18TH
`
`EDITION
`
`Remington's
`
`. .
`
`.
`
`.' i :
`
`ALFONSO R GENNARO
`. .
`.-......
`Editor, and Chairman
`of the Editorial Board
`
`DRL - EXHIBIT 1015
`DRL001
`
`

`
`-Pharmaceutical
`
`Sciences
`
`1990
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`DRL - EXHIBIT 1015
`DRL002
`
`

`
`Remington Historical I Diographical Data
`
`The followlng Is o record of the edlrors ond rhe doles of publlcollon of successive edllons of lhls book. prior to the 13rh
`Edition known os Remington's Procllce of Pharmacy ond subsequently os Remington's Phormaceullcal Sciences.
`
`First Edition, 1886
`Second Ed!tloi;i, 1889
`Third Edition. 1897
`Fourth Edition, 1905
`
`Fifth Edition, 1907
`Si xth Edition, 19 17
`
`Seventh Editi on, 1926
`
`Editors
`E Fullerton Cook
`Charles H LoWoll
`
`Eighth Edition, 19:16
`
`Editors
`E Fullerlon Cook
`Charles H Lo Woll
`
`Ninth Edition, 1948
`
`Tenth Edition, 1951
`
`Eleventh Edition, 1956
`
`Ed/tots
`Eric W Morrin
`E Fullerton Cook
`
`Twelfth Edi tion, 1961
`
`Editors
`Eric W Morfin
`E Fullerron Cook
`E Emerson Leuollen
`Arthur Osol
`Linwood F Tice
`Clarence T Von Meter
`
`Joseph P Remington
`
`Thirteenth Edition. 1965
`
`. Joseph P Remington
`Assisted by
`E Fullerton Cook
`
`Associate Editors
`Ivor Griffith
`Adley 0 Nichols
`Arthur Osol
`
`Editors
`E Fullerton Cook
`Eric W Mortin
`
`Editors
`E Fullerton Cook
`ErlcW Morfin
`
`Associate Edltots
`E Emerson Leuollen
`Arthur Osol
`Linwood F Tlce
`Clarence T Von Meter
`
`Assistant ro the Editors
`John E Hoover
`
`Editor-In.Chief
`Eric W Mortin
`Editors
`Grafton D Chose
`Herald R Cox
`Richard A Deno
`Alfonso R Gennaro
`Stewart C Harvey
`
`Fourte&nth Edition, 1970
`
`Chairman, Edltot/ol Boord
`Arthur Osol
`Edftors
`Grafton D Chose
`Richard A Deno
`Alfonso R Gennaro
`Melvin R Gibson
`Stewart C Harvey
`
`Fifteenth Edition, 1975
`
`Chairman. Editorial Boord
`Arrhur Osol
`Editors
`John T Anderson
`Cecil L Dendush
`Grohon D Chose
`Alfonso R Gennaro
`Melvln R Gibson
`
`Slxfe&nth Edition, 1980
`
`Chairman, Editor/of Boord
`Arthur Osol
`Editors
`Grofron D Chose
`Alfonso R Gennaro
`Melvin P. Gibson
`C Ooyd Gronberg
`Stewart C Harvey
`
`Seventeenth Editi on, 1985
`
`Chaltman. Editor/of Boatd
`Alfonso R Gennaro
`Editors
`Groflon D Chose
`Aro Der Morderoslon
`Stewart Harvey
`Doniel A Hussor
`Thomas Medwick
`
`Managing Editor
`John E Hoover
`
`Robert E King
`E Emerson Leuollen
`Arthur Osol
`Ewort A Swinyord
`Clarence T Von Meter
`
`Managing Editor
`John E Hoover
`
`Robert E King
`Alfred N Morfin
`Ewort A Swlnyord
`Clarence T Von Meter
`Bernard Willln
`
`Managing Editor
`John E Hoover
`
`C Ooyd Gro'nberg
`Stewart C Horv,ey
`Roberl E King
`Alfred N Mortin
`Ewort A Swlnyord
`
`~oberl E King
`Alfred N Morfin
`Ewart A Swlnyord
`Giibert L Zink
`
`Edword G Ripple
`Joseph D Schworlz
`Ewart A Swlnyord
`Gilbert L Zink
`
`viii
`
`DRL - EXHIBIT 1015
`DRL003
`
`

`
`Tobie of Cont•nts
`
`Part 1
`
`Orientation
`
`1 Scope •••••••••.••••••••••..••.•••.•••••••
`2 Evolullon of Phormocy .•••••••••..••••••••••
`3 ElhlC$ •••••••••••••••••••• • •••••••••••.••.
