`
`Medical Division of Longman Group UK Limited
`Distributed in the United States of America by
`Churchill Livingstone Inc., 550 Avenue of the Americas,
`New York, 10011, and associated companies, branches
`and representatives throughout the world.
`
`© Michael Aulton 1983
`
`M1 rights reserved. No part of this publication may
`be reproduced, stored in a retrieval system, or
`transmitted in any form or by any means, electronic,
`mechanical, photocopying, recording, or otherwise,
`without the prior permission of the publishers
`(Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter's Place, Leith Walk, Edinburgh EH1 3AF), or
`a Licence pemiitting restricted copying in the United
`Kingdom issued by the Copyright Licensing Agency Ltd.
`90 Tottenharn Court Road, London, WIP 9HE.
`
`First published 1988
`Reprinted 1939
`Reprinted 1990
`Reprinted 1991
`Reprinted 1992
`
`ISBN El-ll’-t3-[I|3l:~LIEl-Eli
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. Aulton, Michael E.
`6l5'.l9
`RS403
`
`2. Drugs
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gunrfs tutorial pharmacy.
`6th ed. 1972.
`Includes bibliographies and index.
`1. Drugs — Design of delivery systems.
`— Dosage forms. 3. Biopharmaccutics.
`4. Pharmaceutical technology.
`5. Chemistry,
`Pharmaceutical.
`6. Microbiology, Pharmaceutical.
`1. Aulton, Michael E.
`2. Chemistry,
`[DNLM: 1. Biopharmaceutics.
`Pharmaceutical.
`3. Dosage Forms.
`4. Technology,
`Pharmaceutical.
`5. Microbiology, Pharmaceutical.
`QV 785 P5366]
`RS420.P4S
`1987
`
`615.5'3
`
`86-25333
`
`Printed in Hong Kong
`CPP/U5
`
`The
`flubilshefls
`policyisto use
`papermanutactured
`from sustalnablefotesis
`
`Astrazeneca Ex. 2104 p. 2
`
`
`
`Contents
`
`
`
`Preface
`Contributors
`
`Acknowledgements
`About this book
`
`1 The design of dosage forms
`
`PART ONE Physicochemical
`principles of pharmaceutics
`2 Rheology and the flow of fluids
`3 Solutions and their properties
`4 Surface and interfacial phenomena
`5 Solubility and dissolution rate
`6 Disperse systems
`7 Kinetics and stability testing
`
`‘
`
`PART TWO Biopharmaceutics
`8 Introduction to biopharmaceutics
`9 Factors influencing bioavailability
`10 Assessment of bioavailabilit
`
`11 Dosage regimens
`
`"
`
`PART THREE Drug delivery systems
`12 Packs for pharmaceutical products
`13 Preformulation
`
`14 Solutions
`
`15 Suspensions
`16 Emulsions
`
`17 Powders and granules
`18 Tablets
`
`19 Capsules
`20 Therapeutic aerosols
`21 Parenteral products
`22 Topical preparations
`23 Suppositories and pessaries
`
`PART FOUR Pharmaceutical
`
`microbiology
`24 Fundamentals of microbiology
`_25 The action of physical and chemical
`agents on micro—organisms
`26 Principles of sterilization
`27 Microbiological contamination and
`preservation of pharmaceutical
`preparations
`28 Pharmaceutical applications of
`microbiological techniques
`
`-PART FIVE Pharmaceutical
`
`technology
`29 Materials of fabrication and corrosion
`
`30 Heat transfer and the properties of
`steam
`
`31 Filtration
`
`32 Mixing
`33 Particle size analysis
`34 Particle size reduction
`
`35 Particle size separation
`36 Powder flow
`
`37 Granulation
`
`.38 "Drying
`39 Tableting
`40 Tablet coating
`41 Encapsulation
`42 Design and operation of clean rooms
`43 Sterilization practice
`44 Packaging technology
`
`Index
`
`vii A
`ix
`xi
`xiii
`
`15
`17
`38
`
`50
`62
`81
`119
`
`129
`131
`135
`
`174
`191
`
`213
`215
`223
`254
`269
`282
`
`. 300
`304-
`322
`341
`
`359 '
`
`381
`412
`
`423
`425
`
`452
`472
`
`479
`
`491
`
`509
`511
`
`525
`538
`550
`564
`581
`
`591
`600
`616
`629
`
`647
`669
`678
`686
`
`700
`712
`
`725
`
`Astrazeneca Ex. 2104 p. 3
`
`
`
`
`
`6 J B Kayes
`
`Disperse systems
`
`
`
`DISPERSE SYSTEMS
`
`COLLOID SCIENCE
`
`Preparation of colloids
`Lyophilic colloids
`Lyophobic colloids
`Dispersion methods
`Colloid mills
`Ultrasonic treatment
`
`Condensation methods
`
`Diigfrlifltration
`
`Electrodialysis
`Pharmaceutical applications of dialysis
`Properties of colloids
`Kinetic properties
`Brooonoon noon-on
`Diffusion
`Sedimentation
`Sedimentation velocity
`Sedimentation equilibrium
`
`‘
`
`,
`
`The Donnan membrane effect
`Visoosig,
`Optical properties
`Light Scattering
`Ultnomiorosoopo
`
`Electrical properties
`Electrical properties of interfaces
`.
