School of Food Science and Nutrition RELATING CRYSTALLINE PHYSIOCHEMICAL PROPERTIES WITH BULK CHEMISTRY OF DIFFERENT SOLID FORMS OF QUERCETIN USING MOLECULAR MODELLING AND EXPERIMENTAL STUDIES P. Klitou 1 *, I. Rosbottom 2 , L. Onoufriadi 3 , E. Simone 1* 1 School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom 2 Department of Chemical Engineering, Imperial College London, London, United Kingdom 3 School of Chemical and Process Engineering, University of Leeds, Leeds, United Kingdom fspkl@leeds.ac.uk 1
Overview Introduction • Crystals & Solvates • Quercetin & Molecular Modelling • Aims Methodology • Molecular Modelling • Experimental Validation Results and Discussion • Bulk intrinsic synthons & Conformational Analysis • Experimental Validation Conclusions and future developments 2
Introduction Crystals & Solvates: A crystal is a solid material in which the molecules are packed in a regular repeating three- dimensional array to give long range order . Quercetin dihydrate crystal Solvates (eg. hydrates ): contain both the host molecule (eg. quercetin) and solvent molecule(s) (specifically water for hydrates) incorporated in the crystal lattice structure. Different solvates exhibit different physiochemical properties , such as solubility, surface chemistry, Quercetin (host) molecule stability and bioavailability. Water (solvent) molecules The crystal structure of quercetin dihydrate 3
Introduction Quercetin : Naturally occurring flavonoid. Quercetin molecule (red- Found in many fruits and vegetables. oxygen, grey-carbon, white- Vast range of health benefits. hydrogen) Used in nutraceutical industry. Exists as anhydrous , monohydrate, dihydrate structure , and a DMSO solvate. SPINACH 4.1 Molecular Modelling: PEARS 4.5 ROMAINE LETTUCE 4.5 Enables the prediction of physiochemical RED APPLES 4.7 properties of crystals through analysis of BLUEBERRIES 5.1 the intermolecular interactions . KALE 7.7 GREEN HOT PEPPERS 15 Requires the crystallographic structure and CRANBERRIES 15 molecular arrangement obtained from X- WHITE ONIONS 21 Ray Diffraction data. RED ONIONS 33 ELDERBERRIES 42 Quercetin Content (mg/100g edible portion) 4
Introduction Aims: Use molecular modelling to examine the structures and explore the bulk intrinsic synthons (intermolecular interactions) of quercetin structures. Predict physiochemical properties , specifically stability , and understand why the molecules take a specific path to crystal structure during crystallization. Understand how the presence, type and number of solvent molecule(s) (water or DMSO) in the lattice affects the structure , packing and conformation of quercetin and hence the physiochemical properties. Validate molecular modelling calculations experimentally . 5
Methodology Molecular Modelling techniques: Experimental techniques: Crystallographic information files obtained from Variable Temperature Powder Cambridge Structural Database ( CSD ). X-ray Diffraction (VT-PXRD) Thermogravimetric Analysis Habit 98 software , a coupled with Differential Central synthonic modelling tool, unit Scanning Calorimetry was used to predict the cell (TGA/DSC) strength, directivity and dispersive nature of intermolecular interactions Sphere in the crystal structures, of 30Å using Momany force-field. radius Calculation of intermolecular interactions in Habit 98 Refcodes: CCDC Mercury software was used to obtain visualizations Quercetin anhydrous: NAFZEC of molecular and crystal packing for the three structures. Quercetin monohydrate: AKIJEK 6 Quercetin dihydrate: FEFBEX
