tsapatsaris, Nikolaos, et al.
(författare)
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Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility through Local Methyl Dynamics.
- 2014
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8392 .- 1543-8384. ; 11:3, s. 1032-1041
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Tidskriftsartikel (refereegranskat)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.
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