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`@) PROPERTY OF THE
`
`NATIONAL
`LIBRARY OF
`MEDICINE
`----- ·- ----- -·------
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`This material wascopie-0
`atthe N Uv1 and may OS
`Subject US Copyright Laws
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`PHYSICOCHEMICAL PRINCIPLES
`OF PHARMACY
`
`A. T. FLORENCE
`The School of Pharmacy
`University of London
`
`and
`
`D. ATTWOOD
`School of Pharmacy and Pharmaceutical Sciences
`University of Manchester
`
`THIRD EDITION
`
`This material was,capied
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`~
`
`© A. T. Florence and D. Attwood 1981, 1 9 8B
`
`All rights reserved. No reproduction, copy or transmission of
`this publication may be made without written permission.
`
`No paragraph of this publication may be reproduced, copied or
`transmitted save with written permission or in accordance with
`the provisions of the Copyright, Designs and Patents Act 1988,
`or under the terms of any licence permitting limited copying
`issued by the Copyright Licensing Agency, 90 Tottenham Court
`Road, London WIP 9HE.
`
`Any person who does any unauthorised act in relation to this
`publication may be liable to criminal prosecution and civil
`claims for damages.
`
`The authors have asserted their rights to be identified as the
`authors of this work in accordance with the Copyright, Designs
`and Patents Act 1988.
`
`First published 1981 by
`MACMILLAN PRESS LTD
`Houndmills, Basingstoke, Hampshire RG21 6XS
`and London
`Companies and representatives
`throughout the world
`
`First edition 1981
`Second edition 1988
`Third edition 1998
`
`ISBN 0-333-69081-8
`
`A catalogue record for this book is available
`from the British Library.
`
`This book is printed on paper suitable for recycling and
`made from fully managed and sustained forest sources.
`
`5
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`Typeset in Great Britain by
`Aarontype Limited
`Easton, Bristol
`
`Printed and bound in Great Britain by
`Creative Print & Design (Wales), Ebbw Vale
`
`This material was copied
`at the NU,;1 ard maybe
`Subj-ect US Copyright Laws
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`Contents
`
`Preface
`Acknowledgements
`
`Introduction
`
`1 Properties of the Solid State
`1.1 Crystal structure
`1.2 Crystal form
`1.2.1 Crystallisation and factors affecting crystal form 2
`1.3 Polymorphism
`1.3.1 Pharmaceutical implications of polymorphism
`1.4 Crystal hydrates
`1.4.1 Pharmaceutical consequences of solvate formation
`1.5 Dissolution of solid drugs
`1.6 Biopharmaceutical importance of particle size
`1.7 Wetting of powders
`1.7.1 Contact angle and wettability of solid surfaces
`1.7.2 Wettability of powders
`1.8 Solid dispersions
`1.8.1 Eutectics and drug identification
`1.9 Summary
`
`2 Gases and Volatile Agents
`2.1 Pressure units
`Ideal and non-ideal gases
`2.2
`2.3 Vapour pressure
`2.3.1 Vapour pressure and solution composition: Raoult's law
`2.3.2 Variation of vapour pressure with temperature:
`Clausius-Clapeyron equation
`2.3.3 Vapour pressure lowering
`2.4 Solubility of gases in liquids
`2.4.1 Effect of temperature on solubility
`2.4.2 Effect of pressure on solubility
`2.4.3 The solubility of volatile anaesthetics in oil
`2.5 The solubility of gases in blood and tissues
`2.5.1 The solubility of oxygen in blood
`2.5.2 The solubility of anaesthetic gases in blood and tissues
`2.6 Summary
`
`3 Physicochemical Properties of Drugs in Solution
`3.1 Concentration units
`3.1.1 Weight concentration
`3.1.2 Molarity and molality
`3.1.3 Milliequivalents
`3.1.4 Mole fraction
`
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`iv Contents
`
`3.2 Thermodynamics: a brief introduction
`3.2.1 Energy
`3.2.2 Enthalpy