`4 The Procllce of Communlly Pharmacy ••••••••••
`5 Opporlunltles for Pharmacists In lhe Phormoceull-
`col lndusrry •••••.•••••••••••••. .• .•••.••••
`6 Phormoclsls In Governmenl .••.••••••••••••••
`7 Drug lnformo1lon ••••••••••••••••••••.••••.•
`8 Research .••••••• . •••••• •••. •••••• •• ••••••
`
`Part 2
`
`Pharmaceutics
`
`9 Me1rology and Colculollon • • . ••••••••••••••••
`10 S101Js1Jcs •••••••••••••••••••••••••• . •••••••
`11 Compu1er Science ••••••••..•.••••• • ••••••••
`12 Calculus ••••••.••••••••••••••••••••..•.••.
`13 Molecular Slructure. Properties and States of
`Motter ' •..••••••..•.•..•••••••••••••••.•••
`14 Complex Formollon •••••••••..•••••••••••.•
`15 Thermodynamics •• . ••••.• .•.• •••..•••••••••
`16 Solutions and Phase Equlllbrlo • ••••• • • . ••.••..
`17
`Ionic Solutions and Elecrrolytlc Equlllbrlo ••••••••
`18 Reodlon Kinetics • .• •.••••••.•••••••••••••••
`19 Disperse Systems ••••••••••••••••••••••••• .•
`20 Rheology •••••• •. ••••••. . • . • •••••.•• ••••••
`
`Part 3
`
`Pharmaceutical Chemistry
`
`21
`lnorgonlc Pharmaceutical Chemistry •• •.• •••• .•
`22 Organic Phormoceutlcol Chemistry ••• • ••••••••
`23 Natural Products •••••••••••••••••••••••••••
`24 Drug Nomencloture-Uniled Stoles Adopled
`Names ••••••••• . ••••••• . •••••••••••••••••
`25 Slructure-Actlvlty Relollonshlp and Drug
`Design ••••.••.•..••••.•••.•••••••.••.•..•
`
`Part 4
`
`Testing and Analysis
`
`26 Analysis of Medicinals • • • • • • • • • • • • • • • • • • • • • •
`27 Dlologlcol Testing
`. • • • • • • • • • • • • • • • • . . • . . • . • .
`28 Cllnlcol Anolysls • . . • • • • • • . • . • • • • . • • • • • • • • • •
`29 Chromorogrophy . . . . . • • • • • • . • • • • • • • • • • • • • • •
`30
`lnsrrumenral Me1hods of Analysis • • • . . . • • • • . • .
`31 Dlssolu1Ion • • • • • • . • • • • • . • . • . • • • • • • • • • • • • • • •
`
`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
`
`Part 5
`
`Radioisotopes In Pharmacy and Medicine
`
`32 Fundomenlols of Radioisotopes • • • • • • • • • • • • • • •
`33 Medical Applications of Rodlolsolopes • • • • . • • . .
`
`605
`624
`
`Part 6
`
`Pharmaceutical and Medicinal Agents
`
`34 Diseases: Monlfestollons and Polho.
`physiology • • • • • • • • • . • • • . • • • • • • . • • • • • • • • • • .
`35 Drug Absorption, Action and Disposition • • • • • • • •
`36 Dasie Phormocoklnetlcs • • • • • • • • • • • • • • • • • • • • • .
`37 Cllnlcol Phormocoklnetlcs • • • • • • • . . • • . • • • • • • . .
`38 Topical Drugs • • • • • • . . • • . . • . • • • • • • . • • • • • . . . •
`39 Gostrolnlestlnol Drugs • • • • . • • • • • • • • • • • • • • • • • •
`40 Dlood, Fluids, Electrolytes and Hemo1ologlc
`Drugs • • • • • • • • • • • • • • • • • • • • . . • • • • • . . • • • • . . •
`41 Cordlovosculor Drugs ••••••••.••.•••••••• : . •
`42 Resplrotory Drugs • • • . • . . • • . • • • • • • • • • • • . • • • •
`43 Sympothomlmetlc Drugs • • • • • • • • • • • • • . • • . • • • •
`
`655
`697
`725
`746
`757
`774
`
`800
`831
`860
`870
`
`889
`
`44 Chollnomlmellc Drugs ••• . ••.•••• .. • . ••..• : • •
`45 Adrenerglc ond Adrenergic Neuron Dlocklng
`Drugs ••••••••••••• . ••••• ·" •••••••••..•••• · 898
`46 Anllmuscorlnlc and Antispasmodic Drugs • • . • . . .
`907
`47 Skelelol Muscle Reloxonts • • • • • • • • • • • • • • • • • • •
`916
`48 Diuretic Drugs
`• . • • • • • • • • • • • • • • • • • • • • • • • • • . •
`929
`49 Uterine and Antlmlgrolne Drugs
`943
`. • • • • • • . • • • • • •
`50 Hormones • . . • . • • . • • • • • • • • • • • • • • • • • • • • • • • • .
