18TH
`
`EDITION
`
`Remington's
`
`Au=;o§u,so% R__ GENI{AR'O
`Editor, and Chairman I
`I
`I
`'
`of the Editorial Board
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022416
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`MACK PUBLISHING COMPANY
`
`Eosron, Pennsylvania 18042
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022417
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Remington Historical I Biographical Data
`
`I
`
`The following is a record ofthe editors and the dates of publico
`Edition known as Remington ’s Practice ofl_’harmacy and
`
`tion of successive editions of this book, prior to the 13th
`subsequently as Remington '5 Pharmaceutical Sciences.
`
`‘Joseph P Remington
`
`. Joseph P Remington
`Assisted by.
`y
`E FulIe‘rton.Cook
`
`Associate Editors
`~
`‘Ivor Griffith ‘
`"
`Adley B Nichols
`Arthur Osol
`
`Editors
`E Fullerton Cook
`Eric W Martin
`
`Editors
`E Fullerton Cook
`Eric W Martin
`
`Associate Editors
`E Emerson Leuallen
`Arthur Osol
`I
`V
`LinwoodFTice
`Clarence T Van Meter
`
`Assistant to the Editors
`John E Hoover
`
`First Edltion','1586
`Second Edition. 1869
`third Edition, 1591
`Fourth Edition, 1905 ‘
`
`Fifth Edition, 1907
`Sixth Edition, 1917
`
`Seventh Edition, 1926
`
`Editors
`E Fullerton Cook
`Charles H LaWall
`
`Eighth Edition, 1936
`
`Editors
`E Fullerton Cook '
`Charles H La‘)/all
`
`Ninth Edition, 1946
`
`Tenth Edition, 1951
`
`Eleventh Edition, 1956
`
`Editors
`Eric W Martin
`E Fullerton Cook
`
`Twelfth Edition, 196 1
`
`Editors
`Eric W Martin
`E Fullerton Cook
`E Emerson Leuallen
`Arthur Osol
`Linwood F Tice
`Clarence T Van Meter
`
`Thirteenth Edition, 1965
`Editor-in-Chief
`Eric W Martin
`Editors
`Grafton D Chase
`Herald R Cox
`Richard A ‘Dena
`Alfonso R Gennaro
`Stewart C Harvey
`
`_
`
`Fourteenth Edition, 1970
`
`Chairman, Editorial Board
`Arthur Osol
`Editors
`I
`
`Grafton D Chase
`Richard A Deno
`Alfonso R Gennaro
`Melvin R Gibson
`Stewart C Harvey
`
`Fifteenth Edition, 1975
`Chairman, Editorial Board
`Arthur Osol
`Editors
`John T Anderson‘
`Cecil L Bendush
`Grafton D Chase
`Alfonso R Gennaro
`Melvin R Gibson
`
`Sixteenth Edition, 1950
`Chairman, Editorial Board
`Arthur Osol
`Editors
`Grafton D Chase
`Alfonso R Gennaro
`Melvin R Gibson
`Clioyd Granberg
`Stewart C Harvey
`
`Seventeenth Edition, 1965
`
`Chairman, Editorial Board
`Alfonso R Gennaro
`Editors
`Grafton D Chase ~
`Ara Der Marderosian
`Stewart Harvey
`Daniel A Hussar
`Thomas Medwick
`
`Managing Editor
`John E Hoover
`
`Robert E King
`E Emerson Leuaiien
`Arthur Osol
`Ewart A Swinyard
`Clarence T Van Meter
`
`Managing Editor
`John E Hoover
`
`. Robert E King
`Alfred N Martin
`Ewart A Swinyard
`Clarence T Van Meter
`Bernard Witlln
`
`Managing Editor
`John E Hoover
`
`C Boyd Grainberg
`Stewart C Harvey
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`, Gilbert L Zlnk
`
`Edward G Rippie
`Joseph D Schwartz
`Ewart A Swinyard
`Gilbert L Zink
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX LLC
`
`RBP_TEVA05022418
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`A Table of contents
`
`Part 1
`
`Orientation
`
`‘
`
`r
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`'
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`- - - --
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`- - -
`Scope-~ -------
`- - -
`-
`-
`- - - -
`-
`- - -
`-
`- - - -
`-
`EV°lUfl°I'I Of Ph0Ym0€Y - - -
`- -' - - -
`-
`- - - -
`-
`- -
`-
`Ethics
`- -
`-
`-
`-
`-
`-
`-
`- - -
`- - - -
`- - - - - - -
`The Practice of Community Pharmacy .
