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Also of interest
Solubility in Pharmaceutical Chemistry
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Contents
List of contributors
1. Solubility โ definition and basic physicochemical considerations
1.1 Introduction
1.2 Why is solubility important?
1.2.1 Drug discovery
1.2.2 API manufacturing
1.2.3 Formulation development for pre-clinical, clinical, and commercial formulations
1.2.3.1 Using buffer systems to optimize solubility
1.2.3.2 Use of co-solvents to optimize solubility
1.2.3.3 Use of surfactants
1.2.3.4 Use of complexing agents
1.2.4 Drug bioavailability for per-oral drugs
1.3 In silico approaches
1.4 Relationships between solubility and physicochemical properties
1.5 Solubility theory
1.6 Approaches to measuring solubility during different phases of research and development
1.7 Application of biopharmaceutical solubility approaches
1.8 Conclusion
References
2. Solubility and supersaturation
2.1 Introduction and fundamental considerations
2.1.1 Definitions and significance of solubility and supersaturation
2.1.1.1 Classical definitions of solubility and supersaturation
2.1.1.1.1 Solubility
2.1.1.1.2 Supersaturation
2.1.1.2 The concept of differential solubility
2.1.1.3 Significance of solubility, differential solubility and supersaturation for oral drug delivery systems
2.1.2 Factors affecting solubility
2.1.2.1 Impact of solid-state on solubility and supersaturation
2.1.2.1.1 Solid-state forms
2.1.2.1.2 Particle size effects
Cs
R T ฯ r
2.1.2.1.3 Degree of crystallinity
2.1.2.2 Impact of the solvent on solubility and supersaturation
2.1.2.2.1 Solvents and co-solvents
2.1.2.2.2 Common ions and common co-formers
2.1.2.2.3 pH values of aqueous systems
2.1.2.2.4 Solubilization/supramolecular assemblies
2.1.2.2.5 Local solubility differences (differential solubility)
2.1.3 Factors affecting supersaturation
2.1.4 Solubility and supersaturation in composed solvents
2.1.4.1 Apparent solubility: alternative terms and definitions
2.1.4.2 Apparent supersaturation
2.1.4.3 Kinetic solubility; dynamic solubility
2.2 Distinguishing truly, molecular dissolved from apparently dissolved and supersaturated states
2.2.1 Solubility/dissolution
2.2.2 True, molecular supersaturation
2.2.2.1 Examples of truly supersaturated systems
2.2.3 Apparently supersaturated systems
2.2.3.1 Examples of apparently supersaturated systems
2.2.4 Experimental considerations for the determination of solubility
2.2.4.1 Solubility by classical shake flask methods
2.2.4.2 Methods for phase separation
2.2.4.3 Kinetic solubility
2.2.4.4 Experimental considerations for supersaturation assays
2.3 Supersaturation: biopharmaceutical aspects
2.3.1 Extent and persistence of supersaturation
2.3.1.1 Springs
2.3.1.2 Parachutes
2.3.2 Supersaturation for improved bioavailability
2.3.2.1 Truly supersaturated systems: impact on PK
2.3.2.2 Apparently supersaturated systems: impact on PK
2.3.3 Redistribution from supramolecular assemblies
2.3.4 Precipitates as a reservoir to maintain high, supersaturated concentrations
2.4 Drug delivery approaches: supersaturable formulations and supersaturating formulations
2.4.1 Enabling formulations for poorly soluble drugs
2.4.2 Formulation approaches
2.4.2.1 Solutions
2.4.2.2 Crystal engineering: polymorphs, habits, particle sizes
2.4.2.3 Pharmaceutical salts
2.4.2.4 Co-crystals
2.4.2.5 Nanocrystals
2.4.2.6 Amorphous and partly amorphous solid dispersions (ASD)
2.4.2.7 Solid solutions and co-amorphous systems
2.4.2.8 Mesoporous silica
2.4.2.9 Complexes: inclusion complexation with cyclodextrins
2.4.2.10 Polymeric micelles
2.4.2.11 Lipid-based formulations (LBFs)
2.4.2.12 Prodrugs
2.5 Conclusion
References
3. In Silico methods to predict solubility
3.1 Solubility: What is all the fuss about?
3.2 Definitions and concepts
3.2.1 Solubility data and experimental determinations
3.2.1.1 Equilibrium solubility
3.2.1.2 Kinetic solubility
3.2.2 Intrinsic solubility
3.2.3 The solvation process and factors which affect solvation
3.2.3.1 Solvation: equilibrium solubility and dissolution
3.2.3.2 Thermodynamic effects on solubility
3.3 Computational prediction of solubility
3.3.1 Standard state conventions