`3.2.3 Entropy
`3.2.4 Free energy
`3.3 Activity and chemical potential
`3.3.1 Activity and standard states
`3.3.2 Activity of ionised drugs
`3.3.3 Solvent activity
`3.3.4 Chemical potential
`3.4 Osmotic properties of drug solutions
`3.4.1 Osmotic pressure
`3.4.2 Osmolality and osmolarity
`3.4.3 Clinical relevance of osmotic effects
`3.4.4 Preparation of isotonic solutions
`Ionisation of drugs in solution
`3.5.1 Dissociation of weakly acidic and basic drugs and
`their salts
`3.5.2 The effect of pH on the ionisation of weakly acidic or
`basic drugs and their salts
`Ionisation of amphoteric electrolytes
`Ionisation of polyprotic drugs and microdissociation
`constants
`3.5.5 pK3 values of proteins
`3.5.6 Calculation of the pH of drug solutions
`3.5.7 Preparation of buffer solutions
`3.6 Diffusion of drugs in solution
`3.7 Summary
`
`3.5.3
`3.5.4
`
`3.5
`
`4 Drug Stability
`
`4.1 The chemical decomposition of drugs
`4.1.1 Hydrolysis
`4.1.2 Oxidation
`4.1.3
`Isomerisation
`4.1.4 Photochemical decomposition
`4.1.5 Polymerisation
`4.2 Kinetics of chemical decomposition in solution
`4.2.1 Order of reaction
`4.2.2 Zero-order reactions
`4.2.3 First-order reactions
`4.2.4 Second-order reactions
`4.2.5 Third-order reactions
`4.2.6 Determination of the order of reaction
`4.2.7 Complex reactions
`4.3 Kinetics of chemical decomposition in solid dosage forms
`4.4 Factors influencing drug stability
`4.4.1 Liquid dosage forms
`4.4.2 Semisolid dosage forms
`4.4.3 Solid dosage forms
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`Contents
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`v
`
`4.5 Stability testing and prediction of shelf-life
`4.5.1 Effect of temperature on stability
`4.5.2 Other environmental factors affecting stability
`4.5.3 Protocol for stability testing
`4.6 Summary
`
`5 The Solubility of Drugs
`
`5.1 Definitions
`5.1.l Expressions of solubility
`5.2 Factors influencing solubility
`5.2.l Structural features and aqueous solubility
`5.2.2 Hydration and solvation
`5.2.3 The effect of simple additives on solubility
`5.2.4 The effect of pH and ionisation on the solubility of
`ionisable drugs
`5.3 Measurement of solubility
`5.4 The solubility parameter
`5.4.1 Solubility parameters and biological processes
`5.5 Solubility in mixed solvents
`5.6 Cyclodextrins as solubilising agents
`5. 7 Solubility problems in formulation
`5.7.l Mixtures of acidic and basic compounds
`5.7.2 Choice of drug salt to optimise solubility
`5. 7.3 Drug solubility and biological activity
`5.8 Partitioning
`5.8.l Theoretical background
`5.8.2 Free energies of transfer
`5.8.3 Octanol as a non-aqueous phase
`5.9 Biological activity and partition coefficient: thermodynamic
`activity and Ferguson's principle
`5.10 Using log P
`5.10. l The relationship between lipophilicity and behaviour
`of tetracyclines
`5.10.2 Sorption
`5.10.3 A chromatographic model for the biophase
`5.10.4 Calculating logP from molecular structures
`5.10.5 Drug distribution into human milk
`5.11 Summary
`
`6 Surfactants
`
`6.1 Amphipathic compounds
`6.2 Surface and interfacial properties of surfactants
`6.2.l Effects of amphiphiles on surface and interfacial tension
`6.2.2 Gibbs adsorption equation
`6.2.3 Application of the Gibbs equation to surfactant solutions
`6.2.4 Surface activity of drugs
`6.2.5
`Insoluble monolayers
`6.2.6 Pharmaceutical applications of surface film studies
`6.2.7 Adsorption at the solid/liquid interface
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`vi Contents
`
`6.3 Micellisation
`6.3.l Water structure and hydrophobic bonding
`6.3.2 Theories of micelle formation
`6.3.3 Micellar structure
`6.3.4 Factors affecting the critical micelle concentration and
`micellar size
`6.4 Liquid crystals and surfactant vesicles
