In this work we discuss certain consideration for quantum chemical and chemometric assessing in the crystallographic polymorphism. It is aimed primarily at researchers in ‘Analytical chemistry’ and is designed to help readers’ understanding of the implications of the different quantum chemical theories in the chemical crystallography.
The term ‘polymorphism’ reflects molecular ability to crystalize in more than one structure. Since, properties of polymorphs can vary, their quantification becomes an important task to manufacturing pharmaceutics. It affects packing properties via molar volume and crystal density; optical properties and refractive index; electrical and thermal properties; conductivity; hydroscopicity; other differences associated with thermodynamics; kinetics; surface and mechanical properties, and more.
In order to make a complex prediction of correlation among ‘molecular structure’–‘electronic structure’–‘energetics’ using crystallographic and quantum chemical data it should be taken into consideration various polymorph modifications.
Table of Contents
1. Introduction
2. Crystallographic and theoretical analyses of crystals of 5–hydroxy thryptophan
3. Crystallographic and quantum chemical analyses of crystals of biogenic amines
4. Crystallographic and quantum chemical analyses of crystals of 2’,3’-o-isopropylideneadenosine
Conclusion
References
Objectives and Research Themes
This work aims to quantify the complex correlations between molecular structure, electronic structure, and energetics in pharmaceutical compounds, specifically focusing on the crystallographic polymorphism of aspirin and other related molecules. By utilizing crystallographic data in conjunction with ab initio and DFT-based quantum chemical methods and chemometric statistical analysis, the authors seek to define the quantitative boundaries of perturbations in electronic structures and energetics within polymorph modifications.
- Investigation of the polymorphism of aspirin using quantum chemical ab initio and DFT molecular dynamics.
- Assessment of experimental crystallographic parameter variations and their error contributions to theoretical energetics.
- Application of chemometric methods to distinguish between modifications in crystal structures and electronic effects.
- Analysis of electron density distributions and bond orders to provide insights into bonding properties and biological activity.
Excerpt from the Book
Introduction
The term ‘polymorphism’ reflects molecular ability to crystalize in more than one structure (Bond et al; 2007; Higashi et al. 2017). Since, properties of polymorphs can vary, their quantification becomes an important task to manufacturing pharmaceutics. It affects packing properties via molar volume and crystal density; optical properties and refractive index; electrical and thermal properties; conductivity; hydroscopicity; other differences associated with thermodynamics; kinetics; surface and mechanical properties, and more (Datta and Grant, 2004). In order to make a complex prediction of correlation among ‘molecular structure’–‘electronic structure’–‘energetics’ using crystallographic and quantum chemical data it should be taken into consideration various polymorph modifications. On this view, we have struggled with an analytical chemical problem to define quantitatively borders of perturbation of electronic structure and energetics of polymorphs, using as molecular templates crystals of (1) and (2) (Scheme 1), respectively. Compound (1) appears a structural analogous of aspirin, but is a conformational blocked, due to presence of intramolecular (OH…O=C) hydrogen bond.
Aspirin is a remarkable example of a bestselling pharmaceutics, which is broadly used to treat cardiovascular diseases, in addition to reduce angiogenesis of cancer (Xie et al. 2021). It is already implemented in the practice, however, shows complex polymorphism, including few known polymorphs (Bond et al. 2007a,b, 2011; Vishweshwar et al. 2005; Bag and Reddy, 2012; Wen and Beran, 2012; Shtukenberg et al. 2017; Arputharaj et al. 2012; LeBlanc et al. 2016); Price et al. 2009; Ouvrard and Price, 2004; Brela et al. 2016). The employment of crystallographic data for purposes of computational chemistry needs a detail assessment of variations of experimental crystallographic parameters, in order to, determine the error contribution to energy – the major parameter assessing bonding properties of molecules and thus their biological activity – and/or molecular properties, in parallel to, error contributions from theoretical methods.
Summary of Chapters
1. Introduction: Discusses the significance of polymorphism in pharmaceuticals and the need for accurate computational predictions of molecular energetics based on crystallographic data.
2. Crystallographic and theoretical analyses of crystals of 5–hydroxy thryptophan: Examines the conformational analysis and electronic structures of 5-hydroxytryptophan zwitterions using crystallographic input coordinates.
3. Crystallographic and quantum chemical analyses of crystals of biogenic amines: Focuses on the statistical correlations between experimental crystallographic electron densities and bond energies in biogenic amine crystals.
4. Crystallographic and quantum chemical analyses of crystals of 2’,3’-o-isopropylideneadenosine: Analyzes the energetics of two non-equivalent molecules in the crystal structure of the nucleoside derivative to model real-world interactions.
Conclusion: Synthesizes the findings on the relations between molecular structure, electronic structure, and energetics across the studied compounds.
References: Provides a comprehensive list of literature sources cited throughout the work.
Keywords
Polymorphism, Pharmaceutics, Quantum chemistry, Crystallography, Chemometrics, Aspirin, 5-hydroxytryptophan, Biogenic amines, Nucleosides, Molecular dynamics, Electron density, Bond dissociation energy, DFT, Statistical analysis, Electronic structure
Frequently Asked Questions
What is the primary focus of this research?
This work focuses on the crystallographic polymorphism of pharmaceutical compounds, aiming to quantify the correlations between molecular structure, electronic structure, and energetic stability using both computational and statistical methods.
Which specific pharmaceutical compound is the central template for the analysis?
Aspirin is used as the focal molecular template for the study of polymorphism, alongside structural analogs like salicylic acid and other pharmaceutically relevant molecules.
What is the main research objective?
The primary objective is to define quantitative borders for the perturbation of electronic structures and energetics in polymorphs to improve the reliability of computational predictions in chemical crystallography.
Which scientific methods are employed in this study?
The research employs a combination of crystallographic measurements, quantum chemical ab initio methods, Density Functional Theory (DFT) molecular dynamics, and chemometric statistical analyses such as ANOVA and regression modeling.
What topics are covered in the main body of the work?
The main body covers the crystallographic and theoretical analyses of 5-hydroxytryptophan, various biogenic amines, and the nucleoside 2’,3’-o-isopropylideneadenosine, analyzing their electron densities and bond energetics.
Which keywords best describe this study?
Key terms include polymorphism, pharmaceutics, quantum chemistry, crystallography, chemometrics, molecular dynamics, electron density, and bond dissociation energy.
Why is the accuracy of crystallographic data critical in this context?
High-quality crystallographic data is essential because even slight variations in structural parameters can lead to significant differences in computed energy values, affecting the reliable assignment of polymorphs.
How do the authors define a polymorph in their analysis?
The authors align with McCrone's definition, viewing a polymorph as a solid crystalline phase resulting from different arrangements of molecules, while also considering that distinct crystal structures may be treated as different polymorphs due to subtle electronic variations.
What role does chemometrics play in the results?
Chemometrics is used to provide statistical information that allows the authors to distinguish between electronic effects caused by perturbations of atomic positions, disorders, and other structural factors that might otherwise be indistinguishable by total energy alone.
- Arbeit zitieren
- Prof. Dr. Bojidarka Ivanova (Autor:in), Michael Spiteller (Autor:in), 2021, The Crystallographic Polymorphism of Pharmaceutics. A Quantum Chemical and Chemometric Treatment, München, GRIN Verlag, https://www.grin.com/document/1014678