`.
`Ion d1SSOll1t10fl
`Ionization
`Ion adsorption
`The electrical double layer
`Electrokinetic phenomena
`Electrophoresis
`Other electroldnetic phenomena
`
`Physical stability of colloidal systems
`Stability of lyophobic systems
`DLVO theory
`Repulsive forces between particles
`Attractive forces between particles
`Total potential energy of interaction
`Stability of lyophilic systems
`Coacervation and microencapsulation
`Effect of addition of macromolecular
`
`material to lyophobic colloidal sols
`
`Steric stabilization (protective colloid action)
`
`GEL3
`Types of go]
`Applications
`
`SURFACE-ACTIVE AGENTS
`Micellization
`Physical properties of surface active agent
`5°l“t‘°“5
`Surface properties
`
`Solubllllfi’-' the Kmff‘ Pom‘
`Light scattering
`Other methods of determining CMCs
`Solubilization
`.
`_
`Applications of solubilizazion
`
`Detergeflcy
`
`COURSE DISPERSE SYSTEMS
`
`SUSPENSIONS
`The controlled flocculation approach to
`suspension formulation
`The effect of adsorbed polymer layers on the
`physical stability of suspensions’
`Stability of non-aqueous dispersions
`
`81
`
`Astrazeneca Ex. 2104 p. 4
`
`
`
`82
`
`PI-IYSICOCHEMICAL PRINCIPLES OF PHARMACEUTICS
`
`Table 6.1 Types of disperse systems
`
`Dispersed
`phase
`
`Dispersion
`medium
`
`Name
`
`Example:
`
`Wetting agents
`Rheological properties of suspensions
`
`EMULSIONS
`
`Microemuisions
`
`Theory of emulsion stabilization
`Interfacial free energy and emulstfication
`Interfacial complexes
`Emulsion stabilization by non-ionic surfactants
`Hydrophilic colloids as emulsion stabilizers
`Solid particles in emulsion stabilization
`Emulsion type
`HydrophiIe—IipopFn'le balance (HLB)
`Phase vtscartty
`Determination of emulsion type
`Stability of emulsions
`Flocculatitm
`Phase inversion
`
`Creaming
`Assessment of emulsion stability
`Phase inversion temperature
`
`FOAMS
`
`AEROSOLS
`
`Preparation of aerosols
`Applications of aerosols in pharmacy
`
`DISPERSE SYSTEMS
`
`A disperse system may be defined as a system in
`which one
`substance,
`the disperse phase,"
`is
`dispersed as particles throughout another,
`the
`dispersion medium.
`the
`Although systems in which the size of
`dispersed particles are within the range of about
`10'9rn (1 nm)
`to 10“5n1 (1 nm) are termed
`colloidal, and have specific properties, there is no
`sharp distinction between colloidal and non-
`colloidal systems, particularly at
`the upper size
`limit. For example the droplet size in emulsions,
`the particle size in suspensions and the natural
`systems of microorganisms and blood are
`normally in excess of
`1 am and yet
`such
`dispersions
`show many of
`the properties of
`colloidal systems. Some examples of the different
`disperse systems are given in Table 6.1.