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`. .
`OPP°”U"m‘=‘5 f°’ Ph°'m°Cl5'5 3“ ‘he Ph°Tm9C9U”-
`Cal l0dU5lTY
`-
`-
`Pharmacists in Government
`Drug information . . .
`. . . . . . . .
`Reseclch
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`- - --- - - - -
`- - - - - -
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`pg" 2
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`phgl-mg¢eufi¢5
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`Metrology and Calculation .
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`Statistics . .
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`Computer Science .
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`Calculus . .
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`Molecular Structure. Properties and States of
`Matter Y. . . . . . .
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`Complex Formation .
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`Thermodynamics . .
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`Solutions and Phase Equilibria . . .. . . . . . .
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`ionic Solutions and Electrolytic Equilibria .
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`Reaction Kinetics . .
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`Disperse Systems .
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`Rheology . .
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`69
`104
`138
`145
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`158
`182
`197
`207
`228
`247
`257
`310
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`44 Cholinomimetic Drugs .. .
`45 Adrenergic and Adrenergic Neuron Blocking
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`* Drugs .......
`......
`.......
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`46 Antimuscarinic and Antlspasmodlc Drugs
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`47 Skeletal Muscle Relaxants .
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`43 Diuretic Drugs
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`49 Uterine and Antimigraine Drugs
`50 Hormones . . . . .
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`51 Vitamins and Other Nutrients .. .
`52 Enzymes
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`53 General Anesthetics . . . .
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`54 Local Anesthetics .
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`55 Sedatives and Hypnotics .
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`56 Antiepileptics
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`57
`Psychopharmacologlc Agents
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`55 Analgesics and Antipyretics .
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`59 Histamine and Antihistamines . .
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`60 Central Nervous System Stimulants .
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`61 Antineopiastic and lmmunosuppressive Drugs . .
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`62 Antimicrobial Drugs .
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`63
`Parasiticides . . .
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`64
`Pesticides .
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`65 Diagnostic Drugs
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`66 Pharmaceutical Necessities
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`67 Adverse Drug Reactions . .
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`68 Pharmacogenetics .
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`69 Pharmacological Aspects of Drug Abuse .
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`70
`introduction of New Drugs
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`669
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`B98
`907
`916
`929
`943
`948
`1002
`1035
`1039
`1046
`1057
`1072
`1052
`1097
`1123
`1132
`1138
`1163
`1242
`1249
`1272
`1286
`1330
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`1349
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`1365
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`Part 3
`
`Pharmaceutical Chemistry
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`Part 1
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`Biological Products
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`Inorganic Pharmaceutical Chemistry . .
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`Organic Pharmaceutical Chemistry .
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`Natural Products
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`Drug Nomenclature—United States Adopted
`Names
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`Structure-Activity Relationship and Drug
`Design . .
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`Part 4
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`Testing and Analysis
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`Part 0
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`Principles of immunology .
`immunizing Agents and Diagnostic Skin
`Antigens . .
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`Allergenic Extracts . . . . . . .
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`Biotechnology and Drugs
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`1379
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`1359
`1405
`1416
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`V PharmaceuticalPreparations and Their
`Manuiacture
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`26 Analysis of Medicinuls
`27 Biological Testing
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`28 Clinical Analysis
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`29 Chromatography . . .
`30
`instrumental Methods of Analysis .
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`31 Dissolution .
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`
`435
`464
`495
`529
`555
`569
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`'
`
`nudioisompes in phmmmy and Medicine
`pun 5
`32 Fundamentals of Radioisotopes . .
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`605
`33 Medical Applications of Radioisotopes
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`624
`
`Part 6
`Pharmaceutical and Medicinal Agents
`Diseases: Manifestations and Patho-
`_ _ _ _ _
`_ _ _
`_
`physiology _
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`Drug Absorption, Action and Disposition .
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`Basic Pharmacokinetics .
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`Clinical Pharmacokinetics . .
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`Topical Drugs .
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`Gastrointestinal Drugs . .
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`Blood, Fluids, Electrolytes and Hematologic
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`Drugs
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`Cardiovascular Drugs
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`Respiratory Drugs
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`Sympathomimetic Drugs . . .
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`655
`697
`725
`746
`757
`. 774
`‘
`600
`831
`560
`870
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`Preformulatlon . . . . .
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`Bioavailabllity and Bioequivalency Testing . . .
`Separation . . .
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`Sterilization
`Tonicity, Osmoticlty, Osmolality and Osmolarity .
