Actavis - IPR2017-01100, Ex. 1006, p. 1 of 68
`
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`
`Actavis - IPR2017-01100, Ex. 1006, p. 1 of 68
`
`

`

`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`~:_\'-~'! ~-~_~,t~ ~ '_
`\:;0--:/f i~#-'l -b_ -_,_
`The use of structuralifo"flmUl:;~]r!~"us~and the USP Dictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.) { fl (
`
`; ~ ( '~
`
`NOTICE-This tex,t isen.ofA~t,er;<f;,ed to]epr,~~!ff"[jt, nor shall it be interpreted to be, the equivalent
`of or a subsiit'itte Yhl-t:h~ bfticf'fiH.!ftiterl States Pharmacopeia ( USP) and/or the National
`Formulary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`representations of them herein, the context and effect of the official compendia shall
`prevail.
`
`Printed in the United States of America by the Mack Printing Company, Ea.~ton, Pennsylvania
`
`Actavis - IPR2017-01100, Ex. 1006, p. 2 of 68
`
`

`

`Table of Contents
`
`Port 1
`
`Orientation
`
`1 Scope .....•.....•....•...•.......•. • · · ·. ·
`2 Evolution of Pharmacy •.•..•••••...•.••.....
`3 Ethics .•••.......•••••.....••••••.......•..
`4 The Practice of Community Pharmacy ••.....••.
`5 Opportunities for Pharmacists in the Pharmaceuti-
`cal Industry ..•.........•..........•..••...
`6 Pharmacists in Government .••......•.•......
`7 Drug Information .•..•••.....•.•..........••
`8 Research •......••..••......•.••..........
`
`Port 2
`
`Pharmaceutics
`
`9 Metrology and Calculation ....•••..••........
`10 Statistics ••......•.•••••......•••••........
`11 Computer Science .......•..••........•.....
`12 Calculus ••...•..........•.........•...•...
`13 Molecular Structure, Properties and States of
`Matter .•••.....••••••...•..•.•.•......•.•
`14 Complex Formation ••••.........••......•.•
`15 Thermodynamics ........•..••......••......
`16 Solutions and Phase Equilibria ...........•....
`17
`Ionic Solutions and Electrolytic Equilibria ••......
`18 Reaction Kinetics .•••••••....••.•..•......•.
`19 Disperse Systems .•.•••.......••••.•.....•.•
`20 Rheology ....•••..•.......••.......•..•...
`
`Port~
`
`Pharmaceutical Chemistry
`
`Inorganic Pharmaceutical Chemistry ••......••.
`21
`22 Organic Pharmaceutical Chemistry ...•........
`23 Natural Products •..•.....•••......••.•••...
`24 Drug Nomenclature-United States Adopted
`Names •.•..••..••••••.....•••..•........•
`25 Structure-Activity Relationship and Drug
`Design ...••..••......•••.••......•••.....
`
`Port4
`
`Testing and Analysis
`
`26 Analysis of Medicinals • • . . • . . • . • • . • . . . . . . • • .
`27 Biological Testing
`• . . . . . . • . • • • . . . . . • . • • • . . . .
`28 Clinical Analysis • . . . . . . . • • . . • . . . . . . . . . • . . . .
`29 Chromatography . . . . . . . . • • . . • . . . . . . • . . . . . . .
`30
`Instrumental Methods of Analysis . . . . . . . . . . • . .
`31 Dissolution . • . • . . • • • • • • . . . • • . • • . . . • . . . . . . • •
`
`3
`8
`20
`28
`
`33
`38
`49
`60
`
`69
`104
`138
`145
`
`158
`182
`197
`207
`228
`247
`257
`310
`
`329
`356
`380
`
`412
`
`422
`
`435
`484
`495
`529
`555
`589
`
`Port 5
`
`Radioisotopes in Pharmacy and Medicine
`
`32 Fundamentals of Radioisotopes • . . • . . . • . . . . . . •
`33 Medical Applications of Radioisotopes
`. . . . . . • • •
`
`605
`624
`
`Port 6
`
`Pharmaceutical and Medicinal Agents
`
`34 Diseases: Manifestations and Patho-
`physiology . . . . . • • • • • • . . . . . . . . • • . . • . . . . . • . .
`35 Drug. Absorption, Action and Disposition . . . . . • . •
`36 Basic Pharmacokinetics • • . . . . . . • • • • . • . . . . . . . •
`37 Clinical Pharmacokinetics . . . . . . . . . . . • . . . . . • . .
`38 Topical Drugs . . • . . . . . . . . • . • . . . . . . . . . • . . . . . .
`39 Gastrointestinal Drugs . . . • . . . . . . . . . . . . . . . • . . .
`.. 40 Blood, Fluids, Electrolytes and Hematologic
`Drugs • • • • . . . . . . . • . • • • . . . . . • • • . . . . . . . . . . . •
`41 Cardiovascular Drugs
`. . . . . . . . . . . . • . • . . . . . . • .