`The essential character common to all disperse
`
`Liquid
`
`Solid
`
`Gas
`
`Gas
`
`Gas
`
`Liquid
`aerosol
`
`Fogs, mists,
`aerosols
`
`Solid aerosol
`
`Smoke, powder
`aerosols
`
`Liquid
`
`Foam
`
`Foam on
`surfactant
`solutions
`
`Milk,
`phannaceutical
`emulsions
`
`Silver iodide sol,
`aluminium
`hydroxide
`suspension
`
`Expanded
`polystyrene
`
`Liquids dispersed
`in soft paraffin,
`opals, pearls
`
`Pigmented
`plastics,
`colloidal gold
`in glass (ruby
`glass)
`
`Liquid
`
`Liquid
`
`Emulsion
`
`Solid
`
`Liquid
`
`Sol,
`suspension
`
`Gas
`
`Solid
`
`Solid foam
`
`Liquid
`
`Solid
`
`Solid
`
`Solid
`
`Solid
`emulsion
`
`Solid
`suspension
`
`systems is the large area to volume ratio for the
`particles involved, for example, when a cube of
`1 cm edge is subdivided into cubes of 100 nm
`edge there is a 105 increase in surface area and
`associated free energy. This free energy will be
`decreased if the particles aggregate or coalesce
`because of the reduction in interfacial area that
`
`acconipanies such aggregation. Since any system
`will tend to react spontaneously to decrease its free
`energy to a minimum it
`follows that disperse
`systems are often unstable,
`the particles aggre-
`gating rather than rcrnaining in contact with the
`dispersion medium. Dispersions that exhibit this
`behaviour are termed braphobic, or solvent hating,
`dispersions. In other systems known as Iyophilic,
`solvent
`loving, dispersions
`an_ affinity exists
`between the dispersed particles and the dispersion
`medium and this contributes to the stability of
`these systems. The terms hydrophobic and hydro-
`philic may be used when the dispersion medium
`is water.
`Whilst the majority of dispersions used in phar-
`macy are aqueous they are by no means limited
`to water, thus dispersions of solids in oils include
`
`Astrazeneca Ex. 2104 p. 5
`
`
`
`suspensions for injection and oral use and suspen-
`sions of solids in aerosol propellants.
`This chapter is an attempt to describe colloidal
`systems and to show how their properties may be
`applied to the study of coarse dispersions of phar-
`maceutical interest.
`
`COLLOID SCIENCE
`
`Colloid science concerns systems in which one or
`more of the components has at least one dimen-
`sion within the range of about 1 nm to 1 jam and
`thus includes shapes
`such as spheres, cubes,
`ellipsoids, rods, discs and random coils, where
`other dimensions may be significantly larger than
`1 pm. As indicated, some colloids can be broadly
`classified as
`those that are lyophobic,
`these
`dispersions or sols are thermodynamically unstable
`and the particles tend to aggregate to lower the
`surface free energy of the system. They are irre-
`versible systems in the sense that
`they are not
`easily reconstituted after phase separation. ‘Water-
`insoluble drugs and clays such as kaolin and
`bentonite and oils form lyophobic dispersions. On
`the other hand macromolecular material such as
`the proteins, tragacanth and methylcellulose form
`lyophilic
`sols which,
`as
`true
`solutions,
`are
`thermodynamically stable. These are reversible
`systems because, after separation of' solute from
`solvent,
`they are easily reconstituted. Surfactant
`molecules, because of their affinity for water and
`their tendency to form micelles which are of
`colloidal dimensions, form hydrophilic colloidal
`dispersions in water but are usually classified
`separately as association colloids,
`the older term
`being colloidal electrolyte.
`the efficiency of
`It has been suggested that
`certain substances, used in pharmaceutical prep-
`arations, may be increased if colloidal forms are
`used since these have large surface areas. Thus,
`for example,
`the adsorption of toxins from the
`gastrointestinal
`tract by kaolin, and the rate of
`neutralization of excess acid in the stomach by
`aluminium hydroxide, may be increased if these
`compounds are used in colloidal form.
`In the purification of proteins, use is made of
`the changes in solubility of colloidal material with
`alteration of pH and addition of electrolyte.
`
`DISPERSE sYs'rEMs
`
`33
`
`The protective ability, or, as it is now known,
`the steric stabilization effect of hydrophilic colloids
`is used to prevent the coagulation of hydrophobic
`particles in the presence of electrolytes. Thus
`hydrophobic sols for injection, such as colloidal
`gold (193Au) injection, must be sterically stabilized
`in this case by gelatin. Hydrophilic sols are
`viscous and use is made of this property in
`retarding the sedimentation of particles in phat»
`maceutical suspensions.