`6.4.l Liposomes, niosomes and surfactant vesicles
`6.5 Properties of some commonly used surfactants
`6.5.1 Anionic surfactants
`6.5.2 Cationic surfactants
`6.5.3 Non-ionic surfactants
`6.6 Solubilisation
`6.6.l Determination of maximum additive concentration
`6.6.2 Location of the solubilisate
`6.6.3 Factors affecting solubilisation
`6.6.4 Pharmaceutical applications of solubilisation
`6.7 Summary
`
`7 Emulsions, Suspensions and Other Dispersions
`
`7.1 Classification of colloidal systems
`7.2 Colloid stability
`7.2.l Forces of interaction between colloidal particles
`7.2.2 Repulsion between hydrated surfaces
`7.3 Emulsions
`7.3.J Stability of o/w and w/o emulsions
`7.3.2 HLB system
`7.3.3 Multiple emulsions
`7.3.4 Microemulsions
`7.3.5 Structured (semisolid) emulsions
`7.3.6 Biopharmaceutical aspects of emulsions
`7.3.7 Preservative availability in emulsified systems
`7.3.8 Mass transport in oil-in-water emulsions
`7.3.9
`Intravenous fat emulsions
`7.3.10 The rheology of emulsions
`7.4 Suspensions
`7.4.1 Stability of suspensions
`7.4.2 Aspects of suspension stability
`7.4.3 Extemporaneous suspensions
`7.4.4 Suspension rheology
`7.4.5 Non-aqueous suspensions
`7.4.6 Adhesion of suspension particles to containers
`7.5 Applications of colloid stability theory to other systems
`7.5.1 Cell-cell interactions
`7.5.2 Adsorption of microbial cells to surfaces
`7.5.3 Blood as a colloidal system
`7.6 Foams
`7.6.1 Clinical considerations
`7.7 Summary
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`l~~-
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`Contents
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`vii
`
`8 Polymers and Macromolecules
`
`8.1 Pharmaceutical polymers
`8.1.l Definitions
`8.1.2 Polydispersity
`8.1.3 Solubility
`8.2 Water-soluble polymers
`8.3 General properties of polymer solutions
`8.3.1 Viscosity of polymer solutions
`8.3.2 Gelling water-soluble polymers
`8.3.3 Syneresis
`8.3.4 Polymer complexes
`8.3.5 Binding of ions to macromolecules
`Interaction of polymers with solvents including water
`8.3.6
`8.3.7 Adsorption of macromolecules
`8.4 Some water-soluble polymers used in pharmacy and medicine
`8.4.1 Carboxypolymethylene (Carbomer, Carbopol)
`8.4.2 Cellulose derivatives
`8.4.3 Natural gums and mucilages
`8.4.4 Dextran
`8.4.5 Polyvinylpyrrolidone
`8.4.6 Polyoxyethylene glycols (macrogols)
`8.4.7 Bioadhesivity of water-soluble polymers
`8.4.8 Polymers used as wound dressings
`8.4.9 Polymer crystallinity
`8.5 Water-insoluble polymers and polymer membranes
`8.5.1 Permeability of polymers
`Ion-exchange resins
`8.5.2
`8.5.3 Silicone oligomers and polymers
`8.6 Some applications of polymeric systems in drug delivery
`8.6.1 Film coatings
`8.6.2 Matrices
`8.6.3 Microcapsules and microspheres
`8.6.4 Rate-limiting membranes and devices
`8.6.5 Eroding systems
`8.6.6 Osmotic pumps
`8.7 Summary
`
`9 Drug Absorption and Routes of Administration
`9.1 Biological membranes and drug transport
`9.1.l Permeability and the pH-partition hypothesis
`9.1.2 Problems in the quantitative application of the
`pH-partition hypothesis
`9.2 The oral route and oral absorption
`9.2.1 Drug absorption from the gastrointestinal tract
`9.2.2 Structure of the gastrointestinal tract
`9.2.3 Bile salts and fat absorption pathways
`9.2.4 Gastric emptying, motility and volume of contents
`9.3 Buccal and sublingual absorption
`9.3.1 Mechanisms of absorption
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`viii Contents
`
`-------
`
`9.4
`
`Intramuscular and subcutaneous injections
`9.4.1 Vehicles
`9.4.2 Blood flow
`9.4.3 Formulation effects
`9.4.4
`Insulin
`9.5 Transdermal delivery
`9.5.1 Routes of skin penetration
`Influence of drug
`9.5.2
`Influence of vehicle
`9.5.3