Results: Bulk Synthons – QA, QMH, QDH Quercetin anhydrous (QA) Quercetin monohydrate (QMH) Quercetin dihydrate (QDH) Crystallization + 1H 2 O + 2H 2 O Torsion angle = 1.3 ° Torsion angle = 7.0 ° Torsion angle = 32 ° More planar conformation, More planar conformation, Less planar conformation, close packing close packing less closely packed π - π stacking interactions π - π stacking interactions Mostly H-bonds and polar interactions H-bonds only between Q-W No π - π stacking H-bonds both between Q-Q and Q-W Degree of hydration H-bonding more satisfied by interaction with incorporated water molecules more planar conformation Contribution of π - π stacking interactions increases QDH has higher relative stability : smaller amount of de-solvation and conformational rearrangement during crystallization from aqueous solvent 7 Panayiotis Klitou, Ian Rosbottom, Elena Simone, Crystal Growth & Design 2019 19 (8), 4774-4783
Results: Bulk Synthons – QDMSO Quercetin – DMSO solvate (QDMSO) Crystallization Several π - π stacking interactions in 70%(w/w) DMSO 30%(w/w) water solvent Torsion angle = 31 ° Less closely packed compared to QDH & QMH, bulkier size of DMSO molecule High contribution of quercetin-solvent interactions (45.1%) similar to that of QDH (45.9%) to total lattice energy. H-bonding between Q-Q Higher contribution of H-bonds and dipole-dipole interactions to total lattice energy (39.2%) compared to all other quercetin structures (<10.9%). H-bonding between Q-DMSO Quercetin-solvent H-bonds in QDMSO stronger in energy compared to Q-solvent in QMH and QDH. 8
Results: DSC-TGA 120 1.0 De-solvation Melting Decomposition QDH 0.5 De-solvation onset 100 Mass 0.0 temperature: Heat flow Heat Flow (Wg-1) 80 -0.5 QDH: 94.9 ± 2.7 °C Mass (%) -1.0 60 QDMSO: 135.9 ± 2.8 °C -1.5 QDMSO is more heat stable! 40 -2.0 Onset: 94.9 °C Observed weight change for -2.5 Weight change: -10.0% 20 QDH (-10.0%) and QDMSO (- -3.0 Onset: 315.8 °C Onset: 330.0 °C Heat flow: -300.3 Jg -1 0 -3.5 26.4%) match theoretical 0 50 100 150 200 250 300 350 400 450 500 550 600 weight loss for dehydration. Temperature (°C) Dehydration of QDMSO 120 0.5 De-solvation Melting Decomposition QDMSO exhibits a shoulder at a higher 0.0 100 Mass temperature DMSO solvent -0.5 Heat Flow (Wg-1) Heat Flow 80 molecules lost in consecutive -1.0 Mass (%) steps. 60 -1.5 Melting and decomposition 40 -2.0 Onset: 135.9 °C occur at very similar Weight change: -26.4% 20 -2.5 temperatures. Onset: 317.1 °C Onset: 331.1 °C Heat flow: -165.2 Jg -1 0 -3.0 0 50 100 150 200 250 300 350 400 450 500 550 600 Temperature (°C)
Results: VT-PXRD QDH 25°C QDH: 140°C Stable between 25-70 °C 120°C Phase transition at 100 °C Intensity 110°C dehydration QDMSO: 100°C Stable between 25-120 °C 70°C Phase transition at 120 °C 25°C de-solvation. 5 10 15 20 25 30 35 40 45 50 QDMSO 2θ Dehydrated & de-solvated 25°C structures are identical. 180 °C Higher thermal stability of QDMSO related to 140°C Intensity stronger hydrogen 120°C bonding network in 100°C lattice. 80°C 35°C 5 10 15 20 25 30 35 40 45 50 2 θ
Conclusion and Future Work As the degree of hydration increases: o H-bonding more satisfied by water molecules o Contribution of π - π stacking interactions increases due to more planar quercetin molecule Experimental validation confirms QDMSO to have higher thermal stability than QDH – Higher contribution and stronger H-bonding in QDMSO. Synthonic modelling as a predictive tool to relate crystal structure to product properties leading to more efficient product formulation and faster development. Future work involves experimental validation of surface chemistry of the different forms. 11
School of Food Science and Nutrition Acknowledgements Synthonic Modeling of Quercetin and Its Hydrates: Explaining Crystallization Dr Elena Simone & Professor Megan Povey Behavior in Terms of Molecular Dr Ian Rosbottom Conformation and Crystal Packing School of Food Science and Nutrition for Panayiotis Klitou, Ian Rosbottom, Elena Simone funding this doctoral project Crystal Growth & Design 2019 19 (8), 4774-4783 DOI: 10.1021/acs.cgd.9b00650 12
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