`42 Respiratory Drugs
`. . . . . . • . • . . . . . . . . . . . • . . . . .
`43 Sympathomimetic Drugs . . . • . . . . . . . . . . . . . . . . .
`
`655
`697
`725
`7 46
`757
`774
`
`800
`831
`860
`870
`
`889
`
`44 Cholinomimetic Drugs • • . . . . . . . . . • . . • • • . . . . . .
`45 Adrenergic and Adrenergic Neuron Blocking
`898
`. . . . . . . • • . . . . . . . . . •. . . . . . . . . . . . . . . . .
`Drugs
`907
`46 Antimuscarinic and Antispasmodic Drugs • . . • . . .
`·47 Skeletal Muscle Relaxants ...•... , • • • . • . . . . . .
`916
`929
`48 Diuretic Drugs
`. . . . . . • • • . . . . . . . . . . • . • . . . . . . .
`943
`49 Uterine and Antimigraine Drugs
`. • . . . . . . . . . • . .
`948
`50 Hormones . . . . • . . . • . . . . . . . . • • . . . . . . . . . . . . . .
`1002
`51 Vitamins and Other Nutrients • • • • • . • • • . . . . . . . .
`1035
`52 Enzymes
`. . . . . . • . . • . • . . . . . . . . . . . . • • • . . . . . .
`1039
`53 General Anesthetics • . • . . . . . . . . . • . . . • . . . . . . .
`54 Local Anesthetics . . • . . . . . . . • . . • . . . . . . . . . . . . .
`1048
`1057
`55 Sedatives and Hypnotics . . . . • . • . • . . . . . . . . . . . .
`1072
`56 Antiepileptics
`. . . • • . . . . . . . . . • . . . . . . . . . . • . . .
`1082
`57 Psychopharmacologic Agents
`. . . . • • • . • • . . . . . .
`1097
`58 Analgesics and Antipyretics . . . . . . . • . . . . . . . . . .
`1123
`59 Histamine and Antihistamines • . • . . . . . . . • . . . . .
`60 Central Nervous System Stimulants . . . . . . • . • • • •
`1132
`1138
`61 Antineoplastic and Immunosuppressive Drugs . . .
`1163
`62 Antimicrobial Drugs . . . .. .. . . . .. . .. . .. • .. . .. .
`1242
`63 Parositicides . • . . . . . . • . . • • . . . . . . . . • . . • . . . . . .
`1249
`64 Pesticides . . . . . . • . . . . . . . . . . . . . . . . . . . . . . . . . .
`1272
`65 Diagnostic Drugs . • • . . . . . . • • . . . . . . . . . . . . . . . .
`66 Pharmaceutical Necessities
`. . . • • . . . . . . . . . . • • • 1286
`67 Adverse Drug Reactions • . . . . . . . . . • • . • . . . . . . .
`1330
`68 Pharmacogenetics ..••.•••...•.•••••••.......• 1344
`69 Pharmacological Aspects of Drug Abuse . . • . . . . .
`1349
`70
`Introduction of New Drugs
`. . . . . . • . . . . . . . . . . . .
`1365
`
`Port7
`
`Biological Products
`
`71 Principles of Immunology ..•...•..........•..
`72
`Immunizing Agents and Diagnostic Skin
`Antigens ........••..•.....••..............
`73 Allergenic Extracts ..••••.•......••••••......
`74 Biotechnology and Drugs .••.......•.••...•..
`
`1379
`
`1389
`1405
`1416
`
`Porte
`
`Phormoceuticol Preparations and Their
`Manufacture
`
`75 Preformulotlon ........•.•....•.••••••. , ....
`76 Bioavailabllity and Bioequivalency Testing .••..
`77 Separation ..•.••.........••..•......••....
`78 Sterilization .•...••.....•••••..............
`79 Tonicity, Osmoticity, Osmolality and Osmolarity .
`80 Plastic Packaging Materials .•.•.....••.......
`81 Stability of Pharmaceutical Products .......•...
`82 Quality Assurance and Control .............••
`83 Solutions, Emulsions, Suspensions and
`Extractives .••.....••.•••.•....•.••.•......
`84 Parenteral Preparations .•......•.•••.•......
`85
`Intravenous Admixtures ...•.................
`86 Ophthalmic Preparations ...•••........•.....
`87 Medicated Applications ....•..•........•....
`88 Powders •.•••.....•.•.••........•.........
`89 Oral Solid Dosage Forms •••......•..•••......
`90 Coating of Pharmaceutical Dosage Forms ...... .
`91 Sustained-Release Drug Delivery Systems ..... .
`92 Aerosols •..••.......•...•.......••.•......
`
`1435
`1451
`1459
`1470
`1481
`1499
`1504
`1513
`
`1519
`1545
`1570
`1581
`1596
`1615
`1633
`1666
`1676
`1694
`
`Port 9
`
`Pharmaceutical Practice
`
`93 Ambulatory Patient Core
`94
`Institutional Patient Care
`95 Long-Term Care Facilities ..•.................
`96 The Pharmacist and Public Health ............•
`
`1715
`1737
`1758
`1773
`
`XV
`
`Actavis - IPR2017-01100, Ex. 1006, p. 3 of 68
`
`