`Blood plasma substitutes such as dextran, poly-
`vinylpyrrolidone
`and gelatin are hydrophilic
`colloids which exert an osmotic pressure similar
`to that of plasma and are thus used to restore or
`maintain blood volume.
`
`Iron—dextran complexes form non-ionic hydro-
`philic sols suitable for injection for the treatment
`of anaemia.
`
`Preparation of colloids
`
`Lyaphilir colloids
`
`The affinity of lyophilic colloids for the dispersion
`medium leads to the spontaneous formation of
`colloidal dispersions. For example, acacia,
`traga—
`canth, methylcellulose and certain other cellulose
`derivatives disperse in water. This simple method
`of dispersion is a general one for the formation of
`lyophilic colloids.
`
`Lyophobic colloids
`
`The preparative methods for lyophobic colloids
`may be divided into those methods that involve
`the breakdown of larger particles into particles of
`colloidal dimensions
`(dispersion methods) and
`those in which the colloidal particles are formed
`by aggregation of smaller particles such as mol-
`ecules (condensation methods).
`
`Dispersion methods
`
`The breakdown of coarse material may be effected
`by the use of a colloid mill or ultrasonics.
`Colloid mills These mills cause the dispersion
`of coarse material by shearing in a narrow gap
`between a static cone (the stator) and a rapidly
`rotating cone (the rotor).
`
`Astrazeneca Ex. 2104 p. 6
`
`
`
`Eh
`V-T317000}-IEMICAL PRINCIPLES or PHARMACETJTICS
`
`U111-asonic treatment The passage of ultrasonic
`waves
`through a dispersion medium produces
`alternating regions of cavitation and compression
`in the medium. The cavities collapse with great
`force and cause the breakdown of coarse particles
`dispersed in the liquid.
`With both these. methods the particles will tend
`to reunite unless a stabilizing agent such as a
`surface—active agent is added.
`
`Condensation methods
`
`These involve the rapid production of supersatu-
`rated solutions of the colloidal material under
`conditions
`in which it
`is deposited in the
`dispersion medium as colloidal particles and not
`as
`a precipitate. The supersaturation is often
`obtained by means of a chemical reaction that
`results in the formation of the colloidal material.
`For example, colloidal
`silver
`iodide may be
`obtained by reacting together dilute solutions of
`silver nitrate and potassium iodide, sulphur from
`sodium thiosulphate and hydrochloric
`acid
`solutions, and ferric chloride boiled with excess of
`water produces colloidal hydrated ferric oxide.
`A change in solvent may also cause the
`production of colloidal particles by condensation
`methods. If a saturated solution of sulphur in
`acetone is poured slowly into hot water,
`the
`acetone vaporizes leaving a colloidal dispersion of
`sulphur. A similar dispersion may be obtained
`when a solution of a resin, such as benzoin in
`alcohol, is poured into water.
`
`to maintain a high
`hastened by stirring so as
`concentration gradient of diffusible molecules
`across the membrane and by renewing the outer
`liquid from time to time.
`(or
`pressure
`Ultrafiltration By
`applying
`suction) the solvent and small particles may be
`forced across a membrane whilst the larger colloidal
`particles are retained. The process is referred to
`as ultrafiltration.
`It
`is possible
`to prepare
`membrane filters with known pore size and use of
`these allows the particle size of a colloid to be
`determined. However, particle size and pore size
`cannot be properly correlated because
`the
`membrane permeability is affected by factors such
`as electrical repulsion, when both the membrane
`and particle carry the same charge, and particle
`adsorption which can lead to blocking of the
`pores.
`
`Electrodialysis An electric potential may be
`used to increase the rate of movement of ionic
`impurities through a dialysing membrane and so
`provide a more rapid means of purification. The
`concentration of charged colloidal particles at one
`side and at the base of the membrane is termed
`electrodecantation.
`
`Pfiannaceutical applications of dialysis These
`include the use of membrane filters, artificial
`membranes as models for the diffusion of drugs
`through natural membranes,
`in the study of
`drug/protein binding and as
`the principle of
`haemodialysis where
`small molecular weight
`impurities from the body are removed by passage
`through a membrane.
`
`Dialysis
`
`Colloidal particles are not retained by conventional
`filter papers but are too large to diffuse through
`the pores of membranes such as those made from
`regenerated cellulose products,
`e.g.
