RELATING CRYSTALLINE PHYSIOCHEMICAL PROPERTIES WITH BULK CHEMISTRY - - PowerPoint PPT Presentation

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. Klitou1*, I. Rosbottom2, L. Onoufriadi3, E. Simone1*

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

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• 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

Overview

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.

• 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, stability and bioavailability.

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Quercetin (host) molecule Water (solvent) molecules The crystal structure of quercetin dihydrate Quercetin dihydrate crystal

Introduction

Quercetin:

• Naturally occurring flavonoid.
• Found in many fruits and vegetables.
• Vast range of health benefits.
• Used in nutraceutical industry.
• Exists as anhydrous, monohydrate,

dihydrate structure, and a DMSO solvate.

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Molecular Modelling:

• Enables the prediction of physiochemical

properties of crystals through analysis of the intermolecular interactions.

• Requires the crystallographic structure and

molecular arrangement obtained from X- Ray Diffraction data.

Quercetin molecule (red-

• xygen, grey-carbon, white-

hydrogen)

42 33 21 15 15 7.7 5.1 4.7 4.5 4.5 4.1 ELDERBERRIES RED ONIONS WHITE ONIONS CRANBERRIES GREEN HOT PEPPERS KALE BLUEBERRIES RED APPLES ROMAINE LETTUCE PEARS SPINACH

Quercetin Content (mg/100g edible portion)

Introduction

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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.

Introduction

Methodology

• Crystallographic information files obtained from

Cambridge Structural Database (CSD).

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Central unit cell Sphere

• f 30Å

radius Calculation of intermolecular interactions in Habit 98

• Habit 98 software, a

synthonic modelling tool, was used to predict the strength, directivity and dispersive nature of intermolecular interactions in the crystal structures, using Momany force-field.

• CCDC Mercury software was used to obtain visualizations
• f molecular and crystal packing for the three structures.

Refcodes: Quercetin anhydrous: NAFZEC Quercetin monohydrate: AKIJEK Quercetin dihydrate: FEFBEX

Molecular Modelling techniques: Experimental techniques:

• Variable Temperature Powder

X-ray Diffraction (VT-PXRD)

• Thermogravimetric Analysis

coupled with Differential Scanning Calorimetry (TGA/DSC)

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Results: Bulk Synthons – QA, QMH, QDH

Panayiotis Klitou, Ian Rosbottom, Elena Simone, Crystal Growth & Design 2019 19 (8), 4774-4783

Degree of hydration

Crystallization + 1H2O + 2H2O

Quercetin anhydrous (QA)

Torsion angle = 32° Less planar conformation, less closely packed Mostly H-bonds and polar interactions No π-π stacking

Quercetin monohydrate (QMH)

Torsion angle = 1.3° More planar conformation, close packing π-π stacking interactions H-bonds both between Q-Q and Q-W

Quercetin dihydrate (QDH)

Torsion angle = 7.0° More planar conformation, close packing π-π stacking interactions H-bonds only between Q-W

• 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

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Results: Bulk Synthons – QDMSO

Several π-π stacking interactions H-bonding between Q-Q H-bonding between Q-DMSO

• 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.

• Higher contribution of H-bonds and dipole-dipole interactions

to total lattice energy (39.2%) compared to all other quercetin structures (<10.9%).

• Quercetin-solvent H-bonds in QDMSO stronger in energy

compared to Q-solvent in QMH and QDH.

Crystallization

Quercetin – DMSO solvate (QDMSO)

in 70%(w/w) DMSO 30%(w/w) water solvent

• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 0.5 20 40 60 80 100 120 50 100 150 200 250 300 350 400 450 500 550 600 Heat Flow (Wg-1) Mass (%) Temperature (°C) Mass Heat Flow

• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 0.5 1.0 20 40 60 80 100 120 50 100 150 200 250 300 350 400 450 500 550 600 Heat Flow (Wg-1) Mass (%) Temperature (°C) Mass Heat flow

Results: DSC-TGA

QDH QDMSO

Onset: 135.9 °C Weight change: -26.4% Heat flow: -165.2 Jg-1

De-solvation Melting

Onset: 317.1 °C

Decomposition

Onset: 331.1 °C

• De-solvation onset

temperature: QDH: 94.9 ± 2.7 °C QDMSO: 135.9 ± 2.8 °C QDMSO is more heat stable!

• Observed weight change for

QDH (-10.0%) and QDMSO (- 26.4%) match theoretical weight loss for dehydration.

• Dehydration of QDMSO

exhibits a shoulder at a higher temperature  DMSO solvent molecules lost in consecutive steps.

• Melting and decomposition
• ccur at very similar

temperatures.

De-solvation

Onset: 94.9 °C Weight change: -10.0% Heat flow: -300.3 Jg-1

Melting

Onset: 315.8 °C

Decomposition

Onset: 330.0 °C

Results: VT-PXRD

• QDH:

Stable between 25-70 °C Phase transition at 100 °C  dehydration

• QDMSO:

Stable between 25-120 °C Phase transition at 120 °C  de-solvation.

• Dehydrated & de-solvated

structures are identical.

• Higher thermal stability
• f QDMSO related to

stronger hydrogen bonding network in lattice.

5 10 15 20 25 30 35 40 45 50 Intensity 2θ 5 10 15 20 25 30 35 40 45 50 Intensity 2θ

QDH QDMSO

25°C 140°C 120°C 110°C 100°C 70°C 25°C 25°C 180 °C 140°C 120°C 100°C 80°C 35°C

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• As the degree of hydration increases:
• H-bonding more satisfied by water molecules
• 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.

Conclusion and Future Work

School of Food Science and Nutrition

Acknowledgements

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• Dr Elena Simone & Professor Megan Povey
• Dr Ian Rosbottom
• School of Food Science and Nutrition for

funding this doctoral project Synthonic Modeling of Quercetin and Its Hydrates: Explaining Crystallization Behavior in Terms of Molecular Conformation and Crystal Packing Panayiotis Klitou, Ian Rosbottom, Elena Simone Crystal Growth & Design 2019 19 (8), 4774-4783 DOI: 10.1021/acs.cgd.9b00650