`

`97 The Patient: Behavioral Determinants ....•....•
`98 Patient Communication ..••....•..•.•..••..•
`99 Drug Education ...••.•..•.•......•..••.....
`100 Patient Compliance
`' •••..•.•..••.•.••.•....•
`101 The Prescription .•.••.••..........•..•......
`102 Drug lnte.roctions •.•••..•••.......•..•.•••• '.
`103 Clinical Drug Literature ...••.......•.••.•••••
`104 Health Accessories •..••••.••.•••.•••.••... •'
`105 Surgical Supplies ...•.••••••.•.••...••••....
`
`1788
`1796
`1803
`1813
`1828
`1842
`1859
`1864
`1895
`
`.Poison Control ...••..............••.....•..
`106
`107 Lows Governing Pharmacy ................. .
`108 Community Pharmacy Economics and
`Management .........••.........•.....•..
`109 Dental Services .••• ·· .....•.....•..........•
`
`1905
`1914
`
`1940
`1957
`
`Index
`
`Alphabetic Index .......•••.....•....... , ••
`
`1967
`
`xvi
`
`Actavis - IPR2017-01100, Ex. 1006, p. 4 of 68
`
`

`

`CHAPTER 19
`
`Disperse Systems
`
`George Zografi, PhD
`Professor
`School of Pharmacy, University of Wisconsin
`Madison. WI 53706
`
`Hans Schott, PhD
`Professor of Pharmaceutics and Colloid Chemistry
`School of Pharmacy, Temple University
`Philadelphia, PA 19140
`
`James Swarbrick, DSc, PhD
`Professor and Chairman
`Division ofPharmace.utics
`School of Pharmacy, University of North Carolina at Chapel Hill
`Chapel Hill, NC 27599-7360
`
`Interfacial Phenomena
`
`Very often it is desirable or necessary in the development
`of pharmaceutical dosage forms to produce multiphasic dis(cid:173)
`persions by mixing together two or more ingredients which
`are not mutually miscible and capable of forming homoge(cid:173)
`neous solutions. Examples of such dispersions include sus(cid:173)
`pensions (solid in liquid), emulsions (liquid in liquid) and
`foams (vapor in liquids). Because these systems are not
`homogeneous and thermodynamically stable, over time they
`will show some tendency to separate on standing to produce
`the minimum possible surface area of contact between
`phases. Thus, suspended particles agglomerate and sedi(cid:173)
`ment, emulsified droplets cream and coalesce and the bub(cid:173)
`bles dispersed in foams collapse, to produce unstable and
`nonuniform dosage forms. In this chapter the fundamental
`physical chemical properties of dispersed systems will be
`discussed¥·along with the principles of interfacial and colloi(cid:173)
`dal physics and chemistry which underly these properties.
`
`Interfacial Forces and Energetics
`
`In the bulk portion of each phase, molecules are attracted
`to each other equally in all directions, such that no resultant
`forces are acting on any one molecule. The strength of these
`forces determines whether a substance exists as a vapor,
`liquid or solid at a particular temperature and pressure.
`At the boundary between phases, however, molecules are
`acted upon unequally since they are in contact withother
`molecules exhibiting different forces of attraction. For ex(cid:173)
`ample, the primary intermolecular forces in water are due to
`hydrogen bonds, whereas those responsible for intermolecu(cid:173)
`lar bonding in hydrocarbon liquids, such as mineral oil, are
`due to London dispersion forces.
`Because of this, molecules situated at the interface con(cid:173)
`tain potential forces of interaction which are not satisfied
`relative to the situation in each bulk phase. In liquid sys(cid:173)