`Plastic Packaging Materials .
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`Stability of Pharmaceutical Products
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`" Quality Assurance and Control
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`Solutions‘, Emulsions, -Suspensions and
`Extractives .
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`Parenteral Preparations
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`intravenous Admixtures . .
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`Ophthalmic Preparations . . . . .
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`Medicated Applications
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`P°Wd°’§
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`Oral Solid Dosage Forms .
`- -
`-
`C°0fin9 Of Ph0Tm0CE‘UflC°' D050‘.-J9 F°Tm5 - - - -
`5U5*°”‘9d'R°'e°59 DTU9 D9“V9'Y 5Y5l9m5 -
`-
`- - -
`-
`Ae'°5°'5 - - - -
`-
`-
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`_
`
`pg” 9
`
`phqm-m¢eufi¢q| pi-qcfige
`
`1435
`1451
`1459
`1470
`1461
`1499
`1504
`1513
`1519 _
`1545
`1570
`1581
`1596
`1615
`1633
`1696
`1979
`1694
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`Ambulatory Patient Care . . .
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`institutional Patient Care . .
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`Long-Term Care Facilities .
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`The Pharmacist and Public Health . .
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`1715
`1737
`1758
`1773
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX LLC
`
`RBP_TEVA05022419
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`The Patient: Behavioral Determinants . . .
`Patient Communication
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`Drug Education .
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`Patient Compliance
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`The Prescription .
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`.1.’
`Drug Interactions . . . .
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`Clinical Drug Literature .
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`Health Accessories
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`Surgical Supplies .
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`.v
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`1788
`17%
`1803
`1613
`1826
`1842
`1859
`1864
`1595
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`"
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`Poison Control
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`Laws Governing Pharmacy .
`Community Pharmacy Economics and
`Management
`I
`Dental Services . . i.
`'.
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`.
`
`. . . .
`
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`
`.
`
`.
`
`.
`
`.
`
`.
`
`[ndex
`
`'
`Alphabetic Index . . . . .
`
`.
`
`.
`
`.
`
`‘
`. . . . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`1
`. ..'
`
`1967.
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022420
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`296
`
`CHAPTER 19
`
`Some of the major differences between suspensions of floc-
`culated and deflocculated particles are presented in Table
`XV.
`.~
`.
`Effect of Flocculation—-In a deflocculated system con-
`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 flocs tend to fall together so that a distinct bound-
`ary between the sediment and the supernatant is readily
`observed; second, thesupernatant is clear, showing that the
`very fine particles have been incorporated into the flocs.
`The initial rate of settling in flocculated systems is deter-
`mined by the size of the flocs and the porosity of the‘aggre-
`gated mass. Under these circumstances it is perhaps better
`to use the term subsidence, rather than sedimentation.
`
`Quantitative Expressions of Sedimentation and
`Flocculation
`’
`
`Frequently, the pharmacist needs to assess a formulation
`in terms of the amount of flocculation in the suspensionand
`to compare this withthat found in other 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 sediment, V,,,,to
`_ the total volume of the suspension, V0. "Thus,
`I (36)
`F = V,/V,‘
`As the volume of suspension which appears occupied by the
`sediment increases, the value of E, which normally ranges
`from nearly .0 to 1, increases.
`In the system where F 7-‘ 0.75,
`for example, 75% of the total volume in the container is
`apparently occupied by the loose, porous flocs forming the
`sediment: This is illustrated in Fig 19-38. 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-
`thermore, the suspension is esthetically pleasing, there being
`no visible, clear supernatant.
`Degree of Floccu1ation—A better parameter for com-
`paring flocculated systems is the degree of flocculation, B,
`which relates the sedimentation volume of the flocculated
`suspension, F, to the sedimentation volume of the suspen-
`sion when deflocculated, Fa);
`It is expressed as
`
`ti = F/Fm
`
`(37)
`
`The degree of flocculation is, therefore, an expression of
`the increased sediment volume resulting from flocculation.
`
`*
`
`Flocculated
`Deflocculated
`Fig 19-33. Sedimentation parameters of suspensions. DefIoccu-
`Ijtzdosuspension:
`F... F 0.15. Flocculated suspension: F= 0.75; ,8
`
`If, for example, (3 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 d 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-
`tion in the system decreases, [3 approaches unity, the theo-
`retical minimum value.
`‘
`
`,
`Suspensions and their Formulation
`A’ pharmaceutical suspensionmay be defined as a coarse _
`dispersion containing finely divided insoluble material sus-
`pended" in a liquid medium. Suspension dosage forms are
`given by the oral route, injected intramusculary or subcuta-
`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-
`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 include these products.