`collodion
`(cellulose nitrate evaporated from a solution in
`alcohol and ether) and cellophane..The smaller
`particles in solution are able to pass through these
`membranes. Use is made of this difference in
`diffusibility to separate micromolecular impurities
`from colloidal dispersions. The process is known
`as dialysis. The process of dialysis may be
`
`Properties of colloids
`
`Kinetic properties
`
`section several properties of colloidal
`In this
`systems, which relate to the motion of particles
`with respect to the dispersion medium, will be
`considered. Thermal motion manifests itself in the
`form of Brownian motion, diffusion and osmosis.
`Gravity (or a centrifugal field) leads to sedimen-
`tation. Viscous flow is the result of an externally
`applied force. Measurement of these properties
`enables molecular weights or particle size to be
`determined.
`
`Astrazeneca Ex. 2104 p. 7
`
`
`
`DISPERSE SYSTEMS
`
`35
`
`Brownian motion
`
`Colloidal particles are subject to random collisions
`with the molecules of the dispersion medium with
`the result that each particle pursues an irregular
`and complicated zig—zag path. If the particles (up
`to about 2 nm diameter) are observed under a
`microscope or
`the light scattered by colloidal
`particles is viewed using an ultramicroscope, the
`erratic motion seen is referred to as Brownian
`
`motion after Robert Brown (1327) who first
`observed this phenomenon with pollen grains
`suspended in water.
`
`change in concentration, via refractive index
`gradients, of the free boundary which is formed
`when the solvent and solution are brought
`together and allowed to diffuse. The diffusion
`coefficient can be used to obtain the molecular
`
`weight of an approximately spherical particle,
`such as egg albumin and haemoglobin, by using
`Eqn 6.4 in the form
`
`RT
`
`D :
`
`61mN '
`
`3 4nN
`3Mv
`
`(6.5)
`
`where M is the molecular weight and i7 the partial
`specific volume of the colloidal material.
`
`Diffusion
`
`Sedimentation
`
`As a result of Brownian motion colloidal particles
`spontaneously diffuse from a region of higher
`concentration to one of lower concentration. The
`
`rate of diffusion is expressed by Fick’s first law
`
`Consider a spherical particle of radius a and
`density 0 falling in a liquid of density p and
`viscosity W. The velocity v of sedimentation is
`given by Stokes’ law
`
`dC
`dm
`_=_DA _
`cit
`dx
`
`(61)
`
`'v =
`
`2a2g(o — p)
`
`97!
`
`(6.6)
`
`where rim is the mass of substance diffusing in
`time dt across an area A under the influence of a
`concentration gradient dC/dx.
`(The minus sign
`denotes that diffusion takes place in the direction
`of decreasing concentration.) D is the diffusion
`coefficient and has the dimensions of area per unit
`time. The diffusion coefficient of a dispersed
`material is related to the frictional coefficient of
`
`the particles by Einsteiffs law of diffusion
`
`Df = H"
`
`(6.2)
`
`the Boltzmann constant and T.
`is
`where k
`_
`temperature.
`Therefore as the frictional coefficient f is given
`
`by Stokes
`
`f = fimaa
`
`(6.3)
`
`where In is the viscosity of the medium and a the
`radius of the particle, as a sphere
`‘
`
`D _ kT
`7 6m]a
`
`_ RT
`— 6m'|aN
`
`(6-4)
`
`where N is the Avogadro number and R is the
`universal gas constant. The diffusion coefficient
`may be obtained by an experiment measuring the
`
`where g is acceleration due to gravity.
`If the particles are only subjected to the force
`of gravity then, due to Brownian motion,
`the
`lower size limit of particles obeying Eqn 6.6 is
`about 0.5 ,u.m. A stronger force than gravity is
`therefore needed for colloidal particles to sediment
`and use is made of a high speed centrifuge, usually
`termed an ultracentrifuge, which can produce a
`force of about 105g. In a centrifuge, g is replaced
`by (11335, where this the angular velocity and x the
`distance of the particle from the centre of rotation
`and Eqn 6.6 becomes
`
`‘V:
`
`2512 (o — p) tnlx
`
`9n
`
`(6.7)
`
`Modification of the sedimentation method using
`the ultracentrifuge is used in two distinct ways in
`investigating colloidal material.
`In the sedimentation velocity method a high
`centrifugal field is applied —— up to about 4 X l05g
`-— and the movement of the particles, monitored
`by changes in concentration,
`is measured from
`time to time.