`tems such unbalanced forces can be satisfied by spontaneous
`movement of molecules from the ·interface into the bulk
`phase. This leaves fewer molecules per unit area at the
`interface (greater intermolecular distance) and reduces the
`actual contact area between dissimilar molecules.
`Any attempt to reverse this process by increasing the area
`of contact between phases, ie, bringing more molecules into
`the interface, causes the interface to resist expansion and to
`
`behave as though it is under a tension everywhere in a tan(cid:173)
`gential direction. The force of.this tension per unit length
`of interface generally is called the interfacial tension, except
`when dealing with the air-liquid interface, where the terms
`surface and surface tension are used.
`To illustrate the presence of a tension in the interface,
`consider an experiment where a circular metal frame, with a
`- looped piece of thread loosely tied to it, is dipped into a
`liquid. When removed and exposed to the air, a film of
`liquid will be stretched entirely across the circular frame, as
`when one uses such a frame to blow soap bubbles. Under
`these conditions (Fig 19-1A), the thread will remain col(cid:173)
`lapsed. If now a heated needle is used to puncture and
`remove the liquid film from within the loop (Fig 19-1B), the
`loop will stretch spontaneously into a circular shape.
`The result of this experiment demonstrates the spontane(cid:173)
`ous reduction of interfacial contact between air and the
`liquid remaining and, indeed, that a tension causing the loop
`to remain· extended exists parallel to the interface. The
`circular shape of the loop indicates that the tension in the
`plane of the interface exists at right angles or normal to every
`part of the looped thread. The total force on the entire loop
`divided by the circumference of the circle, therefore, repre(cid:173)
`sents the tension per unit distance of surface, or the surface
`tension.
`Just as work is required to.extend aspring under tension,
`work should be required to reverse the process seen in Figs
`19-1A and B, thus bringing more molecules to the interface.
`This may be seen quantitatively by considering an experi(cid:173)
`ment where tension and work may be measured directly.
`Assume that we have a rectangular wire with one movable
`side (Fig 19-2). Assume further that by dipping this wire
`into a liquid, a film of liquid will form within the frame when
`it is removed and exposed to the air. As seen earlier in Fig
`19-1, since it comes in contact with air, the liquid surface will
`tend to contract with a force, F, as molecules leave the
`surface forthe bulk. To keep the movable side in equilibri(cid:173)
`um, an equal force must be applied to oppose this tension in
`the surface. We then may define the surface tension,/', of
`the liquid as F/21, where 2l is the distance of surface over
`which F is operating (2l since there are two surfaces, top and
`bottom). If the surface is expanded by a very small dis(cid:173)
`tance, ~x, one can then estimate thatthe work done is
`
`Dr Zografi authored the section on Interfacial Phenomena. Dr
`Schott authored the section on Colloidal Dispersions. Dr Swarbrick
`authored the section on Particle Phenomena and Coarse Dispersions.
`
`and therefore
`
`257
`
`W=F~x
`
`W = ,2lt.x
`
`(1)
`
`(2)
`
`Actavis - IPR2017-01100, Ex. 1006, p. 5 of 68
`
`