`’
`There arecertain criteria that a well-formulated suspen-
`sionshould meet. The dispersed particles should be of such
`a size that they do not settle rapidly in the container.‘ How-
`ever, in the event that sedimentation occurs, the sediment
`must not form a_hard cake. Rather, it must be capable of
`redispersion with a minimum effort on the part of the pa-
`tient. Additionally, the product should be easy toipour,
`pleasant to take, and resistant to microbial attack.
`The three major problem areas associated with suspen-
`sions are (1) adequate dispersion of the particles in the
`vehicle, (2) settling of the dispersed particles, and (3) caking
`of these particles in the sediment so as to resist redispersion.
`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 suspension possessing optimal phys-
`ical stability depends on whether the particles in suspension
`are to be flocculated or to remain deflocculated. One‘ ap-
`proach involves use of a structured vehicle to keep defloccu-
`lated particles in suspension; ‘a second depends on controlled
`flocculationas a means of preventing cake formation. A
`
`
`Addition of wetting agent and dispersion medium
`
`Uniform dispersion of
`defiocculnted particles
`
`A..
`
`.
`
`Incorporation of
`structured vehicle
`
`.
`
`B
`Adrlition of
`{locculating agent
`
`(1:I
`i
`Addition of
`flocculating agent
`
`suspension
`‘Floccuhated
`as final product
`
`suspension
`[Flocculatcd
`
`Deflocculated
`suspension
`in structured vehicle
`as final product‘
`
`Incorpor
`structure
`
`Flocculated -
`suspension
`in structured vehicle
`as final product
`
`Fig 19-34. Alternative approaches to the formulation of suspen-
`sions.
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022421
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`TEVA EXHIBIT 1015
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`
`

`
`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 Particles—The dispersion step has been
`discussed earlier in this chapter. Surface-active agents
`commonly are used as wetting agents; maximum efficiency 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-
`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-
`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-
`colloids, which are usually negatively charged in aqueous‘
`solution. Typical examples are methylcellulose, carboxy-
`methylcellulose, bentonite, and Carbopol. The concentra-
`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-
`parting suspending agents and, as such, reduce the rate of
`sedimentation of dispersed particles.
`‘
`The rheological properties of suspending agents are con-
`sidered elsewhere (Chapter 20).
`Ideally, these form pseudo-
`plastic or plastic systems which undergo shear-thinning.
`Some degree of thixotropy is also desirable. N_on-Newtoni-
`an materials of this type are preferred over Newtonian sys-
`tems because, if the particles eventually settle to the bottom
`of the container, their redispersion is facilitated by the vehi-
`cle thinning when shaken. When the shaking is discontin-
`ued, the vehicle regains its original consistency and the re-
`dispersed particles are held suspended. This process of
`redispersion, facilitated by a shear-thinning vehicle, presup-
`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, B and C), the formulator takes the defloccu-
`lated, wetted dispersion of particles and. attempts to bring
`about flocculation by the addition of a floeculating agentg.
`most commonly, these are either electrolytes, polymers, or
`surfactants. The aimris to control flocculation byradding‘
`that amount of flocculating agent which results in the maxi-
`mum sedimentation volume.
`'
`‘
`Electrolytes are probably the most widely used flocculat-
`ing agents. They act by reducing the electrical forces of
`repulsion between particles,'thereby allowing the particles
`to form the loose flocs so characteristic of a vflocculated
`suspension. Since the ability of particlesto come together
`and form a floc depends on their surface charge, zeta'poten—
`tial’ measurements on the suspension, as an electrolyte ‘is
`added, provide valuable information as to the extent of floc-
`culation in the system.
`'
`—
`-N
`'
`>-
`This principle is illustrated by reference to the‘ following
`example, taken from the work of Haines and Ma1:tin.5°~ Par-
`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-
`tial will reach zero and then become positive as the addition
`of AlCl3 is continued.
`I
`
`DISPERSE SYSTEMS
`
`297
`
`
`
`J‘aumio/\uoiJ,e),uauJipag
`
`.
`
`
`
`"Zeta~potential(mv)
`
`‘
`
`.
`
`l
`
`5
`.
`Cationic floeculating
`agent
`
`‘ Typical relationship beiweencaking, zeta ‘potential and
`Fig 19-35.
`sedimentation_ volume, as a positively charged flocculating agent is
`added to a suspension of negatively charged‘ particles.