3.3.2 Solubility from first principles
3.3.2.1 Computational models of the solvent for first principles calculations
3.3.2.2 Modelling water
3.3.2.3 Computing sublimation energies
3.3.2.4 Computing hydration energies
3.3.2.5 First principles routes to solubility
3.3.2.5.1 Direct coexistence
3.3.2.5.2 Chemical potentials from simulation
3.3.2.5.3 Free energy change via amorphous phases
3.3.2.5.4 Simulation-free approaches
3.3.2.5.5 Solubility from density of states
3.3.3 Solubility from informatics
3.3.3.1 Test sets, comparison, and experimental design
3.3.3.2 General solubility equation
3.3.3.3 Quantitative structure-property relationships (QSPR)
3.3.4 Specific techniques in QSPR and machine learning
3.3.4.1 Linear techniques
3.3.4.1.1 Group contribution and multi-linear regression methods
3.3.4.1.2 Partial least squares
3.3.4.2 Non-linear machine learning methods
3.3.4.2.1 Artificial neural networks
3.3.4.2.2 Random forest
3.3.4.2.3 Support Vector Machine
3.3.4.2.4 k-nearest neighbours
3.3.4.2.5 Gaussian processes
3.3.4.2.6 Deep learning
3.3.4.2.7 Consensus methods
3.4 Conclusions
References
4. How solubility influences bioavailability
4.1 Species differences (physiology)
4.2 Stomach fluids, intestinal fluids โ fed versus fasted state
4.2.1 Stomach: fastedโfed
4.2.2 Intestine: fastedโfed
4.3 Absorption across species
4.3.1 Low-dose PK screening (<5 mg/kg)
4.3.2 High-dose PK (>10 mg/kg)
4.4 What can formulations do/not do?
4.5 When are we able to predict solubility-limited absorption with confidence?
4.5.1 Non-oral routes
4.6 Conclusion and outlook
References
5. Estimation of intraluminal drug solubility
5.1 Intraluminal solubility and drug absorption
5.2 Procedures for aspirating gastrointestinal contents
5.2.1 Aspiration protocols
5.2.1.1 Aspiration from the stomach and the upper intestine
5.2.1.2 Aspiration from the lower intestine
5.2.1.3 Handling of aspirated samples
5.3 Methodology for estimating solubility in gastrointestinal contents
5.4 Estimating drug solubility in the gastrointestinal contents
5.4.1 Estimation of drug solubility in the stomach
5.4.2 Estimation of drug solubility in the upper intestine
5.4.3 Estimation of drug solubility in lower intestine
5.5 Concluding remarks
References
6. Biorelevant media
6.1 A short history of biorelevant media
6.1.1 Fasted gastric media
6.1.2 Fed gastric media
6.1.3 Further versions of intestinal media
6.1.4 Media for the lower intestine
6.1.5 Canine media
6.2 Current versions of biorelevant media
6.3 Selection of appropriate media for solubility and dissolution studies
6.3.1 Solubility studies
6.3.2 Dissolution studies
6.4 Some considerations in solubility measurement with a view to predicting in vivo solubility
6.4.1 Which is more relevant โ thermodynamic or kinetic solubility?
6.4.2 When can the โsolubilityโ change during measurement?
6.4.3 Precautions in measuring solubility in biorelevant media
6.4.4 Miniaturization of the solubility determination
6.4.5 Single or multiple media?
6.5 Outlook
References
7. The role of solubility to optimize drug substances โ a medicinal chemistry perspective
7.1 Introduction
7.2 Molecular interactions with water
7.3 Various solubility measurements that can be applied during the early drug discovery process
7.3.1 Precipitative solubility measurements by diluting DMSO solutions
7.3.1.1 Conditions that affect solubility
7.3.1.1.1 Effect of the co-solvent concentration
7.3.1.1.2 The effect of equilibration time
7.3.1.1.3 Effect of filtration on the measured precipitative solubilit
7.3.1.1.4 Effect of buffer and ionic strength
7.3.1.1.5 Effect of buffer pH on the solubility; solubilityโpH profil
7.3.1.1.6 Effect of the method of quantification on the measured solubility
7.3.2 Solubility measurements from solid
7.4 Structureโsolubility relationships; designing soluble compounds
7.5 Examples to increase solubility by structural modification
7.5.1 Approaches for optimization of solubility in research programs
7.6 Conclusion
References
8. The role of solubility in optimizing drug products โ a pharmaceutical development perspective
8.1 Introduction
8.2 Aqueous-based liquid formulations
8.2.1 Adjustment of pH
8.2.2 Cosolvents
8.2.3 Micellar solubilization using surfactants
8.2.4 Cyclodextrins
