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Microscopic views of drug solubility
KTH, School of Biotechnology (BIO).
2006 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

The development of computational models for predicting drug solubility has increased drastically during the last decades. Nevertheless these models still have diffculties to estimate the aqueous solubility as accurate as desired. In this thesis di erent aspects that are known to have a large impact on the aqueous solubility of a molecule have been studied in detail using various theoretical methods with intension to provide microscopic view on drug solubility. The rst aspect studied is the hydrogen bond energies. Eight drug molecules have been calculated using density functional theory and the validity of additive model that has often been used in solubility models is examined. The impact of hydrogen bonds in Infrared and Raman spectra of three commonly used drug molecules has also been demonstrated. The calculated spectra are found to be in good agreement with the experimental data. Another aspect that is important in solubility models is the volume that a molecule occupies when it is dissolved in water. The volume term and its impact on the solvation energy has therefore also been calculated using three di erent methods. It was shown that the calculated volume di ered signi cantly dependent on which method that had been used, especially for larger molecules.

Most of the solubility models assume the solute molecule to be in the bulk of the solvent. The molecular behavior at the water/gas interface has been investigated to see how it di ers from bulk. It was seen that the concentration close to the interface was almost three times higher than in the bulk. The increase in concentration close to the surface depends on the larger gap between the interface energy and the gas phase energy than between the bulk energy and the gas phase energy.

Place, publisher, year, edition, pages
Stockholm: KTH , 2006. , 43 p.
National Category
Industrial Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-3940ISBN: 91-7178-312-1 (print)OAI: oai:DiVA.org:kth-3940DiVA: diva2:10112
Presentation
2006-05-03, 00:00
Note
QC 20101109Available from: 2006-05-09 Created: 2006-05-09 Last updated: 2010-11-09Bibliographically approved
List of papers
1. Density functional theory calculations of hydrogen bonding energies of drug molecules
Open this publication in new window or tab >>Density functional theory calculations of hydrogen bonding energies of drug molecules
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2006 (English)In: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 776, no 1-3, 61-68 p.Article in journal (Refereed) Published
Abstract [en]

Hydrogen bonding energies of several drug molecules have been calculated using hybrid density functional theory with inclusion of basis set superposition error corrections. The calculated total hydrogen bonding energy of each drug molecule has been compared with the result of a conceptually simple additive model, from which the summation of hydrogen bonding energies of individual polar groups present in the drug molecule are considered. It is shown that the validity of the additive model is strongly conditional, and to some extent predictable: In cases where the hydrogen bonding group is isolated the addition model can be of relevance, while in cases where the hydrogen bonding groups are interconnected through pi-conjugation rings or chains of the drug molecules it introduces substantial errors. It is suggested that such strong cooperative effects of hydrogen bonds should always be taken into account for evaluation of the hydrogen bonding energies of drug molecules.

Keyword
Hydrogen bond energies; Drug molecules; Density functional theory
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-7177 (URN)10.1016/j.theochem.2006.06.042 (DOI)000242433800007 ()2-s2.0-33749430410 (Scopus ID)
Note
QC 20100630Available from: 2007-05-25 Created: 2007-05-25 Last updated: 2017-12-14Bibliographically approved
2. Hydrogen bonding effects on infrared and Raman spectra of drug molecules
Open this publication in new window or tab >>Hydrogen bonding effects on infrared and Raman spectra of drug molecules
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2007 (English)In: Spectrochimica Acta Part A - Molecular and Biomolecular Spectroscopy, ISSN 1386-1425, E-ISSN 1873-3557, Vol. 66, no 2, 213-224 p.Article in journal (Refereed) Published
Abstract [en]

Infrared and Raman spectra of three drug molecules, aspirin, caffeine and ibuprofen, in gas phase and in aqueous solution have been simulated using hybrid density functional theory. The long range solvent effect is modelled by the polarizable continuum model, while the short range hydrogen bonding effects are taken care of by the super-molecular approach with explicit inclusion of water molecules. The calculated spectra are found to compare well with available experimental results. The agreement obtained make grounds for proposing theoretical modeling as a tool for characterizing changes in the bonding environments of drug molecules in terms of particular variations in their IR and Raman spectra.

Keyword
DFT; Drug molecules; Hydrogen bonding; Infrared; Raman; Solvent effect
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-7178 (URN)10.1016/j.saa.2006.02.045 (DOI)000243775500001 ()2-s2.0-33845886099 (Scopus ID)
Note
QC 20100630Available from: 2007-05-25 Created: 2007-05-25 Last updated: 2017-12-14Bibliographically approved
3. Solvation of N3- at the water surface: the Polarizable Continuum Model approach
Open this publication in new window or tab >>Solvation of N3- at the water surface: the Polarizable Continuum Model approach
2006 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 23, 11361-11368 p.Article in journal (Refereed) Published
Abstract [en]

We present a new quantum mechanical model to introduce Pauli repulsion interaction between a molecular solute and the surrounding solvent in the framework of the Polarizable Continuum Model. The new expression is derived in a way to allow naturally for a position-dependent solvent density. This development makes it possible to employ the derived expression for the calculation of molecular properties at the interface between two different dielectrics. The new formulation has been tested on the azide anion (N-3(-)) for which we have calculated the solvation energy, the dipole moment, and the static polarizability at the interface as a function of the ion position. The calculations have been carried out for different ion-surface orientations, and the results have also been compared with the parallel electrostatic-only solvation model.

Keyword
Electric field effects; Interfaces (materials); Molecular dynamics; Negative ions; Quantum theory; Surface properties
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-7179 (URN)10.1021/jp060794p (DOI)000238102800051 ()2-s2.0-84962377250 (Scopus ID)
Note
QC 20100630Available from: 2007-05-25 Created: 2007-05-25 Last updated: 2017-12-14Bibliographically approved
4. Calculations of the cavitation volumes and partial molar volumes of drugs in water
Open this publication in new window or tab >>Calculations of the cavitation volumes and partial molar volumes of drugs in water
(English)Manuscript (preprint) (Other academic)
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-7180 (URN)
Note
QC 20100630Available from: 2007-05-25 Created: 2007-05-25 Last updated: 2010-06-30Bibliographically approved

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