R•nisrto,~ .
`. 'RM Stl~nd! -'Wad lPRlll1llltm
`offlla-.w
`
`II
`
`. I.
`
`'i
`
`• r
`
`,
`
`'·.'
`,}J'
`
`,) .
`.
`
`Slayback Exhibit 1064, Page 1 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Remington: The
`Science and Practice
`of Pharmacy
`
`Volume II
`
`Slayback Exhibit 1064, Page 2 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`19TH
`
`EDITION
`
`Remington:
`Practice of
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`Slayback Exhibit 1064, Page 3 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`The Science and
`Pharmacy
`
`.
`
`1995
`
`MACK PUBLISHING COMPANY
`Easton, Pennsylvania 18042
`
`Slayback Exhibit 1064, Page 4 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`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, I 905, I 907,1917, by Joseph PRemington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951 , by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by The Philadelphia College of
`Pharmacy and Science
`
`AU Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`The use of structuralformulasfrom USAN and the USP Dictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsibl.e for any inaccuracy
`contained herein.
`
`NOTICE-This text is not intended to represent, nor shall it be interpreted to be, the equival.ent
`of or a substitute for the ojficial United States Pharrru:u;apeia ( USP) and I or the National
`Formulary (NF). In the event of any di,fference or discrepancy between the current ojficial
`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, Easton, Pennsylvania
`
`Slayback Exhibit 1064, Page 5 of 59
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`
`

`

`~ RS
`
`4 1
`R41
`
`Table of Contents
`
`Volume I
`Port 1 Orientation
`
`1 Scope ............ . ..... . .
`2 Evolurion of Pharmacy . . .
`3 Ethics . . ...... . . .. ....... . .
`. . ... ... . .. . .
`4 Communiry Phormocy . . . . . . . .
`5 Pharmacists in lndusrry ........... . ... . .. .. . ...... .
`6 Phormocisrs in Government .. . .. ..•...•..•..... . ...
`7 Drug lnformorion . . . . . .
`. .. ...•...•..• ...... .. .
`8 Research .. . .. . .. ..... .. .. . ..... . ...... .. .... . .. .
`
`Port 2 Pharmaceutics
`
`9 Merrology and Colcularion . . ........ . ... . .. . . .. . . .
`10 Storisrics . . ...... . ....... .. ... .. . . . . ...... . • .....
`11 Compurer Science. .. .. . .. .
`. .. .. ... . .. . ..
`12 Calculus . . . . . . .
`. ... . ................ . ..... .
`1 J Molecular Srrucrure, Properties and Srores of Morrer ... .
`14 Complex Formorion .. . .. . . . . . .
`. ..... ....... .
`1 5 Thermodynamics ... . ........................... .
`16 Solurions and Phase Equilibria ....... . . .. ....... . . . .
`17 Ionic Solutions and Electroly!ic Equilibria ... . . ....... .
`1 8 Reaction Kinetics . . . . . . . . . . . .
`. . . . . ... . .. .
`19 lnrerfociol Phenomena .... .. . .................... .
`20 Colloidal Dispersions .... . ..... . .. .. ..... ... .. ... .
`21 Coarse Dispersions . .. ... .. . . .. . . ........ . . ...... .
`22 Rheology .. .... . .. .
`. . ....... . ...... .
`
`Port 3 Pharmaceutical Chemistry
`
`23 Inorganic Pharmaceutical Chemisrry . .. . .. .... .
`24 Organic Phormoceuricol Chemisrry ................ .
`25 Fundamentals of Radioisotopes ... .. ...... . .. .. ... .
`26 Natural Products ....... . .... . ... . ........... .
`27 Drug Nomencloture--Unired Srotes Adopted Names ..
`28 Srrucrure-Activiry Relationship and Drug Design . . .. . . .
`
`J
`7
`18
`25
`29
`33
`42
`52
`
`6J
`94
`128
`1J5
`147
`169
`184
`194
`21J
`231
`241
`252
`278
`292
`
`J15
`J40
`364
`382
`41J
`425
`
`Port 4 Phormoceutlcol Testing, Analysis ond Control
`
`29 Analysis of Medicinals. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`JO Biological Testing . . . . . . . .. . .. . .. . . . . . . . . .. . . . . . . .
`J1 Clinical Analysis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`32 Chromatography . . . . .
`. . . . . . . . . . . . . . . . . . . . . . .