`

`258
`
`CHAPTER 19
`
`A
`8
`Fig 19-1. A circular wire frame with a loop of thread looselytied to
`(A) a liquid film on the wire frame with a loop in it; (8) the film
`it:
`inside the loop is broken. 1
`
`r
`l '
`
`Fig 19-2. A movable wire frame containing a film of liquid being
`expanded with a force, F.
`
`Since
`
`AA = 2lt:.x
`(3)
`where t:.A is the change in area due, to the expansion of the
`surface, we may conc~ude that
`
`· W =' jtl:.A
`
`(4)
`
`Thus, the work required to create a unit area of surface,
`known as the surface free energy/unit area, is equivalent to
`the surface tension of a liquid system, and the greater the
`area of interfacial contact between phases, the greater the
`free-energy increase for the total system. Since a prime
`requisite for equilibrium is that the free energy of a system
`be at a minimum, it is not surprising to observe that phases
`in contact tend to reduce area of contact spon,taneously.
`Liquids, being mobile, may assume spherical shapes
`(smallest interfacial area for a given volume), as when eject(cid:173)
`ed from an orifice into air or when dispersed into another
`immiscible liquid. If a large number of drops are formed,
`further reduction in area can occur by having the drops
`coalesce, as when a foam collapses or. when the liquid phases
`making up an emulsion separate.
`Surface tension is expressed in units of dynes/em, while
`surface free energy is expressed ifl ergs/cm2. Since an erg is
`a dyne-em, both sets of units are equivalent.
`Values for the surface tension of a variety of liquids are
`given in Table I, while interfacial tension values for various
`liquids against water are given in Table II. Other combina(cid:173)
`tions of immiscible phases could be given but most heteroge(cid:173)
`neous systems.encountered in pharmacy usually contain wa(cid:173)
`ter. Values for these tensions are expressed for a particular
`temperature. Since an increased temperature increases the
`thermal energy of molecules, the work required to bring
`molecules to the interface should be less, and thus the sur(cid:173)
`face and interfacial tension will be reduced. For example,
`the surface tension of water at 0° is 76.5 dynes/em and 63.5
`dynes/em at 75°.
`As would be expected from the discussion so far, the rela(cid:173)
`tive values for surface tension should reflect the nature of
`intermolecular forces present; hence, the relatively large val(cid:173)
`ues for mercury (metallic bonds) and water (hydrogen
`bonds), and the lower values for benzene, chloroform, carbon
`tetrachloride and the n-alkanes. Benzene with 1r electrons
`
`Table 1-Surface Tension of Various Liquids at 20°
`
`Substance
`
`Surface tension,
`dynes/em
`
`Mercury
`Water
`Glycerin
`Oleic acid
`Benzene
`Chloroform
`Carbon tetrachloride
`1-0ctanol
`Hexadecane
`Dodecane
`Decane
`Octane
`Heptane
`Hexane
`Perfluoroheptane
`Nitrogen (at 75°K)
`
`476
`72.8
`63.4
`32.5
`28.9
`27.1
`26.8
`26.5
`27.4
`25.4
`23.9
`21.8
`19.7
`18.0
`11.0
`9.4
`
`Table 11-lnterfacial Tension of Various Liquids against
`Water at 20°
`
`.Substance
`
`Interfacial tension,
`dynes/em
`
`Dec1Ule
`Octane
`Hexane
`Carbon tetrachloride
`Chloroform
`Benzene
`Mercury
`Oleic acid
`1-0ctartol
`
`52.3
`51.7
`50.8
`45.0
`32.8
`35.0
`428
`15.6
`8.51
`
`exhibits a higher surface tension than the alkanes of compa(cid:173)
`rable molecular weight, but increasing the molecular weight
`of. the alkanes (and hence intermolecular attraction) in(cid:173)
`creases their surface tension closer to that of benzene. The
`lower values for the more nonpolar substances, perfluoro(cid:173)
`heptane and liquid nitrogen, demonstrate this point e.-ven
`more strongly.
`Values of interfacial tension should reflect the differences
`in chemical structure of the two phases involved; the greater
`the tendency to interact, the less the interfacial tension.
`The 20-dynes/cm difference between air-water tension and
`that at the octane-water interface reflects the small but
`significant interaction between octane molecules and water
`molecules at the interface. This is seen ~o in Table II, by
`comparing values for octane and octanol, oleic acid and the
`alkanes, or chloroform and carbon tetrachloride.
`In each case the presence of chemical. groups capable of
`hydrogen bonding with water markedly reduces the interfa(cid:173)
`cial tension, presumably by satisfying the un balaiiced forces
`at the interface. These observations strongly suggest that
`molecules at an, interface arrange themselves or orient so as
`to minimize differences between bulk phases.
`That this occurs even at the air-liquid interface is seen
`when one notes the relatively low surface-tension values of
`very different chemical structures such as the n-alkanes,
`octanol, oleic acid, benzene and chloroform .. Presumably, in
`each case, the similar nonpolar groups are oriented toward
`the air with any polar groups oriented away toward the bulk
`phase. This tendency for molecules to orient at an interface
`is a basic factor in interfacial phenomena and will be dis(cid:173)
`cussed more fully in succeeding sections.
`Solid substances such as metals, metal oxides, silicates
`and salts, all containing polar groups exposed at their sur(cid:173)
`face, may be classified as high-energy solids, whereas nonpo-
`
`Actavis - IPR2017-01100, Ex. 1006, p. 6 of 68
`
`