`948
`51 Vitamins and Olher Nutrients • • • • • • • • • • • • • • • • • 1002
`52 Enzymes • • • • . . • . • • • • • • • • • • • • • • • • • • • • • • • • • 1035
`53 General Aneslhetlcs • • • • • • • • • • • • • . • . • . • . • . • • 1039
`54 Loco! AnestheliC$ • . • • . • • • • • . • • • . . • • • • • • • • • • • 1048
`55 Sedotlves ond Hypnollcs • • • • • • • • • • • • • • . . • • • . . 1057
`56 Antlepllepllcs • • • . • • • • • . • • . • • • • • • • • • • • • • • • • 1072
`57 Psychophormocologlc Agenu • • • • • • • • • • • • . . • • 1082
`58 Analgesics and Antlpyretics • • . • • . . . . • • • • • • • • • 1097
`59 Hlslomlne ond Antlhlstomlnes • • • • • • • • • • • • . • • • 1123
`60 Central Nervous System Stimulants • • . • • • • • • • • • 1132
`61 Antlneoplostlc ond lmmunosuppresslve Drugs • • . 1138
`62 Antimicrobial Drugs • • • • • • • • • • • • • • • . • . • • • • . . • 1163
`63 Porosltlcldes • • • • • • • • • • • • • • • • • • • • • . • • • • • • • • • 1242
`64 Pesticides . • . . • • • • • • . • • • • • • • • • . • • • • • • • • • • • • 1249
`65 Diagnostic Drugs • • • • • • • • • • • • • • • . • • • • . . . . • • • 1272
`66 Phormoceutlcol Necessities • • • • • • • • • • • • • • • • • • 1286
`67 Adverse Drug Reocllons • • • • • • • • • • • • . • • • • • • . .
`1330
`68 Phormocogenetlcs •••••• .• •.••..•••••••••••••• 1344
`69 Phormocologkol Aspects of Drug Abuse • • • • • • • • 1349
`70
`Introduction of New Drugs • • • • • • • • • • • • . . • • . • • 1365
`
`Part 7
`
`Dlological Products
`
`71 Principles of Immunology ••••••••••••••••••••
`72
`Immunizing Agents and Diagnostic Skin
`Antigens ••••••••••••••••••••. .•. ••••••••••
`73 Allergenic Extrocts •••. . . . ••••.••••••••••••••
`74 Dlotechnology ond Drugs •••••••••....••.•.••
`
`1379
`
`1389
`1405
`1416
`
`Port 8
`
`Pharmaceutical Preparations and Th~lr
`Manufocture
`'·
`
`75 Preformulotlon •••••••••••••••••••••••••••••
`76 Dloovolloblll1y ond Dloequivolency Tesllng .•...
`77 Seporotlon ••••••••••• ..• ••. ..••• ••••••••••
`78 Slerillzotlon •••.•••••••••••••••••••••••• .• •
`79 Tonlclty, Osmotlclty, Osmolollry ond Osmolorily •
`80 Plostlc Pockoglng Moterlols •••.••••••••••••••
`81 Stoblllty of Phormoceu1Jcol Products ••..•.• ....
`82 Quality Assuronce ond Control •••••••••.•••••
`83 Solullon{. Emulsions, Suspensions ond
`Extrocrlves •••••••••••••••..•.• . • .• .• . •••••
`84 Porenterol Preporotlons .. ••••••••••••••• ••••
`85
`lntrovenous Admixtures •••••••••••••••••....
`86 Ophtholmlc Preporotlons •••••.•• . •••••.•••••
`87 Medico1.ed Appllcotlons . ••••• • ••.•••••••••• .
`88 Powders •••. . ••••••••••••••••••• . ••• ... •••
`89 Orol Solld Dosoge Forms •.••.•••.••• •••••••••
`90 Cooling of Ph~rmoceutlcol Dosage Forms •••••.•
`91 Sustolned.Releose Drug Dellvery Systems .• ••••
`92 Aerosols •••••.••..•••.•• . •• . •.•••••••••.••
`
`1435
`1451
`1459
`1470
`1401
`1499
`1504
`1513
`
`1519
`1545 .
`1570
`1581
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`93 Ambulotory Patient Core ••••••• . • .. .. . • .• •••
`94 Jnstitullonol Potlent Core •..•.•.••••••••••••.
`95
`long.Term Core Focllltles .• •••••• • •••••••••.•
`96 The Phormoclst ond Public Heolth • .. •• .•••• •••
`
`1715
`1737
`1758
`1773
`
`xv
`
`DRL - EXHIBIT 1015
`DRL004
`
`

`
`97 The Patient: Dehavloral Determinants .•••• -. ••• .