8.3 Formulations for oral administration
8.3.1 Defining a formulation strategy
8.3.2 Enabling formulations
8.3.2.1 Particle size reduction
8.3.2.2 Lipid-based formulations
8.3.2.3 Solid dispersions
8.4 Use of dissolution data to optimize formulation design
8.5 Concluding remarks
References
9. The relevance of solid-state forms for solubility
9.1 Solid-state forms for pharmaceutical research, development, and commercial manufacturing
9.1.1 Parameters relevant for solid-state form selection
9.1.1.1 Solubility
9.1.1.2 Dissolution rate
9.1.1.3 Melting point
9.1.1.4 Hygroscopicity
9.1.1.5 Particle-shape (habit)
9.1.1.6 Particle-size distribution
9.1.1.7 Stability
9.1.1.8 Molar mass of the API
9.1.1.9 Toxicity and pharmacological properties
9.1.1.10 Processability
9.1.2 Overview on solid-state forms
9.2 Why does solubility matter for solid-state forms?
9.3 Conclusion
References
10. Solubility and phase behaviour from a drug substance manufacturing perspective
10.1 Introduction โ solubility and phase diagrams in in process design and optimization
10.2 Solubility โ basics
10.2.1 Definition of solubility
10.2.2 Parameters influencing solubility
10.2.2.1 Influence of temperature on solubility
10.2.2.2 Influence of the solvent on solubility
10.2.2.2.1 Influence of the choice of solvent on solubility
10.2.2.2.2 Influence of the quality of the solvent on solubility
10.2.2.2.3 Influence of the composition of solvent mixtures on solubility
10.2.2.2.4 Effect of solvent composition and temperature on solubility
10.2.2.3 Purity of the system โ effect of second solute on solubility
10.2.3 Relation between solid residue and solubility
10.2.3.1 Influence of the purity of solid residue on solubility
10.2.3.2 Influence of the solid-state form on solubility โ polymorphs
10.2.3.2.1 Polymorphs
10.2.3.3 Solvates and hydrates
10.2.3.4 Incongruently dissolving systems
10.2.4 Solubility in systems with phase separation
10.3 Determination of solubility
10.3.1 General
10.3.1.1 Units for solubility data
10.3.1.2 Requirements for accuracy of data
10.3.1.3 Reproducibility
10.3.1.4 Kinetics of equilibration
10.3.1.5 Range covered and number density of points
10.3.1.6 Accuracy of solvent composition in solvent mixtures
10.3.1.7 Programme for data measurement
10.3.2 Rendering of data
10.3.3 Flask method
10.3.3.1 Semi-quantitative flask method
10.3.3.2 Quantitative flask method
10.3.3.2.1 Flask method โ stable polymorphs or solvates
10.3.3.2.2 Flask method โ metastable forms
10.3.4 Saturation temperature methods
10.3.4.1 Slow heating โmanual procedure
10.3.4.2 Crystal16 method
10.3.4.3 Bracketing technique
10.3.5 Plausibility checks
10.3.6 Interpolation and extrapolation
10.4 Modelling solubility of crystalline material
10.4.1 General remarks
10.4.2 Thermodynamic basis of models
10.4.3 Modelling solubility via activity coefficients
10.4.3.1 Example of group contribution modelling
10.4.4 Modelling solubility via transfer โ SAC-NRTL
10.4.5 Literature data of solubility
10.5 Solubility and crystallization development
10.5.1 Solubility and crystallization conditions
10.5.2 Choice of solventโsolvent mixture to reduce suspension density
10.5.3 Seeding โ point of addition
10.5.4 Representation of the crystallization process in phase diagrams
10.5.4.1 Polymorphs
10.5.4.2 Solvate-forming systems
10.5.4.3 Incongruent dissolution of solid-state forms
10.5.5 Liquidโliquid phase separation
10.6 Summary
References
11. Biowaivers
11.1 Introduction
11.2 The role of biowaivers
11.3 History and evolution of BCS
11.3.1 BCS definitions
11.3.2 Regulatory history on the use of BCS-based biowaivers
11.3.3 Application of BCS-based biowaivers to essential drugs
11.3.4 Evolution of BCS concepts
11.4 The role of in vitro dissolution testing
11.5 ICH M9: potential discussion points
11.5.1 Supportive data for BCS assessment
11.5.1.1 Solubility
11.5.1.2 Permeability
11.5.1.3 Published literature
11.5.2 Scope of biowaivers
11.5.3 Setting the requirements for in vitro dissolution testing
11.5.4 Pharmaceutical equivalents
11.5.5 The role of excipients in biowaivers and bioequivalence studies
11.5.6 Biowaiver risk assessment
11.6 Conclusion
References
Appendix 1
Additional References (Appendix 1)
List of Abbreviations
Index