`9.5.4 Dilution of topical steroid preparations
`9.5.5 Transdermal medication: patches and devices
`9.5.6 Ultrasound and transdermal penetration
`9.6 Medication of the eye and the eye as a route for systemic
`delivery
`9.6.1 The eye
`9.6.2 Absorption of drugs applied to the eye
`9.6.3
`Influence of formulation
`9.6.4 Systemic effects from eye drops
`9.7 The ear
`9.8 Absorption from the vagina
`9.8.1 Delivery systems
`Inhalation therapy
`9.9.1 Physical factors affecting deposition of aerosols
`9.9.2 Experimental observations
`9.10 The nasal route
`9.11 Rectal absorption of drugs
`9.12 lntrathecal drug administration
`9 .13 Summary
`
`9.9
`
`10 Physicochemical Drug Interactions and Incompatibilities
`
`IO.I pH effects in vitro and in vivo
`In vitro pH effects
`10. l.l
`In vivo pH effects
`10. l.2
`10.2 Effects of dilution of mixed solvent systems
`10.3 Cation-anion interactions
`10.4 Polyions and drug solutions
`10.5 Chelation and other forms of complexation
`10.6 Other complexes
`10.6.l
`Interaction of drugs with cyclodextrins
`10.6.2
`Ion-exchange interactions
`l 0. 7 Adsorption of drugs
`10.7.1 Protein and peptide adsorption
`l 0.8 Drug interactions with plastics
`10.9 Protein binding
`10.9.l Thermodynamics of protein binding
`10.9.2 Lipophilicity and protein binding
`10.9.3 Penetration of specialised sites
`10.10 Summary
`
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`Contents
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`ix
`
`Appendix: Drug interactions based on physical mechanisms
`
`11 Peptides and Proteins
`
`11.1 Structure and solution properties of peptides and proteins
`11.1.1 Structure of peptides and proteins
`11.1.2 Hydrophobicity of peptides and proteins
`11.1.3 Solubility of peptides and proteins
`11.2 The stability of peptides and proteins
`11.2.1 Physical instability
`11.2.2 Formulation and protein stabilisation
`11.2.3 Chemical instability
`11.2.4 Accelerated stability testing of protein formulations
`11.3 Protein formulation and delivery
`11.3.1 Protein and peptide transport
`11.3.2 Lyophilised proteins
`11.3.3 Water adsorption isotherms
`11.3.4 Routes of delivery
`11.4 Two therapeutic proteins
`11.4.1
`Insulin
`11.4.2 Calcitonin
`11.5 Summary
`
`12 Assessment of Dosage Forms In Vitro
`12.1 Dissolution testing of solid dosage forms
`12.1.1 Pharmacopoeia! and compendia! dissolution tests
`12.1.2 Flow-through systems
`In vitro evaluation of suppository formulations
`12.2
`In vitro release from topical products and transdermal systems
`12.3
`12.4 Rheological characteristics of products
`12.5 Adhesivity of dosage forms
`12.6 Analysis of particle size distribution in aerosols
`12.7 Conclusions
`12.8 Summary
`
`Index
`
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`~~----------"""'--"'
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`5 The Solubility of Drugs
`
`In this chapter we will consider the factors controlling the solubility of drugs in solution,
`in particular the nature of the drug substance, its hydrophobicity, its shape, its surface
`area, its state of ionisation, the influence of the pH of the medium and the importance of
`the pKa of the drug. The equation linking solubility to solution pH and drug pKa
`(equation 5.11) is possibly one of the most important in this book. Experimental methods
`of measurement of solubility are essential in drug development, as is the ability to predict
`the solubility of a drug from a knowledge of its chemical structure, recognising hydro(cid:173)
`philic and hydrophobic groups and their influence on solubility. How additives, salts,
`cosolvents, surfactants and other agents affect the solubility of a drug should to an
`extent be predictable from the theory, bearing in mind the complexity of the body.