`0:” zeta
`potential; I:
`sedimentation volume.
`I
`
`If sedimentationstudies are run simultaneously on ‘sus-
`pensions containing the same range of AlCl3 concentrations,
`a relationship is observed (Fig 19‘-35) between the sedimen-
`tation volume, F, the presence or absence of caking, and the
`zeta potential of the particles.
`In order to obtain a flocculat-
`ed, noneaking suspension with the maximum sedimentation
`‘ volume, thezeta 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.
`‘
`Acomparable situation is observedrwhen 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-
`cient additives for inducing flocculation. Thus, it has been
`shown that the sedimentation volume is higher in suspen-
`sions flocculated with‘ an anionic heteropolysaccharide than
`when electrolytes were used.
`»
`'
`'
`Work by Matthews and Rhodes,51“53 involving both ex-
`perimental and theoretical studies, has confirmed the for-
`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 (10”3 mo-‘
`lar) as a wetting agent.
`Increasing‘concentrations of alumi-
`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 of 10‘3 molar aluminumcliloride was reached.
`At this point the zeta "potential had fallen from -46.4 mV to’
`~1’7.0.rnV—. Further reduction of the zeta potential, to -4.5
`mV by use of 10‘? molar aluminum chloride did not increase
`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 DLVO theory (see page 285) predicted the
`results obtained, namely, that the griseofulvin suspensions
`under investigation would remain deflocculated when the
`concentration ofialuminum chloride was 10”‘ molar orless.
`Only at concentrations in the rangeiof 10”3 to 10” molar
`aluminum chloride did the theoretical plots show deep pri-
`mary minima, indicative of flocculation. ‘ These occurred at
`a distance of separation between particles of approximately
`
`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022422
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`TEVA EXHIBIT 1015
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`298.
`
`CHAPTER 19
`
`50 A, and led Matthews and Rhodes to ‘conclude that coagu-
`lation had taken place in the primary minimum.
`Schneider, et al54 have published details of a laboratory
`investigation (suitable for undergraduates) that combines
`calculations based on the DLVO theory carried out with an
`interactive computer program with actual sedimentation ex-
`periments performed on simple systems.
`,
`Flocculation in.Structured Vehicles—The ideal for-
`mulation for a suspension would seem to be when flocculated
`particles are supported in a structuredvehicle.
`As shown in Fig 19-34 (under C), the process involves
`dispersion of the particles and their subsequent flocculation.
`Finally, a lyophilic polymer is added to form the structured
`vehicle.
`In developing the formulation, care must 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
`if the charge on the particles’ is originally negative. Floccu-
`lationin this instance requires the addition of a positively
`char'gedi'flocculating agent or iorij in the presence ofsuch a
`material, the negativelyicharged suspending agent may co-
`agulate and lose its suspendability. This situation does not
`arise with particles that bear a positive charge, as the nega-
`tive flocculating agent which the formulator must employ is
`compatible with the similarly charged suspending agent.
`,Cherni_cal Stability of Suspensions-—Particles that are
`completely insoluble in a liquid vehicle are unlikely to un-
`
`dergo most chemical reactions leading to degradation.
`However, most drugs in suspension have a finite solubility,
`even though this may be of the order of fractions of a micro-
`gram. per mL. As _a result, the material in solution may be
`susceptible to degradation. However, Tingstad and co-
`workers” developed a simplified method for determining
`the stability of drugs in suspension. The approach is based
`on the assumptions that (1) degradation takes place only in
`the solution and is first order, (2) the effect of temperature
`on drug solubility and reaction rate conforms with classical
`theory, and (3). dissolution is not rate-limiting on‘degrada-
`tion.
`.
`«
`.
`
`l’reparation of‘Suspensions—The small-scale prepara-
`tion of suspensions may be readily undertaken by the prac-
`ticing pharmacist with the minimum of equipment. The
`initial dispersion of the particles is best carried out by tritu-
`ration in a mortar, the wetting agent being added in small
`increments to the powder. Once the particlels have been
`wetted adequately, the slurry may be transferred to the final
`container. The negrt step depends on whether the defloccu-
`lated parti_cles_are to be suspended in a structured vehicle,
`flocculated,_o_r flocculated and then suspended. Regardless
`of which of the alternative procedures outlined in Fig 19-34
`is employed, the variousmanipulations can be carried out,
`easily in the bottle, especially if an aqueous solution of the
`suspendingiagent has been preparedbeforehand.
`,
`,
`_.
