Aqueous Drug Solubility – Influence of the Solid State

Aqueous solubility is a key parameter influencing the bioavailability of drugs and drug candidates. In this thesis computational models for the prediction of aqueous drug solubility were explored. High quality experimental solubility data for drugs were generated using a standardised protocol and models were developed using multivariate data analysis tools and calculated molecular descriptors. In addition, structural features associated with either solid-state limited or solvation limited solubility of drugs were identified.Solvation, as represented by the octanol-water partition coefficient (logP), was found to be the dominant factor limiting the solubility of drugs, with solid-state properties being the second most important limiting factor…


1. Introduction
1.1. Solubility in drug discovery and development
1.2. Thermodynamics of dissolution of solids
1.2.1. Estimation of solubility from thermodynamic properties
1.2.2. Computational estimation of thermodynamic properties
1.3. Experimental estimation of drug solubility
1.3.1. Definition of intrinsic solubility
1.3.2. Factors influencing solubility experiments
1.3.3. Kinetic methods
1.3.4. Thermodynamic methods
1.4. Computational estimation of drug solubility
1.4.1. Model development – QSPR
1.4.2. Dataset selection
1.4.3. Molecular descriptors
1.4.4. Experimental data
1.4.5. Statistical and mathematical methods
1.4.6. Available computational solubility models
2. Aims of the thesis
3. Materials and methods
3.1. Selection of dataset
3.2. Structural diversity and drug-likeness
3.3. Chemicals and drugs
3.4. Crystal structures
3.5. Differential scanning calorimetry (DSC)
3.6. Solubility determinations – the shake-flask method
3.7. Hydration free energy calculations
3.8. Molecular descriptor generation
3.8.1. 2D – Selma and Molconn-Z
3.8.2. 3D – Surface area descriptors and VolSurf
3.9. Statistical analysis
3.9.1. Linear regression
3.9.2. Multivariate analysis
4. Results and discussion
4.1. Training drug solubility models
4.1.1. Quality of experimental data (Papers I-III)
4.1.2. Diversity and drug-likeness (Papers I, II and IV)
4.2. Validating drug solubility models (Paper I)
4.3. Global versus local models (Paper I)
4.4. Experimental properties influencing drug solubility
4.4.1. Solvation properties – logP (Paper II)
4.4.2. Solid-state properties (Papers II and III)
4.5. Application of semi-empirical equations on drugs
4.5.1. The general solubility equation (GSE) (Paper II)
4.5.2. The Dannenfelser equation (Paper II)
4.6. Molecular descriptors for drug solubility
4.6.1. Two dimensions or three? (Papers I and IV)
4.6.2. The solid state – LogP-independent solubility (Paper III)
4.6.3 Solvation – The free energy of hydration (Paper IV)
5. Conclusions
6. Acknowledgements
7. References and notes

Author: Wassvik, Carola

Source: Uppsala University Library

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