`There are many reasons why it is vital to understand the way in which drugs dissolve
`in solution and the factors that maintain solubility or cause drugs to come out of
`solution (i.e. to precipitate). These include the facts that:
`
`•
`
`• many drugs are formulated as solutions or are added in powder or solution form to
`liquids such as infusion fluids, in which they must remain in solution for a given
`period
`in whatever way drugs are presented to the body they must usually be in a molecu(cid:173)
`larly dispersed form (that is in solution) before they can be absorbed across biological
`membranes*; the solution process will precede absorption unless the drug is
`administered as a solution, but even solutions may form precipitates in the stomach
`contents or in blood, and the drug will then have to redissolve before being absorbed
`• drugs of low aqueous solubility (e.g. taxol) frequently present problems in relation to
`their formulation and bioavailability.
`
`Pharmaceutical solutions might appear to be extremely simple systems, but it is in the
`solution state that degradation takes place most rapidly, and the solubilisation of poorly
`soluble compounds is often very difficult. It is ideal if a drug can be formulated as a
`simple stable aqueous solution when required for injection, but resort to additives such
`as water-miscible solvents and surfactants, hydrotropes and cyclodextrins to increase
`the solubility of the drug complicates the formulation. Here we deal with simple
`solutions. Some of the special problems related to peptide and protein solubility are
`discussed in Chapter 11.
`;'-queous solvents are the most common in pharmaceutical and, of course, in bio(cid:173)
`log1cal systems, so this chapter is concerned mainly with solutions of aqueous and
`mixed aqueous solvents, such as alcohol-water mixtures. The solution of drugs in non(cid:173)
`aqueous media (such as oils) is also considered because of the many pharmaceutical
`applications of non-aqueous solutions and formulations such as oil-in-water emulsions,
`and because of the need to understand the process of the transport of drugs across
`biological and artificial membranes, which are effectively structured non-aqueous
`
`* In section 9.2.1 we discuss the special circumstances under which microparticulate materials can
`be taken up by specialised cells in the gut and by way of the lymphatic circulation reach the liver
`and blood and other organs. It may be that very insoluble colloidal drug suspensions are taken up
`by this route also.
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`Definitions
`
`153
`
`phases. A primary factor in passive membrane transport is the relative solubility of the
`drug in an aqueous medium and in the lipid cell membrane, the relative affinities being
`quantified in the partition coefficient of the compound, a topic discussed at the end of
`this chapter.
`
`5.1 Definitions
`
`A solution can be defined as a system in which molecules of a solute (such as a drug or a
`protein) are dispersed in a solvent vehicle. When a solution contains a solute at the limit
`of its solubility at any given temperature and pressure, it is said to be saturated. If the
`solubility limit is exceeded, solid particles of solute may be present and the solution
`phase will be in equilibrium with the solid, although under certain circumstances
`supersaturated solutions may be prepared.
`The maximum equilibrium solubility of a drug in a given medium is of practical
`pharmaceutical interest because it dictates the rate of solution (dissolution) of the drug
`(the rate at which the drug dissolves from the solid state). The higher the solubility the
`more rapid is the rate of solution, when no chemical reaction is involved.
`
`5.1.1 Expressions of solubility
`The solubility of a solute in a solvent can be expressed quantitatively in several ways
`(see section 3.1). Other less specific forms of noting solubility include parts per parts of
`solvent (for example, parts per million, ppm). The British Pharmacopoeia and other
`chemical and pharmaceutical compendia frequently use this form and also the expres(cid:173)
`sions 'insoluble', 'very slightly soluble' and 'soluble'. These are imprecise and often not
`very helpful, and for quantitative work it is important that specific concentration terms
`are used.