`

`':4' FACE
`
`Fig 19-3. Adipic acid·crystal showing various faces. 2
`
`Table Ill-Values of -y sv for Solids of Varying Polarity
`
`Solid
`
`')' sv (dynes/ em)
`
`Teflon
`Paraffin
`Polyethylene
`Polymethyl methacrylate
`· Nylon
`Indomethacin
`Griseofui~in
`Hydrocortisone
`Sodium Chloride
`Copper
`
`19.0
`25.5
`37.6
`45.4
`50.8
`61.8
`62.2
`68.7
`155
`1300
`
`lar solids such as carbon, sulfur, glyceryl tristearate, polyeth(cid:173)
`ylene and polytetrafluoroethylene ·(Teflon) may be classi(cid:173)
`fied as low-energy solids.· It is of interest to measure the
`surface free energy of solids; however, the lack of mobility of
`molecules at the surface of s'olids prevents the observation
`and direct measurement of a surface tension. It is possible
`to measure the work required to create new solid surface by
`cleaving a crystal and measuring the work involved. How(cid:173)
`ever, this work n'ot only represents free energy dtie tO ex(cid:173)
`posed' groups but also takes into account the mechanical
`energy associated with the crystal (ie, plastic and elastic
`deformation and strain energies due to crystal structure and
`imperfectiOns in that structure).
`A:lso contributing to the complexity of a solid surface is the
`heterogeneous behavior due to the exposure of different
`crystal faces,each having a different surface free energy/unit
`area. For example, adipic acid, HOOC(CH2) 4COOH, crys~
`tallizes from water as thin hexagonal plates with three .dif(cid:173)
`ferent faces, as shown in Fig 19c3. Each unit cell of such a
`crystal' contains' adipic acid molecules oriented such that the
`hexagonal planes (faces) contain exposed carboxyl groups,
`while the sides and edges (A and B faces) represent the side
`view of the carboxyl and.alkyl groups, and thus are quite
`nonpolar.
`Indeed, interactions involving these different
`faces'reflect the differing surface free energies. 2
`Other .complexities associated with solid surfaces include
`surface roughness, porosity and the defects and contamina(cid:173)
`tion produced during a recrystallization or comminution of
`the solid. In view of all these complica.tions, surface free
`energy values for solids, when reported, should be regarded
`as average values, often dependent on the method used and
`not necessarily the same for other samples of the same sub(cid:173)
`stance.
`In Table Ill are listed some approximate average. values of
`'Ysu for a variety of solids, ranging in polarity from Teflon to
`copper, obtained by various indirect techniques.
`
`Adhesional and Cohesional Forces
`
`Of.prime importance to those dealing with heterogeneous
`~stems is the question of how two phases will behave when
`. rought in contact with each other. It is well known, for
`mstance, that some liquids, when placed in contact with
`other liquid or solid surfaces, will remain retracted in the
`form of a drop (known as a lens), while other liquids may
`
`DISPERSE SYSTEMS
`
`259
`
`exhibit a tendency to spread and cover the surface of this
`liquid or solid.
`Based upon concepts developed to this point, it is appar(cid:173)
`ent that the individual phases will exhibit a tendency to