`98 Patient Communlcarlon •••••••••••••.•••••••
`99 Drug Education •.•• . •••. . ••••...•..•..•••••
`100 Patient Compliance ••••••••••••••••••••••••
`101 The Prescription •••••••.••••••.•••••••.•••••
`102 Drug Interactions • .•. ••.•.... ' •••.•• . ••••.•.
`10::1 Cllnlcal Drug Li terature •••••.••••••••••••••••
`104 Health Accessories •••••••••••••••••.•••••••
`105 Surgical Supplies • ••.• •••• •••••• • .• . . •••••••
`
`1768
`1796
`1803
`1813
`1828
`1842
`1859
`1864
`1895
`
`106
`107
`106
`
`109
`
`Poison Control ••••••.••••••••••••••••.• .. ..
`Laws Governing Pharmacy ••••••••.•••••••••
`Community Pharmacy Economics and
`Management •.••••••••••••••••••••.••••.•
`Dental Services ••••••••.•••••••••.•••.....•
`
`1905
`1914
`
`1940
`1957
`
`Alphabetlc Index
`
`Index
`··························
`.. ·.
`
`'•
`
`1967
`
`..
`
`'.
`
`. ~.
`
`.,
`
`"'
`
`xvi
`
`DRL - EXHIBIT 1015
`DRL005
`
`

`
`296
`
`CHAPTER 19
`
`Some of the major differences between suspensions of floc(cid:173)
`culated and deflocc11l11ted particles are presented in Table
`xv.
`Effect of Flocculation- In a deflocculated system con(cid:173)
`taining a distribution of particle sizes, the larger particles
`naturally settle faster than the smaller particles. The very
`small particles remain suspended for a considerable length
`of time, with the result that no distinct boundary is formed
`between the supernatant and the sediment. Even when a
`sediment becomes discernible, the supernatant remains
`cloudy.
`When the same system is flocculated (in a manner to be
`discussed later), two effects are immediately apparent.
`First, the floes tend to fall together so that a distinct bound(cid:173)
`ary between the sediment and the supernatant is readily
`observed; second, the supernatant is clear, showing that the
`very fine particles have been incorporated into the floes.
`The initial rat.e of settling in flocculated systems is deter(cid:173)
`mined by the size of the floes and the porosity of the aggre(cid:173)
`gated mass. Under these circumstances it is perhaps better
`to use the term subsidence, rather than sedimentation.
`
`Quantitative Expressions of Sedimentation and
`Flocculation
`
`(36)
`
`Frequently, the pharmacist needs to assess a formulation
`in terms of the amount of flocculation in the suspension and
`to compare this with that found in o~her formulations. The
`two parameters commonly used for this purpose are outlined
`below.
`Sedimentation Volume-The sedimentation volume, F,
`is the ratio of the equilibrium volume of the s~diment, Vu, to
`. the total volume of the suspension, Vo. Thus,
`F = VJV0
`As the volume of suspension which appears occupied by the
`sediment increases, the value of F, which normally ranges
`from nearly 0 to l, increases. In the system whereF = 0.75,
`for example, 75% of the total volume in the container is
`apparently occupied by the loose, porous floes forming the
`sediment. This is illustrated in Fig 19-33. When F = 1, no
`sediment is apparent even though the system is flocculated.
`This is the ideal suspension for, under these conditions, no
`sedimentation will occur. Caking also will be absent. Fur(cid:173)
`thermore, the suspension is esthetically pleasing, there being
`no visible, clear supernatant.
`Degree of .Floccul ation- A better parameter for com(cid:173)
`paring flocculated systems is the degree Qf flocculatiori, (3,
`which r elates the sedimentation volume of the flocculated
`suspension, F, to the sedimentation volume of the suspen(cid:173)
`sion when deflocculated, F • . It is expressed as
`(3 == FIF.
`The degree of flocculation is, therefore, an expression of
`the increased sediment volume resulting from flocculation.
`
`(37)
`
`Floccu lated
`Deflocculated
`Fig 19-33. Sedimentation parameters of suspensions. Defloccu(cid:173)
`lated suspension: F. = 0.15. Flocculated suspension: F= 0.75: (3
`= 5.0.
`
`If, for exinnple, f3 has a value of 5.0 (Fig 19-33), this means
`that the volume of sediment in the flocculated system is five
`times that in the deflocculated state. If a second flocculated
`formulation results in a value for {J of say 6.5, this latter
`suspension obviously is preferred, if the aim is to produce as
`flocculated a product as possible. As the degree of floccula(cid:173)
`tion 'in the system decreases, {J approaches unity, the theo(cid:173)
`retical minimum value.