`Most substances have at least some degree of solubility in water and while they may
`appear to be 'insoluble' by a qualitative test, their solubility can be measured and
`quoted precisely. In aqueous media at pH IO chlorpromazine base has a solubility of
`8 x 10-6 moldm-3, that is it is very slightly soluble, but it might be considered to be
`insoluble if judged visually by the disappearance of solid placed in a test-tube.
`
`5.2 Factors influencing solubility
`
`Progress has been made in ways of predicting the solubility of solutes in aqueous media,
`from estimates of their molecular surface area and the nature of the key chemical groups
`in the parent structure. The importance of the surface area becomes clear if we think of
`the processes involved in the dissolution of a crystal (Figure 5.1). Breaking the process
`down into its components:
`
`1. A solute molecule is 'removed' from its crystal.
`2. A cavity for the molecule is created in the solvent.
`3. The solute molecule is inserted into this cavity.
`
`Placing the solute molecule in the solvent cavity requires a number of solute-solvent
`contacts; the larger the solute molecule, the more contacts are created. If the surface area
`of the solute molecule is A, the solute-solvent interface increases by a 12A, where a12 is the
`
`This material was copied
`at th,e r~LM and ma he
`
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`

`

`-- ~ - - --- --------"=""·""==;;:,____,...,..~e:--=-----------------.,--
`
`-~ y
`
`154 The Solubility of Drugs
`
`mm
`mmm-(cid:173)
`ma
`
`Solute
`
`Work
`
`W22
`
`+
`
`fl
`Removal of
`solute molecule
`
`00
`00
`00
`Solvent
`
`00
`--o 0
`00
`Creation of
`cavity
`
`00
`0 0
`00
`Solvent
`cavity
`
`+ m
`
`00
`--ormo
`00
`
`Solute molecule
`
`Figure 5.1 Diagrammatic representation of the three processes involved in the dissolution of a
`crystalline solute: the expression for the work involved is w22 + w11 - 2w12 (solute-solvent inter·
`action in the last stage is -2w12 as bonds are made with one solute and two solvent molecules)
`
`interfacial tension between the solvent (subscript 1) and the solute (subscript 2). u is a
`parameter not readily obtained for solid interfaces on the molecular scale but reason(cid:173)
`able estimates can be made from knowledge of the interfacial tensions of molecules at
`normal interfaces1- 5•
`The number of solvent molecules that can pack around the solute molecule is con(cid:173)
`sidered in calculations of the thermodynamic properties of the solution. The molecular
`surface area of the solute is therefore a key parameter and good correlations can be
`obtained between aqueous solubility and this parameter4
`5
`•
`•
`Of course, most drugs are not simple non-polar hydrocarbons and we have to
`consider polar molecules and weak organic electrolytes. The term w12 in Figure 5.1, a
`measure of solute-solvent interactions, has to be further divided to take into account
`the interactions involving the non-polar part and the polar portion of the solute. The
`molecular surface area of each portion can be considered separately: the greater the area
`of the hydrophilic portion relative to the hydrophobic portion, the greater is the
`aqueous solubility. For a hydrophobic molecule of area A, the free energy change in
`placing the solute in the solvent cavity is -u12A. Indeed it can be shown that the
`reversible work of solution is (w11 + w22 - 2w12)A.