`minimize the area of contact with other phases, thus leading
`to phase separation. On the other hand, the tendency for
`interaction between molecules at the new interface will off(cid:173)
`set this to some extent and give rise to the spontaneous
`spreading of one substance over the other.
`In essence, therefore, phase affinity is increased as the
`forces of attraction between different phases (adhesional
`f()rces) become greater than the forces of attraction between
`molecules of the same phase (cohesional forces). If these
`adhesional .forces become great enough, miscibility will oc(cid:173)
`cur and the interface will disappear. The present discussion
`is concerned only with systems of limited phase affinity,
`.
`whe.re an interface still exists.
`A convenient approach used to express these forces quan(cid:173)
`titatively involves the use of the terms work of adhesion and
`work of cohesion.
`The work of adhesion, Wa, is defined as the energy per cm2
`required to separate .two phases at their boundary and is
`equal.but opposite in sign to the free energy/cm2 released
`In an analogous manner the
`when th.e interface is formed.
`work of cohesion for a pure substance, We, is the work/cm2
`required to produce two new surfaces, as when separating
`different phases, but now both surfaces contain the same
`molecules. This' is equal and opposite in sign to the free
`energy/cm2 released when the same two pure liquid surfaces
`are brought together and eliminated.
`By convention, when the work of adhesion between two
`substances, A and B, exceeds the work of cohesion for one
`substance, eg, B, spo~taneous spreading of B over the sur(cid:173)
`face of A should occur with a net loss of free energy equal to
`the difference between Wa and We. If We exceeds Wa, no
`spontaneous spreading of B over A can occur. The differ(cid:173)
`ence between Wa and We is known as the spreading. coeffi(cid:173)
`cient, S; only when Sis positive will spreading occur.
`The values for Wa and We (and hence S) may be expressed
`in terms of surface and interfacial tensions, when one con(cid:173)
`siders that upon separation of two phases, A and B, 'Y AB ergs
`of interfacial free energy/cm2 (interfacial tension) are lost,
`but that 'Y A and-yB ergs/cm2 of energy (surface tensions of A
`and B) are gained; upon separation of bulk phase molecules
`in an analogous manner, 2')' A or 2'YB ergs/cm2 will be gained.
`Thus
`
`and
`
`We= 2')' A or 2'YB
`ForB spreading on the surface of A, therefore
`SB = 'Y A+ 'YB- 'Y AB- 2'YB
`
`or
`
`(5)
`
`(6)
`
`(7)
`
`(8)
`
`Utilizing Eq 8 and values of surface and interfacial tension
`given in Tables I and II, S can be calculated for three 'repre(cid:173)
`sentative substances:._decane, benzene, and oleic acid-on
`·water at 20°.
`
`S = 72.8- (23.9 + 52.3)
`Decane:
`Benzene: S = 72.8- (2~1.9 + 35.0)
`(32.5 + 15.6)
`Oleic acid: S = 72.8 -
`As expected, relatively nonpolar substances such as decane
`exhibit negative values of S, whereas the more polar materi(cid:173)
`als yield positive values; the greater the polarity of the mole-
`
`= -3.4
`8.9
`
`24.7
`
`Actavis - IPR2017-01100, Ex. 1006, p. 7 of 68
`
`