`
`Suspensions and their Form~lation
`
`A pharmaceutical suspension may be defined as a coarse
`dispersion containing finely divided insoluble material sus(cid:173)
`pended in a liquid medium. Suspension dosage forms arc
`given by the oral route, injected intramusculary or subcuta(cid:173)
`neously, applied to the skin in topical preparations, and used
`ophthalmically in the eye. ·They are an important; class of
`dosage form. Since some products are occasionally pre(cid:173)
`pared in a dry form, to be placed in suspension at the time of
`dispensing by the addition of an appropriate vehicle, this
`definition is extended to irwlude these products.
`There ar~ certain criteria that a well-formulated suspen(cid:173)
`sion 11bould mee~ The dispersed particles should be of such
`a size that they do not settle rapidly in the container. How(cid:173)
`ever, in the event that sedimentation occurs, the sediment
`must not form a hard cake. Rather, it must be capable of
`redispei:sion with a minimum effort on the part of the pa(cid:173)
`tient. Additionally, the product should be easy to · pour,
`pleasant to take, and resistant to microbial attack.
`The three major problem areas associated with suspen(cid:173)
`sions are (1) adequate dispersion of the particles in the
`vehic!e, (2) settling of the dispersed particles, and (3) caking
`of these particles in the sediment so as to resistredispersion.
`Much of the following discussion will deal with the factors
`that influence these processes and the ways in which they
`can be minimized.
`The formulation of a suspensio1i possessing optimal phys(cid:173)
`ical stability depends on whether the particles in suspension
`are to be flocculated or to remain deflocculated. One ap(cid:173)
`proach involves use of a structured vehicle to keep defloccu(cid:173)
`lated particles in suspension; a second depends on controlled
`flocculation as a means of preventing cake formation. A
`
`Particles
`
`Adtlil.ion oC wol..\.hi~ anon\. anti di•poraion nw<lium
`
`/\ I
`
`lncor1>0ralion of
`strucLur'od veh,clo
`
`B
`I
`AclcliLion of
`flocculoLinJ{ ngcnl
`
`Ploccul&ted
`suspension
`as fin&l product
`
`c
`I
`A•ldil ion 0£
`f1n('culnLing os:cnL
`
`Dcftoccutated
`1uspen1ion
`in structuryd vehicle
`as final product ·
`
`lncorvorn.Lion of
`structured vehicle
`
`I
`
`Flocculated
`au spcnsion
`in structur ed vehicle
`a.a final p roduct
`
`Fig 19-34. Alternative approaches to the formulation of suspen(cid:173)
`slO!)S.
`
`DRL - EXHIBIT 1015
`DRL006
`
`

`
`third, a combination of the two previous methods, results in
`a product with optimum stability. The various schemes are
`illustrated in Fig 19-34.
`Dispersion of P a rticles-The dispersion step has been
`discussed earlier in this chapter. Surface-active agents
`conimonly are used as wetting agents; maximum efficiericy is
`obtained when the HLB value lies within the range of 7 to 9.
`A concentrated solution of the wetting agent in the vehicle
`may be used to prepare a slurry of the powder; this is diluted
`with the required amount of vehicle. Alcohol and glycerin
`may be used sometimes in the initial stages to disperse the
`particles, thereby allowing the vehicle to penetrate the pow(cid:173)
`der mass.
`Only the minimum amount of wetting agent should be
`used, compatible with producing an adequate dispersion of ·
`the particles. Excessive amounts maY. lead to foaming or
`impart an undesirable taste or odor to the product. Invari(cid:173)
`ably, as a result of wetting, the dispersed particles in the
`vehicle are deflocculated.
`Structured Vehicles-Structured vehicles are generally
`aqueous solutions of polymeric materials, such as the hydro(cid:173)
`colloids, which are usually negatively charged in aqueous
`solution. Typical examples are methylcellulose, carboxy(cid:173)
`methylcellulose, bentonite, and Carbopol. The concentra(cid:173)
`tion employed will depend on the consistency desired for the
`suspension which, in turn, will relate to the size and density
`of the suspended particles. They function as viscosity-im(cid:173)
`parting suspending agents and, as such, reduce the rate of
`sedimentation of dispersed particles.
`The rheological properties of suspending agents are con(cid:173)
`sidered elsewhere (Chapter 20). Ideally, these form pseudo(cid:173)
`plastic or plastic systems which undergo shear-thinning.