`Implicit in this derivation is the assumption that the solution formed is dilute, so that
`solute-solute interactions are unimportant. The success of the molecular area approach
`is evidenced by the fact that equations can be written to relate solubility to surface area;
`for example, equation 5.1 has been shown to hold for a range of 55 compounds (some of
`which are listed in Table 5.1):
`
`ens= -4.3A + 11.78
`(5.1)
`where Sis the molal (not molar) solubility, and A is the total surface area in nm2
`
`•
`
`This material wast:apied
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`

`

`Table 5.1 Experimental aqueous solubilities, boiling points, surface areas and
`predicted solubilities*
`
`Factors Influencing Solubility 155
`
`Compound
`
`1-Butanol
`1-Pentanol
`1-Hexanol
`1-Heptanol
`Cyclohexanol
`1-Nonanol
`
`* From reference 1
`
`Solubility
`(molkg- 1)
`
`1.006
`2.5 X 10-I
`6.1 X 10-2
`1.55 X 10-2
`3.83 X 10-I
`IX 10-3
`
`A
`(nm2
`
`)
`
`2.721
`3.039
`3.357
`3.675
`2.905
`4.312
`
`Boiling point
`(°C)
`
`Predicted solubilities
`(molkg- 1)
`
`117.7
`137.8
`157
`176.3
`161
`213.1
`
`0.821
`2.09 X 10-I
`5.32 X 10-2
`J.36 X 10-2
`4.3 X 10-I
`8.8 X 10-4
`
`5.2.1 Structural features and aqueous solubility
`Shape
`
`Interactions between non-polar groups and water were discussed above, where the
`importance of both size and shape was indicated. Chain branching of hydrophobic
`groups influences aqueous solubility, as shown by the solubilities of a series of straight(cid:173)
`and branch-chain alcohols (Table 5.2).
`What other predictors of solubility might there be? The boiling point of liquids and the
`melting point of solids are useful in that both reflect the strengths of interactions between
`the molecules in the pure liquid or the solid state. Boiling point correlates with total
`surface area, and in a large enough range of compounds we can detect the trend of
`decreasing aqueous solubility with increasing boiling point. As boiling points of liquids
`and melting points of solids are indicators of molecular cohesion, these can be useful
`indictators of trends in a series of similar compounds. There are other empirical
`correlations that are useful. Melting points, even of compounds which form non-ideal
`
`Table 5.2 Solubilities of pentanol isomers in water*
`
`Solubility
`(molality, m)
`
`2.6 X 10-t
`
`3.11 X 10-t
`
`3.47 X 10-I
`
`5.3 X 10-t
`
`6.15 X 10-I
`
`6.67 X 10-I
`
`A
`(nm 2
`)
`
`3.039
`
`2.914
`
`2.894
`
`2.959
`
`2.935
`
`2.843
`
`n-Pentanol
`
`3-Methyl-1-butanol
`
`2-Methyl-1-butanol
`
`2-Pentanol
`
`3-Pentanol
`
`3-Methy 1-2-butanol
`
`2-Methyl-2-butanol
`
`* From reference 1
`
`1.403
`
`2.825
`
`102.0
`
`/)'<..OH
`
`Thismat€rial wascopied
`at the NU111 am:! mayh,e
`5-ubj-e'l:t US Copyright Laws
`
`Boiling Point
`(OC)
`
`Structure
`
`137.8
`
`131.2
`
`128.7
`
`~OH
`
`~OH
`
`~OH
`
`OH
`--.,,l...
`
`119
`
`115.3
`
`--c-
`111.5 ~
`
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`

`156 The Solubility of Drugs
`
`Table 5.3 Aqueous solubility of sulphonamide derivatives
`
`Compound
`
`Melting point (0 C)
`
`Solubility
`
`Sulphadiazine
`Sulphamerazine
`Sulphapyridine
`Sulphathiazole
`
`253
`236
`192
`174
`
`I g in 13 dm3 (0.077 g dm-3)
`lg in 5dm3 (0.20gdm-3)
`I g in 3.5 dm3 (0.29 g dm-3)
`I g in I. 7 dm3 (0.59 g dm-3)
`
`solutions, can be used as a guide to the order of solubility in a closely related series
`of compounds, as can be seen in the properties of sulphonamide derivatives listed in
`Table 5.3. Such correlations depend on the relatively greater importance of w22 in the
`solution process in these compounds.