`JJ Instrumental Methods of Analysis . . . . . . . . . . . . . . . . . . .
`34 Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`JS Dioovoilobiliryond DioequivolencyTesting .. .
`J6 Toniciry, Osmoticiry, Osmololityand Osmolarity . . . . . .
`J7 Separation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`J8 Stability of Pharmaceutical Products . . . . . . . . . . . . . . . . .
`39 Quality Assurance and Control . .
`. . . . . . . . . . .
`
`Port 5 Phormacodynomlcs
`
`40 Diseases: Monifestorions and Pothophysiology .. . ... .
`41 Drug Absorption. Acrion and Disposition .. .. .. .... . . .
`42 Dasie Phormocokinerics . . . . . . . .
`. ... . .. . .. . .
`43 Clinical Phormocokinerics .. . .. ... . ... . .. ... . ... . .. .
`44 Princip les of Immunology ..... ... .. .. . . ... .. ..... . .
`45 Adverse Drug Reactions . . . . . . .
`. . . . . . . . .. ... . . . .
`46 Pharmocogenetics . . . . . . ... .... . ... .... .. . . .. . . .
`4 7 Pharmacological Aspects of Drug Abuse . .. .. ... . .. . .
`48 Introduction of New Drugs .. .......... . .. .. ... .... .
`49 Diorechnologyond Drugs ........ .• .. • • .. ••.. . • . ••.
`50 Alrernotive Healthcare . . .... . ... .• .. . ... .. . ... . ...
`
`4J7
`491
`501
`534
`559
`59J
`605
`61 J
`628
`6J9
`648
`
`655
`697
`724
`741
`752
`761
`775
`780
`795
`809
`829
`
`Volume II
`
`Port 6 Phormoceutlcol ond Medicinal Agents
`
`51 Medical Applications ofl\odioisoropes .. .
`52 Topical Drugs . . . . . .
`. .... . .. .
`SJ Gosrroinresrinol and Liver Drugs ... .. .... . ... . .. . .. .
`54 Blood, Fluids, Electrolytes ond Hematologic Drugs
`55 Cardiovascular Drugs . . . . . . . . . . . . . .. ... . ..... . .. .
`56 Respirorory Drugs . . . . . .
`. .. . .• ..... . ...... . ...
`5 7 Sympothomimeric Drugs ... . .... . .......... .. .. .. .
`58 Cholinomimetic Drugs . . . . . . . . . . . . ... . .. .. . ..... .
`59 Adrenergic and Adrenergic Neuron Dlocking Drugs ... .
`60 Anrimuscorinic and Anrisposmodic Drugs ........ .. .
`61 Skelerol Muscle Relaxants .. . ... .. .... .
`62 Diuretic Drugs . ... . ... . ...... .. . ..... . ...... ..... .
`63 Urerine and Antimigroine Drugs ....... . ... . ... . ... .
`64 Hormones . .
`. ... ... .. ........ ... ... . ....... .
`65 Vitamins and Other Nutrients ........ .... .. . .. . .... .
`66 Enzymes ... . ... . ... ... ... . ... .... • ••. .. . .. .. .. . .
`67 General Anesthetic Drugs ........... .. . . . . . . ... . . . .
`68 Local Anesthetic Drugs ... . ... .. .... •• ... .. . ...... .
`69 Sedative and Hypnotic Drugs .. . ... . . • . . ...... . ... .
`70 Anriepileptic Drugs . .
`. ... . ... .. . ... . ... .
`71 Psychophormocologic Agents ............. .••• . .• ..
`72 Antipyretic and Anti•inflommorory Drugs .... • . • .. ••. .
`7J Hisromine and Anrihistominic Drugs .. . . ..... •• .. •• ..
`7 4 Central Nervous System Srimulonrs . .. .... .. . . • .. .. ..
`7 5 Antineoplostic and lmmunooctive Drugs . .... .. .. • ...
`7 6 Anti-infective Drugs .. ....... . . .. .... ... . .. . ... . .. .
`77 Porositicides ................................. . .. .
`78 Pesticides ............ . ... . .... . . ... ......... . .. .
`79 Diagnostic Agents .
`. .. . . ... . ................ .
`80 Pharmaceutical Necessities ................... .. .. .
`81 Immunizing Agents and Diagnostic Skin Antigens . . .. . .
`82 Allergenic Exrracrs . . . . . . . .
`. . ......... .