`
`In the sedimentation equilibrium method, the
`colloidal material is subjected to a much lower
`
`Astrazeneca Ex. 2104 p. 8
`
`
`
`86
`
`-PHYSICOCHEMICAI. PRINCIPLES OF PHARMACEUTICS
`
`centrifugal field until sedimentation and diffusion
`tendencies balance one another, and an equilib—
`rium distribution of particles
`throughout
`the
`sample is attained.
`Sedimentation velocity The velocity dx/dt of
`a particle in a unit centrifugal
`force can be
`expressed in terms of the Svedberg coefficient s,
`
`dx/dz
`tozx
`
`(6.8)
`
`force
`the centrifugal
`the influence of
`Under
`particles pass
`from position x1 at
`time I;
`to
`position 3C2 at time :2 — the differences in concen-
`tration with time can be measured using changes
`in refractive index and the. application of the sch-
`lieren optical arrangement whereby photographs
`can be taken showing these concentrations as
`peaks.
`Integration of Eqn 6.8 using the above
`limits gives
`
`
`ln x2/x1
`
`032 (52 " F1)
`
`(6-9}
`
`By suitable manipulation of Eqns 6.7, 6.8 and 6.9
`an expression giving molecular weight M can be
`obtained
`
`M _
`
`RTE
`DU " VP)
`
`_
`
`RT In xz/x1
`DU — 179} (P2 — 30032
`
`(6.10)
`
`where it is the specific volume of the particle.
`Sedimentation equilibrium Equilibrium is
`established when sedimentation and diffusional
`forces balance. Combination of sedimentation and
`diffusion equations is made in the analysis and
`
`03
`
`(1 “‘ V9) (302 ‘ xi)
`
`cam
`
`where C] and C2 are the sedimentation equilib
`rium concentrations at distances x1 and 352 from
`the axis of rotation.
`
`Unfortunately in order to obtain equilibrium
`the centrifuge has to be run for about a week, with
`consequent experimental difficulties. A technique
`has
`therefore been
`developed which
`allows
`analysis to be made at intervals during the early
`
`stages of the experiment. Mathematical treatment
`of the results can then be used to obtain the
`molecular weight.
`
`Osmotic pressure
`
`of
`The determination of molecular weights
`dissolved substances from colligative properties is
`standard procedure but of these, osmotic pressure
`is the only one with a practical value in the study
`of colloidal particles. For example, consider a
`solution of
`1 g of macromolecular material of
`molecular weight 70 000 dissolved in 100 cm?‘ of
`water. Assuming ideal behaviour, the depression
`of the freezing point is 00026 K and the osmotic
`pressure at 20 °C, 350 N m‘? or about 35 mm of
`water. The above freezing point depression is far
`too small to be measured with sufficient accuracy
`by conventional methods and, of rather greater
`importance,
`the presence of about
`1 mg of
`impurity of molecular weight 50 would more than
`double the above value. Not only does the osmotic
`pressure provide an effect which is measurable,
`but also the effect of any low molecular weight
`material, which can pass through the membrane
`is virtually eliminated.
`However,
`the usefulness of osmotic pressure
`measurement
`is limited to a molecular weight
`range of about
`104
`to 105; below 104
`the
`membrane may be permeable to the molecules
`under consideration and above 105 the osmotic
`pressure will be too small
`to permit accurate
`I1'lCE1S1lI‘€.‘llTlf3Il[.
`
`If a solution and solvent are separated by a
`semipermeable membrane the tendency to equalize
`chemical potentials (and hence concentrations) on
`either side of the membrane results in a net
`diffusion of solvent across the membrane. The
`pressure necessary to balance this osmotic flow is
`termed the osmotic pressure.
`For a colloidal solution the osmotic pressure 11'
`can be described by
`
`Tl’/C =' RT/M + BC
`
`(6.12)
`
`where C is the concentration of the solution, M the
`molecular weight of the solute and B a constant
`depending on the degree of interaction between
`the solvent and solute molecules.
`
`Astrazeneca Ex. 2104 p. 9
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`
`
`DISPERSE SYSTEMS
`
`87
`
`Thus a plot of 77/C verses C is linear with the
`value of the intercept as C e 0 giving RT/M
`enabling the molecular weight of the colloid to be
`calculated.