`
`Substituents
`
`The influence of substituents on the solubility of molecules in water can be due to their
`effect on the properties of the solid or liquid (for example, on its molecular cohesion) or
`to the effect of the substituent on its interaction with water molecules. It is not easy to
`predict what effect a particular substituent will have on crystal properties, but as a guide
`to the solvent interactions, substituents can be classified as either hydrophobic or
`hydrophilic, depending on their polarity (see Table 5.4). The position of the substituent
`on the molecule can influence its effect, however. This can be seen, for example, with the
`aqueous solubilities of the o-, m- and p-dihydroxybenzenes; as expected, all are much
`greater than that of benzene but they are not the same, being 4, 9 and 0.6moldm-3,
`respectively. The relatively low solubility of the para compound is due to the greater
`stability of its crystalline state. The melting points of the derivatives indicate this is so, as
`
`I
`
`Table 5.4 Substituent group
`classification in relation to
`water solubility
`
`Substituent
`
`Classification
`
`-CH3
`-CH,
`-Cl,-Br, -F
`-N(CH3)i
`-SCH3
`-OCH2CH3
`-OCH3
`-N02
`-CHO
`-COOH
`-coo-
`-NH2
`-NHf
`-OH
`
`Hydrophobic
`Hydrophobic
`Hydrophobic
`Hydrophobic
`Hydrophobic
`Hydrophobic
`Slightly hydrophilic
`Slightly hydrophilic
`Hydrophilic
`Slightly hydrophilic
`Very hydrophilic
`Hydrophilic
`Very hydrophilic
`Very hydrophilic
`
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`

`Fdctors Influencing Solubility 157
`
`Table 5.5 The effect of substituents on solubility of acetanilide
`derivatives in water
`
`X
`
`Solubility (mg dm- 3
`)
`
`H
`Methyl
`Ethoxyl
`Hydroxyl
`Nitro
`Aceto
`
`6.38
`1.05
`0.93
`13.9
`15.98
`9.87
`
`they are 105, 111, and 170 °C, respectively. In the case of the or tho derivative the possi(cid:173)
`bility ofintramolecular hydrogen bonding in aqueous solutions, decreasing the ability of
`the OH group to interact with water, may explain why its solubility is lower than that
`of its meta analogue.
`One can best illustrate the use of the information in Table 5.4 by considering the
`solubility of a series of substituted acetanilides, data for which are provided in Table 5.5.
`The strong hydrophilic characteristics of polar groups capable of hydrogen bonding with
`water molecules are evident. The presence of hydroxyl groups can therefore markedly
`change the solubility characteristics of a compound; phenol, for example, is 100 times
`more soluble in water than is benzene. In the case of phenol, where there is considerable
`hydrogen bonding capability, the solute-solvent interaction (w 12) outweighs other
`factors (such as w22 or w11 ) in the solution process. But, as we have discovered, the
`position of any substituent on the parent molecule will affect its contribution to solubility.
`
`Steroid solubility
`
`The steroids as a group tend to be poorly soluble in water. The complex structure makes
`prediction of solubility somewhat difficult, but one can generally rationalise, post hoc,
`the solubility values of related steroids. T&ble 5.6 gives solubility data for several
`steroids. As examples, the substitution of an ethynyl group has conferred increased
`solubility on the oestradiol molecule, as would be expected. Oestradiol benzoate with its
`3-hydroxy substituent is much less soluble than the parent oestradiol because of the loss
`of the hydroxyl and its substitution with a hydrophobic group. The same relationships
`are seen in testosterone and testosterone propionate. As both oestradiol benzoate and
`testosterone propionate are oil-soluble they are used as solutions in castor oil and
`sesame oil for intramuscular and subcutaneous injection (see Chapter 9).
`Methyltestosterone might be expected to be less soluble in water than is testosterone
`but in fact it is not; this demonstrates the importance of crystal properties in deter(cid:173)
`mining solubility. The methyl compound is more soluble because of the smaller heat of
`fusion of this derivative, hence the solid state more readily 'disintegrates' in the solvent.
`Dexamethasone and betamethasone are isomeric fluorinated derivatives of methyl(cid:173)
`prednisolone, but their solubilities are not identical, which might be a crystal or a
`solution property. A simpler example of differences in isomeric solubility is that of the
`o-, m-, and p-dihyd