`
`Port 7
`
`Industrial Pharmacy
`
`83 Preformulorion . . . .. . . ... . .... . ..... . ... . ....... .
`84 Sterilization ...... . ....... . ..... .... . .... . .... .. . .
`85 Plastic Packaging Materials ............... . ...... . .
`86 Solutions. Emulsions. Suspensions and Exrrocrs .. . .. .. .
`87 Parenteral Preparations .. .. ... . ......... .. ... ... . .
`88 Intravenous Admixtures .. .. . .. .......... .
`89 Ophthalmic Preparations. .
`. ... ...... . ... . .. .. .
`90 Medicated Applications . . . .. .. . ..... . ... . .. ... . .. .
`91 Powders ........ .. .. ....... .. .... . .... . .... .
`92 Oral Solid Dosage Forms ..... .. .... .
`93 Coating of Pharmaceutical Dosage Forms .......... .
`94 Sustained-Release Drug Delivery Systems . . ...... .. . .
`95 Aerosols . . . ... . ... . ... . .... . .... ... .. . . .
`
`Port 8 Pharmacy Practice
`
`96 Ambulatory Patient Core . . .. . .... . ............... .
`97 Institutional Patient Core ................... .
`98 Long-Term Core Facilities ............... . . . .... .
`99 The Pharmacist and Public Health .. . ..... . ...... .
`100 The Patient: Behaviora l Determinants ... .. .. . ... .
`101 Patient Communication . .... . ... . . ..... . ........ . .
`1 02 Drug Education ....... .. ...... ..• ..... . . ..... . ...
`1 03 Patient Compliance ... •...•.. . ... ................
`1 04 The Prescription .. .. .. ... .. . ... ... .... . .... ... . .. .
`
`84J
`866
`886
`910
`943
`971
`981
`1000
`1009
`1020
`1027
`10J9
`1052
`1057
`1106
`1137
`1140
`11 46
`1154
`1171
`1180
`1196
`1222
`12J1
`12J6
`1263
`1JJ7
`1J43
`1J65
`1J80
`1417
`1434
`
`1447
`146J
`1487
`1495
`1524
`1549
`156J
`1577
`1598
`1615
`1650
`1660
`1676
`
`1695
`1720
`1740
`1755
`177J
`1779
`1786
`1796
`1808
`
`vii
`
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`

`105 Drug Interactions ................................ .
`106 Clinical Drug literature ........ ... ... ... .......... .
`107 Health Accessories . .. ........................... .
`108 Surgical Supplies ... .. ....................... .... .
`1 0Q Poison Control .... ..... .. . ................ ... ... .
`110 Laws Governing Pharmacy ... .. ........... . ... ... .
`111 Communiry Pharmacy Economics and Management ..
`112 Pharmacoecanomics ........................ .. .. .
`
`1822
`1837
`1842
`187J
`188J
`1892
`191J
`1929
`
`Appendix
`Dose Equivalents ..... .. ..... ............ ........ .
`Periodic Charr ......................... .. ... .... .
`Logarithms ................. . ....... . ........... .
`Glossary and lnd•x
`Alphabetic Index .......... . .................. .. . .
`Glossary ....................................... .
`
`A1
`A2
`A4
`
`11
`G1
`
`viii
`
`Slayback Exhibit 1064, Page 7 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Pharmacy Library
`University of Wisconsin - Madison
`2130 Chamberlin Hall
`425 N. Charter Street
`Madison, WI 53706-1508
`
`Slayback Exhibit 1064, Page 8 of 59
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`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`CHAPTER 80
`
`Pharmaceutical Necessities
`
`WIiiiam J ~•Illy, Jr
`Manager. Technlcol 5ervices
`PhcrmoceuHcol DMslon
`FMC Corp
`Princeron , NJ 08.543 ·
`
`Significant changes are underway which could alter the
`rights of pharmacy practitioners. Extemporaneous com(cid:173)
`pounding is being reviewed carefully by the FDA to ensure
`that manufacturing operations are not being conducted under
`the guise of pharmacy-practice rights. Additionally, some
`serious accidents have resulted from the improper compound(cid:173)
`ing and handling of extemporaneously prepared prescriptions.
`This chapter does not address the legalities of compound(cid:173)
`ing by a practitioner, but rather is intended as a reference
`source which highlights substances of little or no therapeutic
`
`value which are useful in the compounding of pharmaceuticals.
