title: Polymorphism and disorder in natural active ingredients. Low and high-temperature phases of anhydrous caffeine: Spectroscopic ((1)H-(14)N NMR-NQR/(14)N NQR) and solid-state computational modelling (DFT/QTAIM/RDS) study.
abstract: The polymorphism of anhydrous caffeine (1,3,7-trimethylxanthine; 1,3,7-trimethyl-1H-purine-2,6-(3H,7H)-dione) has been studied by (1)H-(14)N NMR-NQR (Nuclear Magnetic Resonance-Nuclear Quadrupole Resonance) double resonance and pure (14)N NQR (Nuclear Quadrupole Resonance) followed by computational modelling (Density Functional Theory, supplemented Quantum Theory of Atoms in Molecules with Reduced Density Gradient) in solid state. For two stable (phase II, form β) and metastable (phase I, form α) polymorphs the complete NQR spectra consisting of 12 lines were recorded. The assignment of signals detected in experiment to particular nitrogen sites was verified with the help of DFT. The shifts of the NQR frequencies, quadrupole coupling constants and asymmetry parameters at each nitrogen site due to polymorphic transition were evaluated. The strongest shifts were observed at N(3) site, while the smallest at N(9) site. The commercial pharmaceutical sample was found to contain approximately 20-25% of phase I and 75-80% of phase II. The orientational disorder in phase II with a local molecular arrangement mimics that in phase I. Substantial differences in the intermolecular interaction phases I and II of caffeine were analysed using computational (DFT/QTAIM/RDS) approach. The analysis of local environment of each nitrogen nucleus permitted drawing some conclusions on the topology of interactions in both polymorphs. For the most stable orientations in phase I and phase II the maps of the principal component qz of EFG tensor and its asymmetry parameter at each point of the molecular system were calculated and visualized. The relevant maps calculated for both phases I and II indicates small variation in electrostatic potential upon phase change. Small differences between packings in phases slightly disturb the neighbourhood of the N(1) and N(7) nitrogens, thus are meaningless from the biological point of view. The composition of two phases in pharmaceutical material should not be any obstacle, which is relevant from the pharmaceutical industry point of view.
authors.affiliation: "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Seliger
authors.affiliation: "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia.
authors.forename: Veselko
authors.initials: V
authors.lastname: Žagar
authors.affiliation: "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia.
authors.forename: Tomaž
authors.initials: T
authors.lastname: Apih
authors.affiliation: "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia.
authors.forename: Alan
authors.initials: A
authors.lastname: Gregorovič
authors.affiliation: Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Latosińska
authors.affiliation: Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland.
authors.forename: Grzegorz Andrzej
authors.initials: GA
authors.lastname: Olejniczak
authors.affiliation: Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland. Electronic address: Jolanta.Latosinska@amu.edu.pl.
authors.forename: Jolanta Natalia
authors.initials: JN
authors.lastname: Latosińska
mesh_terms: D002110:Caffeine / Q000737:chemistry*; D003198:Computer Simulation; D006859:Hydrogen / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry*; D011789:Quantum Theory; D013696:Temperature
chemical_list: D002110:Caffeine; D006859:Hydrogen; D009584:Nitrogen
keywords: Biological activity of caffeine; Composition of two phases; Magnetic resonances; Natural active ingredient; Polymorphism; Solid-state computational modelling; Structural and dynamical disorder