`
`Since volume fraction is directly related to
`concentration Eqn 6.15 may be written as
`
`Tisp/C = K
`
`(6.16)
`
`The Donnan membrane effect
`
`The diffusion of small ions through a membrane
`will be affected by the presence of a charged
`macromolecule that
`is unable to penetrate the
`membrane because of its size. At equilibrium the
`distribution of the diffusible ions is unequal, being
`greater on the side of the membrane containing
`the non-diffusible ions. This is known as the
`Donnan membrane effect. For a full discussion,
`the reader is referred to Shaw (1980).
`Application of this principle suggests that co-
`administration of a large concentration of an anionic
`macromolecule, e.g. sodium carboxymethylcellu-
`lose, with a diffusible anion, e.g. potassium
`benzylpenicillin, should enhance the diffusion of
`the benzylpenicillin anion across body membranes.
`
`Viscosity
`
`Viscosity is an expression of the resistance to flow
`of a system under an applied stress and these
`properties are discussed in detail
`in Chapter 2.
`Some of those relationships are repeated here.
`Einstein developed an equation of flow appli-
`cable to colloidal dispersions of spherical particles,
`
`7] = no (1 + 2.5 (1))
`
`(6.13)
`
`where no is the viscosity of the dispersion medium
`and 11
`the viscosity of the dispersion when the
`volume fraction of colloidal particles present
`is
`
`(1).
`
`A number of viscosity coefficients may be
`defined with respect to Eqn 6.13. These include
`relative viscosity
`
`where C is the concentration expressed as grams
`of
`colloidal particles per
`100 ml of
`total
`dispersion. If 7]
`is determined for a number of
`concentrations of macromolecular material
`in
`
`solution, 715,,/C plotted versus C and the line
`obtained extrapolated to infinite dilution the
`constant obtained is [7]] known as the intrinsic
`viscosity.
`This constant may be used to calculate the
`molecular weight of the macromolecular material
`by making use of the Mark—Houwink equation
`
`[7]] = KM“
`
`(6.17)
`
`where K and 0c are constants characteristic of the
`
`particular polymer—solvent system. These constants
`are obtained initially by determining [n]
`for a
`polymer fraction whose molecular weight has been
`determined by another method such as sedimen-
`tation, osmotic pressure or light scattering. The
`molecular weight of theunknown polymer frac-
`tion may then be calculated. This method is suit-
`able for use with polymers like the dextrans used‘
`as blood plasma substitutes.
`
`Optical properties
`
`Light scattering
`
`When a beam of light is directed at a colloidal sol
`some of the light may be absorbed (when light of
`certain wavelengths
`is
`selectively absorbed a
`colour is produced), some is scattered and the
`remainder transmitted undisturbed through the
`sample. Due to the light scattered the sol appears
`turbid; this is known as the Tyndall effect: The
`turbidity of a sol is given by the expression M,
`
`me; = 71/71., = 1 + 2.5 (1)
`
`(6.14)
`
`I = [0 eXp_tl
`
`specify viscosity
`
`nsp = T1/no * 1 = (n - no)/no = 2.5 ¢
`
`or
`
`mp/¢ = 2.5
`
`(6.15)
`
`where 1., is the intensity of the incident beam, I
`that of the transmitted light beam, l.the_ length of
`the sample and t the turbidity.
`,
`:
`V
`Light scattering _ measurements ._ are of great
`value for estimating particle size, shape and inter-
`
`Astrazeneca EX. 2104 p. 10
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`BB
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`BHYSICOCI-IEMICAL PRINCIPLES OF PI-IARMACEUTICS
`
`actions, particularly of dissolved macromolecular
`materials, as the turbidity depends on the size
`(molecular weight) of
`the
`colloidal material
`involved. Measurements are simple in" principle
`but experimentally difficult because of the need to
`keep the sample free from dust, the particles of
`which would scatter light strongly and introduce
`large errors.
`As most colloids show very low turbidities,
`instead of measuring the transmitted light (which
`may differ only marginally from the incident
`beam),
`it
`is more convenient and accurate to
`measure the scattered light, at an angle — usually
`90° — relative to the incident beam.
`The turbidity can then be calculated from the
`intensity of
`the scattered light, provided the
`dimensions of the particle are small compared to
`the wavelength of the light used, by the expression
`16”
`'
`(5.19)
`
`R90» is given by Igrz/1,, known as the Rayleigh
`ratio —- where 1,, is the intensity of the scattered
`and 19 the incident, light; r is the distance from
`the scattering particle to the point of observation.