`Some degree of thixotropy is also desirable. Non-Newtoni,
`an materials of this type are preferred over Newtonian sys(cid:173)
`tems because, if the particles eventually settle to the bottom
`of the container, their redispersion is facilitated by the vehi(cid:173)
`cle thinning when shaken. When the shaking is discontin(cid:173)
`ued, the vehicle regains its original consistency and the re(cid:173)
`dispersed particles are held suspeuded. This process of
`redispersion, facilitated by a shear-thinning vehicle, presup(cid:173)
`poses that the deflocculated particles have not yet formed a
`cake. If sedimentation and packing have proceeded to the
`point where considerable caking has occurred, redispersion
`is virtually impossible.
`Controlled Flocculation- When using this approach
`(see Fig 19-34, Band C), the formulator takes the defloccu(cid:173)
`lated, wetted dispersion of particles and attempts to bi·ing
`about flocculation by the addition of a flocculating agent; .
`most commonly, these are either electrolytes, polymers, or
`surfactants. The aim is to control flocculation by adding
`that amount of flocculating agent which results in the maxi(cid:173)
`mum sedimentation volume.
`Electrolytes are probably the most widely used flocculat(cid:173)
`ing agents. They act by reducing the electrical forces of
`repulsion between particles, thereby allowing the particles
`to form the loose floes so characteristic of a flocculated
`suspension. Since the ability of particles to come together
`and form a floe depends on their surface charge, zeta ·poten(cid:173)
`tial measurements on the suspension, as an electrolyte ·is
`added, provide valuable information as to the extent of floc(cid:173)
`culation in the system.
`This principle is illustrated by reference to the following
`example, taken from the work of Haines and Martin.50 Par(cid:173)
`ticles of sulfamerazine in water bear a negative charge. The
`serial addition of a suitable electrolyte, such as aluminum
`chloride, causes a progressive reduction in the zeta potential
`of the particles. This is due to the preferential adsorption of
`the trivalent aluminum cation. Eventually, the zeta poten(cid:173)
`tial will reach zero and then become positive as the addition
`of AIC13 is continued.
`
`DISPERSE SYSTEMS
`
`297
`
`Coking
`
`I No c~ktng I Cokins;
`
`e
`
`___ _... __ ,..
`
`Cationic flocculatong
`agent
`Fig 19-35. ' Typical relationship between caking, zeta 'potential and
`sedimentation v'olume, as a positively charged flocculating agent Is
`added to a suspension of negatively charged particles. e: zeta
`potential; • : sedimentali(!n volume.
`
`If sedimentation studies are run simultaneously on sus(cid:173)
`pensions containing the same range of AIC13 concentrations,
`a relationship is observed (Fig 19-35) between the sedimen(cid:173)
`tation volume, F, the presence or absence of caking, and the
`zeta potential of the particles. In order to obtain a flocculat(cid:173)
`ed, noncaking suspension with the maximum sedimentation
`volume, the.zeta potential must be controlled so as to lie
`within a certain range (generally less than 25 mV). This is
`achieved by the judicious use of an electrolyte.
`A comparable situation is observed when a negative ion
`such as P043- is added to a suspension of positively-charged
`particles such as bismuth subnitrate. Ionic and nonionic
`surfactants and lyophilic polymers also have been used to
`flocculate particles in suspension. Polymers, which act by
`forming a "bridge" between particles, may be the most effi(cid:173)
`cient additives for inducing flocculation. Thus, it has been
`shown that the sedimentation volume is higher in suspen(cid:173)
`sions flocculated with"an anionic heteropolysaccharide than
`when electrolytes were used.
`Work by Matthews and Rhodcs,51-53 involving both ex(cid:173)
`perimental and theoret.ical 11tmliAR, hll!I confirmed the for(cid:173)
`mulation principles proposed by Martin and Haines. ··The
`suspensions used by Matthews and Rhodes contained 2.5%
`w/v of griseofulvin as a fine powder together with the anionic
`surfactant sodium dioxyethylated dodecyl sulfate c10-3 mo(cid:173)
`lar) as a wetting agent. Increasing concentrations of alumi(cid:173)
`num chloride were added and the sedimentation height
`(equivalent to the sedimentation volume, see page 295) and
`the zeta potential recorded. Flocculation occurred when a
`concentration ofl0-3 molar aluminum chloride was reached.
`At this point the zeta·potential had fallen from -46.4 m V to
`-17.0 mV. Further reduction of the zeta potential, to -4.5
`m V by use of io-2 molar aluminum chloride did not iii.crease
`sedimentation ··height, in agreement with the principles
`shown in Fig 19-35.
`Matthews and Rhodes then went on to show, by computer
`analysis, that the DL VO theory (see page 285) predicted the
`results obtained, namely, that the griseofulvin suspensions
`under investigation would remain deflocculated when the
`concentration of aluminum chloride was 10-• molar or less.