`

`260
`
`CHAPTER 19
`
`cule, the more positive the value of S. The importance of
`the cohesive energy of the spreading liquid may be noted
`also by comparing the spreading coefficients for hexane on
`water and water on hexane:
`Sww = 72.8- (18.0 + 50.8) ,=
`4.0
`S W/H = 18.0- (72.8 + 50.8) = -105.6
`
`Here, despite the fact that both liquids are the same, the
`high cohesion and air-liquid tension of wate.r prevents
`spreading on the low-energy hexane surface, while the very
`low value for hexane allows spreading on the water surface.
`This also is seen when comparing the positive spreading
`coefficient of hexane to the negative value for decane on
`water.
`To see whether spreading does or does not occur, a powder
`such as talc or charcoal can be sprinkled over the surface of
`water such that it floats; then, a drop of each liquid is placed
`on this surface. As predicted, decane will remain as an
`intact drop, while hexane, benzene and oleic acid will spread
`out, as shown by the rapid movement of solid particles away
`from the point where the liquid drop was placed originally.
`An apparent contradiction to these observations may be
`noted for hexane, benzene and oleic acid when more of each
`substance is added, in that lenses now appear to form even
`though initial spreading occurred. Thus, in effect a sub(cid:173)
`stance does not appear to spread over itself.
`It is now established that the spreading substance forms a
`monomolecular film which creates a new surface having a
`lower surface free energy than pure water. This arises be(cid:173)
`cause of the apparent orientation of the molecules in such a
`film so that their most hydrophobic portion is oriented to(cid:173)
`wards the spreading phase. It is the lack of affinity between
`this exposed portion of the spread molecules and the polar
`portion of the remaining molecules which prevents further
`spreading.
`·
`This may be seen by calculating a final spreading coeffi(cid:173)
`cient where the new surface tension of water plus monomo(cid:173)
`lecular film is used. For example, the presence of benzene
`reduces the surface tension of water to 62.2 dynes/ em so that
`the final spreading coefficient, Sp, is
`
`SF= 62.2- (28.9 + 35.0) = -1.7
`The ·lack of spreading exhibited by oleic acid should be
`reflected in an even more negative final spreading coeffi(cid:173)
`cient since the very polar carboxyl groups should have very
`little' affinity for the exposed alkyl chain of the oleic acid
`film. Spreading so as to form a second layer with polar
`groups exposed to the air would also seem very unlikely, thus
`leading to the formation of a lens. +
`
`Wetting Phenomena
`
`In the experiment described above it was shown that talc
`or charcoal sprinkled onto the surface of water float despite
`the fact that their densities are much greater than that of
`In order for immersion ofthe solid to occur, the
`water.
`liquid must displace air and spread over the surface of the
`solid; when liquids cannot spread over a solid surface spon(cid:173)
`taneously, and, therefore, S, the spreading coefficient, is
`negative, we say that the solid is not wetted.
`An important parameter which reflects the degree of wet(cid:173)
`ting is the angle which the liquid makes with the solid sur(cid:173)
`face at the point of contact (Fig 19-4). By convention, when
`wetting is complete, the contact angle is zero; in nonwetting
`situations it theoretically can increase to a value of 180°,
`where a spherical droplet makes contact with solid at only
`one point.
`
`VAPOR
`
`~>Lv
`\
`\
`
`rsv
`
`Fig 19-4. Forces acting on a nonwetting liquid drop exhibiting a
`contact angle of ().3
`
`In order to express contact angle in terms of solid-liquid(cid:173)
`air equilibria, one can balance forces parallel to the solid
`surface at the point of contact between allthreephases (Fig
`19-4), as expressed in
`lsv = lsL + ILvcos fJ
`(9)
`where rsv, ISL, and 'YLV represent the surface free ener(cid:173)
`gy/unit area of the solid-air, solid-liquid, and liquid-air
`interfaces, respectively. Although difficult to use quantita(cid:173)
`tively because of uncertainties with rsvand ISL measure(cid:173)
`ments, conceptually the equation, known as the Young
`equation, is useful because it shows that the loss of free
`energy due to elimination of the air-solid interface by wet(cid:173)
`ting is offset by the increased solid-liquid and liquid-air
`area of contact as thedrop spreadsout.
`. The 1 L v cos fJ term arises as the horizontal vectorial com(cid:173)
`ponent of the force acting along the surface ()f the drop,, as
`represented by 'YLV· Factors tending to reduce !LV and ISL,
`therefore; will favor wetting, while the greater the vaLue of
`'Ysv the greater the chance for wetting to occl.lr. Thisis s~en
`in Table IV for the wetting of a low-energy surface, paraffin
`(hydrocarbon), and a higher energy surface, nylon; (polyhex(cid:173)
`amethylene adipamide). Here, the lower the surface ten(cid:173)
`sion of a liquid, the smaller the contact angle on a given solid,
`and the more polarthe solid, the s.maller the contact angle
`with the same liquid.
`With Eq 9 in mind and looking at Fig 19-5, it is now
`possible to understand how the forces acting at the solid-
`
`Table IV-Contact Angle on Paraffin and Nylon for Various
`· Liquids of Differing Surface Tension
`
`Substance
`
`Surface tension,
`dynes/em
`
`<:;ontact angle
`Paraffin
`Nylon
`
`·Water
`Glycerin
`Fori:namide
`Methylene iodide
`a-Bromonaphthalene
`tert-Butylnaphthalene
`Benzene
`Dodecane
`De cane
`Nonane
`
`72.8
`63.4
`58.2
`50.8
`44.6
`33:7
`28.9
`25.4
`23.9
`22.9
`
`70°
`60°
`50°
`41°
`16°
`·spreads
`"
`
`105°
`'96°
`91°
`66°
`47°
`38°
`240
`170
`70
`spreads
`
`Ysv
`
`VAPOR
`
`LIQUID
`Fig 19-5. Forces acting on a nonwettable solid at the air+liquid+so(cid:173)
`lid interface: contact angle fJ greater than 90°.
`
`Ysc
`
`Actavis - IPR2017-01100, Ex. 1006, p. 8 of 68
`
`

`

`Table V-Critical Surface. Tensions of Various P