`By use of the so—called fluctuation theory of stat-
`istical mechanics whereby light
`scattering is
`treated as
`a
`consequence of
`random non-
`unifotmities of concentration, and hence refractive
`index, arising from random molecular movement
`the following relationship between turbidity and
`molecular weight was derived by Debye in 1947:
`
`HC/1: = 1/M + 230
`
`(6.20)
`
`C is the concentration of the solute and B an
`interaction constant allowing for non-ideality. H
`is an optical constant
`for a particular system
`depending on refractive
`index changes with
`concentration and the wavelength of light used.
`A plot of HC/1: against concentration results in a
`straight line of slope 2B. The intercept on the
`HC/'5 axis is 1/M allowing the molecular weight
`to be calculated.
`Light scattering measurements are particularly
`suitable for finding the size of association colloids
`and the number of molecules of surface-active
`agent forming them and for the study of proteins
`and natural and synthetic polymers.
`
`It can be shown that the intensity of the scat-
`tered light is inversely proportional to the wave-
`length it of the light used; so that blue light
`OL == 450 nm) is scattered much more than red
`light (is W 650 nm). With incident white light, a
`scattering material will, therefore, tend to be blue
`when viewed at right angles to the incident beam
`and red when viewed from end on — evident in
`the blue colour of the sky,
`tobacco smoke etc.,
`and the yellowish-red of the rising and setting sun.
`
`Ultrczmicroscape
`
`Colloidal particles are too small to be seen with an
`optical microscope. Light scattering is made use
`of in the ultramicroscope first developed by Zsig-
`mondy, in which a cell containing the colloid is
`viewed against a dark background at right angles
`to an intense beam of incident light. The particles,
`which exhibit Brownian motion, appear as spots
`of light against the dark background. The ultra-
`microscope is used in the technique of microelec-
`trophoresis for measuring particle charge.
`
`Electron microscope
`
`The electron microscope, capable of giving actual
`pictures of the particles,
`is used to observe the
`size, shape and structure of colloidal particles.
`The success of the electron microscope is due to
`its high resolving power, defined in terms of d, the
`smallest distance by which two obiects are separ-
`ated yet remain distinguishable. The smaller the
`wavelength of the radiation used the smaller is d
`and the greater the resolving power. An optical
`microscope, using visible light as its radiation
`source, gives a d of about 0.2 urn. The radiation
`source of the electron microscope is a beam of
`high energy electrons having wavelengths in the
`region of 0.01 nm, a’ is thus about 0.5 nm. The
`electron beams are focused using electromagnets
`and the whole system is under a high vacuum of
`about 10-5 to 1043 mmHg to give the electrons at
`free path. With wavelengths of the order indicated
`the image cannot be viewed direct, so use is made
`of a fluorescent screen.
`One big disadvantage of the electron microscope
`for viewing colloidal particles is that only dried
`
`AstraZeneca Ex. 2104 p. 11
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`
`
`samples can be examined. Consequently it gives
`no information on solvation or configuration in
`solution and the particles may be affected by
`sample preparation.
`
`Electrical properties
`
`Electrical properties of interfaces
`
`Most surfaces acquire a surface electric charge
`when brought
`into contact with an aqueous
`medium, the principal charging mechanisms being
`as follows.
`
`Ion dissolution Ionic substances can acquire a
`surface charge by virtue of unequal dissolution of
`the oppositely charged ions of which they are
`composed, for example, silver iodide in a solution
`with excess [I‘] the particles will carry a negative
`charge, but the charge will be positive if excess
`[Agt] is present. Since the concentrations of Ag’'
`and I“ determine the electric potential at
`the
`particle surface, they are termed potential deter-
`mining ions. In a similar way Ht and OH‘ are
`potential determining ions for metal oxides and
`hydroxides such as magnesium and aluminium
`hydroxides.
`I
`Ionization Here the charge is controlled by the
`ionization of surface groupings, examples include
`the model
`system of polystyrene latex which
`frequently has carboxylic acid groupings at
`the
`surface which ionize to give negatively charged
`particles. In a similar way acidic drugs such as
`ibuprofen and nalidixic acid also acquire a nega-
`tive charge.
`Aminoracids and proteins acquire their charge
`mainly through the ionization of carboxyl and
`amino groups to give —COO” and NH; ions. The
`ionization of these groups and so the net molecular
`charge depends on the pH of the system. At low
`pH the protein will
`be positively
`charged
`—NH2 + NH;
`and at high pH, negatively
`charged, —COOH —-> COO‘. At a certain definite
`pH, specific for each individual protein