`Only at concentrations in the range of 10-3 to io-2 molar
`aluminum chloride did the theoretical plots show deep pri(cid:173)
`mary minima, indicative of flocculation. These occurred at
`a distance of separation between particles of approximately
`
`DRL - EXHIBIT 1015
`DRL007
`
`

`
`298
`
`CHAPTER 19
`
`50 A, and led Matthews aud Rhodes to _conclude that coagu(cid:173)
`lation had taken place in the primary minimum.
`Schneider, et azs4 have published details of n laboratory
`investigation (suitable for undergraduates) that combines
`calculatioris based on the DL VO theory carried out with an
`interactive computer program with actual sedimentation ex-
`periments performed on simple systems.
`.
`Flocculation in Structured Vehic les-The ideal for(cid:173)
`mulation for a suspension would seem to be when flocculated
`particles are supported in a structured· vehicle.
`As shown in Fig 19-34 (under C), the process involves
`dispersion of the particles imd their subsequent flocculation.
`Finally, a lyophilic polymer is added to form the structured
`vehicle. In developing the formulation, care IJlUSt be taken
`to ensure the absence of any incompatibility between the
`flocculating agent and the polymer used for the structured
`vehicle. A limitation is that virtually all the structured
`vehicles in common use are hydrophilic colloids and carry a
`negative charge. This means that an incompatibility arises
`ifthe charge on the particles· is originally negative. Floccu(cid:173)
`lation in this instance requires the addition .pf a positivP.ly
`charge'd'floccuiating agent or iop,; in the presenc.e of .~uch. a
`material, the negatively cJ,larged suspending agent may co(cid:173)
`agulate and lose its suspendability. Thi!! situatio11 does not
`arise with particles that bear a positive charge, as the nega(cid:173)
`tive flocculating agent which the formulator must employ is
`compatiblf! with the similar)y charged suspending agent.
`.Chen,iital Stability of Suspensious-Partic~es that are
`completely ~nsolub\\l ii1 ~ liquid" vehicle are unli.ke~y to u~-
`
`derg9 mos~ chemical r.eactions leading to degradation.
`However, most drugs in suspension have a finite solubility,
`even though this may be of the order of fractions of a mi<;ro(cid:173)
`gram pe_r mL. As .a result, the material in solution may be
`su~eptible to degradation. However, Tingstad and co(cid:173)
`workers55 developed a simplified method for determining
`the stability of dr1,1gs in susp~nsion. The approach is based
`on the assumptions that (1) degradation takes place only in
`the sqlution and is first order, (2) the effect of temperature
`on drug solubility !).nd re.action rate conforms with classical
`theory, and (3) dissolution. is not rate-limiting on .degrada(cid:173)
`tion.
`Preparation of Suspensions- The small-scale prepara(cid:173)
`tion of suspensions i:nay be reiidily undertaken by the prac(cid:173)
`ticing pharmacist with the minimum of equipment. The
`initial dispersion of the particles is best carried out by tritu(cid:173)
`ration in a ~ortar, the wetting agen~ being added in smail
`increments .to the powder. Once thE} .particlEjs have been
`wetted adequately, the slurry may be transferred to the final
`container. The neJ<t step depends on whether the defloccu(cid:173)
`lated pai:ti.cles.are to b.e suspended in a structured vehicle,
`flocculated, or flocculated and then suspended. Regardless
`of which of the a,lternative procedures o.utlined in Fig 19-34
`is ~mpJoyed, the various. manipulations Cl).n be carried out .
`easily in the bottle, especially if an .aqueous solution of the
`suspending agent has been prepared beforeh~nd.
`.
`. .
`For a detailed discussion of the methods used in the large(cid:173)
`sc!lle prodµction of suspensions, .see the relev,ant section in
`Chapter 82.
`
`J
`
`•
`
`..
`..
`Emulsion~ in P~a~~acy
`..
`. ..
`.
`.
`An emulsion is a d ispersed system containing at l<;aSt·tY/O
`protection to drugs susceptible to oxidation or hydrolysis.
`Jmmiscihle liqu.id.d:>fiases.. The majority of conventional There is still a neeq .for well-characterized dermatological
`emulsions Jn pharmaceutical use have dispersed particles
`products with reproducible properties, regardless of whether
`ranging in .d iameter.from 0.1 to 100 µm. As wit}) suspen-
`th~e products are antil:ltJ.cteriaI, sustained-release, protec-
`sions, emulsions are thermqdynamically unstable as a,result
`tjye, or emollient lotions, creams Qr. ointments. ThEj.~nci­
`o( the excess. fre~ energy associated with the s11~face,of the
`P]~~~ ~~l!~s~~!.s~E~.!~_il!~~o.~v.~~-~9..,fill.iBq~~l!$i~w!.R!>~i:·or
`droplets.. The dispersed droplets, thereforn, strive to come
`·
`·
`·
`.