`,
`For a detailed discussion of the methods used in the large-
`scale production of suspensions, ‘see the relevant section in
`Chapter 82.
`
`Emulhsihonsiiin Pharmacy
`Q
`protection to drugs susceptible to oxidation or hydrolysis.
`An emulsion is-a dispersed system containing at leasttwo
`There is still a need,-for well-characterized dermatological
`_igm_1_iscihla,aliquida..phases.—, The majority of conwiehtiorial
`products with reproducible properties, regardless of whether
`emulsions ,_in,pharInaceutical use have dispersed‘ particles
`these products are antibacterial, sustained-release, protec-
`ranging in diameterfrom 0.1 to 100 pm. As with suspen-
`sions, emulsions are thermodynamically unstable as a,result,
`tive, or emollient lotions, creams orointments.
`_’l‘_~l_1He~prri_nci-
`of the excess. free energy associated with the surface of the
`pleof emulsification is involved
`'
`M i "
`droplets. Thedispersed droplets, therefore, strive to come
`.
`_
`.I.5iliiiEts.
`W
`.
`The pharmacist must be familiar with the types of emul-
`together and reduce the surface area.
`-lnhagddit‘
`’
`'
`sions and the properties and theories underlying their prep-
`f;1.0'.0Cu1a“°“
`Ct.»al§i9..Qhseryeri.yvit11.s_usne11§i§fns...t.
`am
`coalesce or fuse and this
`aration and stability; such is the purpose of the remainder of
`this, chapter. Microemulsions, which can be regarded as
`isotropic, swollen micellar systems are discussed_in Chapter
`83.
`
`ration of an emul-
`pr
`critical
`fying g
`em_u_l
`sion‘ pos_se_ss_ing optimum stability. The efficiency of
`present-day emulsifiers permits the preparation of emul-
`sions which are stable for many months and even years, even
`though they are thermodynamically unstable.
`“Emulsions are widely used in pharmacy and medicine, and
`emulsified, materials can possess advantages not observed
`whenformulated inother. dosage forms. Thus, certain me-
`dicinal agents having .an,objecti_onable taste have been made_
`more palatable for oral administration when formulated in
`an emulsion. The principles of emulsification have been
`applied4_ex_tensi_vely,in the formulation of dermatological
`creams and lotions ..I.r.1_tLaysa9i1s.e;nulsions,Qtco t:ast.n.1.9..-
`de1‘.t.ak.-..
`.,a.v.e..b.._
`,,
`..
`.
`'
`.
`_
`iE.8..?$;.£s3!....e..
`In
`‘ 0. ’.ith9..b0dy rga ..
`e>sp..9§i,1:!g
`the-patie_nt_tothe.m1nunum-ofrgdiation_.,. Considerable. at-
`tention has been directed towards the use of sterile, stable
`intravenous emulsions containing. fat, carbohydrate, and.vi-
`~;.,»-.»_. ,~
`4
`tamins all in one preparation. rwSg_1‘1,<_:‘h products“ 1'
`dminis-
`" tered...to..patients-unable..to..ass.iII1ilateth exits mat
`*1
`_,_by,,the..n
`_rn,al..oral.route.-»--
`.Lm’ulsions offer potential in the design of systems capable
`of. giving controlled rates of drug release and of affording
`
`/
`
`’
`x,.»
`
`Emulsion'Type and Means. of Detection ‘
`A stable emulsion must contain at least three components;
`namely,.the dispersed phase, the dispersion medium, and
`the emulsifying agent.
`Invariably, one of thetwo immisci-
`ble liquids is aqueous while the second is an oil, Whether
`the_aque0us or the oil phase becomes the dispersed phase
`depends, primarily on the emulsifying agent used and the
`relative amounts of the two liquid phases. Hence, an emul-
`sion in“which the oil is dispersed as droplets throughout the
`aqueous phase istermed an oil-in-water, 0/W, emulsion.
`When water is the dispersed phase and an oil the dispersion
`medium, the emulsion _is of the water-in-oil, W/O, type.
`Most pharmaceutical emulsions designed for. oral adminis-
`tration are of the O/W type; emulsified lotions and creams
`are either O/W or W/O, depending on their use. Butter and
`salad creams are W/O emulsions.
`Recently, so-called multiple emulsions have been devel-
`oped with a view to delaying the release of an active ingredi-
`ent.
`In these types of emulsions three phases are present, ie,-
`the emulsion has the form W/O/W or O/W/O.
`In these,
`
`TEVA EXHIBIT 1015
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`
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