`~!lJ.2.~.9linoCluct$.
`together-a1~d reduce ~he surface area. I~<Y!i..<l!L~tbJ.s · The pharmacist must be familiar with the types of emul(cid:173)
`f!.~~~.!!!J<?.1?:.,.~~t .. ~Q_Q.rui.ex..vJtii.g{.itJ1.,s.us!l.!!~l.1S_,.,t.h.f}Jii§..:
`sions and the properties and theories underlying their prep(cid:173)
`aration and stability; such is the purpose of the remainder of
`per_.s~~.J1~-tticlell.J;llll...q2fil~£~.J>.£.iilll~-·~·!J.~~~~.Ik!.~taj.t.l!1:
`-tne~n..!!J,&J.,destruction of the emulsio~. In.order.to mini-
`this chapter. Microemulsions, which can be regarded as
`mlze this effect"athird~compon.ent";'ffie«i'mID'Si.ffi."!lc.'.flill.l!G:i'S
`isotropic, swollen micellar systems are discussed.in Chapter
`~<:lP'.eg~t&-~11~.~Y.!~~ml.Pi§yfi~ii"GiliJ.frtY;.:' rriie-ciloice of
`83.
`. .•
`.
`epll.!lsifY,ing agent is critical to the preparation of an emul-
`'I'he efficiency of
`sion po~.se.ss.i.l}g optimum stability.
`preS\lI\t-day emulsifiers permits the pr~paration of emul(cid:173)
`sions whi<rh are stable for many months and even ye!). rs, even
`thq1,1gl1 tJ:iey ~re thermodynamically unst,able .
`.. Emulsiqns a~e wid~ly used in pharmacy and m.edicine, and
`emµlsified. materials can possess advantages not observed
`when.formajated in other. dosage forr.ns. Thus,. certain me(cid:173)
`dicinal agf!nts h.aving an 9bjectionable taste have be.en made.
`more palatable .for oral administration ..vhen formulated in
`an emulsion.
`'J;'he principles of em.ulsification hav.e been
`applied· ex~ensively._ i1.1 the formulation of dermatological
`creams and lotions. lu.tmY!'JJlQJJll.filRul.si@ii~Q.(,cQ!ltta!l.t..m.11;
`dM\Jliiv.~ .. b~.~ll <:l~ie.lru>~Ato .. a.ssis.t .. t!k~P..QY!\i!<ifilJ..i.n,\Ul.der.t.ak-.
`i&.ll.Ei!U-~~mi .. nf.l.tiID.!fi.~Qf.!ue.J:iQd.Y.. .prgans.,w.hile.,!l.1f.P.9JiiUg
`the patient..t.o..the.miniµium.~aJiim . ., , Considerable at~
`tention has been dire~t.e(;{ towards the use of sterile, stable
`intravenous emul13ions containing.fat, carbohydrate; and.vi(cid:173)
`t<tmins all in one preparation. ·,.§..l!.£Q. proilJ.s!~~~.t~.!l.Q.!UiHl~-
`tar.ed..to .patients_unable...to...assimila.tufile~_yi.ta~.m.M..e.i.:\aJs
`.• J:>Y ... t.h~.,,t.l.Q!!l'lJl.1-o.tal.r.Ql.IJ;e.-. .
`;
`Emul$ions offer potential in the design of systems capable
`of. giving controlled rates of drug release and of affording
`
`namely,. the dispersed phase, .the- djspersion meliiu.m, and
`the emulsifying agent. Invariably, one of the' two im1.nisl!i(cid:173)
`ble liquids is aqueous while the second is an oil. Whether
`the. aqueous or the oil phase becomes the dispersed phase
`depends primarily on the emulsifying agent used and t}\e
`relative amounts of the two liquid phases. Hence, an emul(cid:173)
`sion in· .which the. oil is dispersed as droplets throughout the
`aqueous phase is. termed an oil-in-water, 0/W, emulsion.
`When water is the dispersed phase and an oil the dispersion
`medium, t he emulsion .is of the water-in-oil, W/O, type.
`Most pharmaceutical emulsions designed for oral adminis(cid:173)
`tration are of t he O/W type; emulsified lotions and crea.ms
`are either 0/Vv or W /0, depending on their use. Butter and
`salad creams are W /0 emulsions.
`Recently, so-called multiple emulsions have been devel(cid:173)
`oped with a view to delaying the release of an active ingredi(cid:173)
`ent. In these types of emulsions three phases are present, ie, ·
`the emulsion has the form W/0/W or 0/W/0. It~ these.
`
`Emulsion· Type and Means of Detection_
`A stable emulsion must contain at least three co~ponen,ts;
`
`\,/
`
`DRL - EXHIBIT 1015
`DRL008