`These substances, referred to as excipients, also are used for
`the bulk manufacture of pharmaceutical products, but usually
`for different purposes. The excipients described include an(cid:173)
`tioxidants and preservatives; coloring and flavoring agents;
`diluents and binders; emulsifying and suspending agents, oint(cid:173)
`ment bases, solvents and miscellaneous agents. A more de(cid:173)
`tailed review of these excipients and their industrial applica(cid:173)
`tions can be found in the various chapters of Part 8 of this
`text.
`
`0
`
`Butylated Hydroxytoluene
`Phenol, 2,6-bis(l , l •dimethylethyi)-4-methyl- , Butylated
`Hydroxytoluene Crystalline (Diamond-Shamrock) ; Tenox l;JHT
`(Eastman)
`
`Antioxidants and Preservatives
`An antioxidant is a substance capable of inhibiting oxida(cid:173)
`tion and that may be added for this purpose to pharmaceutical
`products subject to deterioration by oxidative processes as,
`for example, the development of rancidity in oils and fats or
`the inactivation of some medicinals in the environment of
`their dosage forms. A preservative is, in the common phar(cid:173)
`maceutical sense, a substance that prevents or inhibits micro(cid:173)
`bial growth and may be added to pharmaceutical preparations
`for this purpose to avoid consequent spoilage of the prepara(cid:173)
`tions by microorganisms. Both antioxidants and preserva(cid:173)
`tives have many applications u:i making medicinal products.
`Alcohol- page 1404.
`Ascorbyl Palmltat~see RPS-18, page 1286.
`Anoxomer-see RPS-1 8, page 1288.
`Benzoic Acid- see RPS-18, page 1235.
`Benzalkonlum Chlorld~page 1264.
`Benzethonium Chlorid~page 1265.
`Benzyl Alcohol- page 1151.
`
`Butylated Hydroxyanlsole
`Phenol , (l ,l-dimethylethyl)-4-methoxy-, Tenox BHA (Eastman)
`
`2,6-Di-tert-butyl-p-cresol I 128-37-0] C16H24O (2 20.35).
`interaction of p-cresol and
`an addition
`Preparation- By
`2-methylpropene. US Pat 2,428,745.
`Description- White, tasteless crystals with a mild odor; stable in light
`or air; melts at 70°.
`Solubillty-lnsoluble in water; l g in 4 mL alcohol, I . I mL chlorofonn
`or I. I mL ether.
`Uses--An anti.oxi.dant employed to retard oxidative degradation of
`oils and fats in various cosmetics and pharmaceuticals.
`Cetylpyridinlum Chloride-see RPS-18, page 1171.
`
`tert-Butyl-4-methoxyphenol (25013-16-5IC 11H160 2 (180 .25).
`Preparation- By an addition interaction of p-methoxyphenol and
`2-methylpropene. US Pat 2,428,745.
`Description- White or slightly yellow, waxy solid having a faint, char(cid:173)
`acteristic odor.
`Solubillty-lnsoluble in water; I gin 4 mL alcohol, 2 mL chloroform or
`l.2mLether.
`Uses--An antioxidant in cosmetics and pharmaceuticals containing
`fats and oils.
`Butylparaben-see APS-18 page 1170.
`
`Chlorobutanol
`2-Propanol, I ,l, l-trichloro-2-methyl-, Chlorbutol; Chlorbutanol;
`Acetone chloroform; Chloretone (Stauffer)
`{CC l, )C{CH:,)2OH
`1,1,1-Trichloro-2-methyl-2-propanol [57-15-8] C4H7CI3O (177.46);
`hemihydrate I 6001 -64-5] (186.46).
`Preparation--Chloroform undergoes chemical addition to acetone
`under the catalytic influence of powdered potassium hydroxide.
`Description--Colorless to white crystals, of a characteristic, some(cid:173)
`what camphoraceous odor and taste; anhydrous melts about 95°; hydroUI
`melts about 76°; boils with some decomposition between 165 and 168".
`Solubillty- 1 gin 125 mL water, I mL alcohol or about IO mL gJycerini
`freely soluble in chloroform, ether or volatile oils.
`
`1380
`
`Slayback Exhibit 1064, Page 9 of 59
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`
`

`

`Incompatibilities-The anhydrous form must be used in order to
`prepare a clear solution in liquid petrolatum. It is decomposed by alka(cid:173)
`lies; ephedrine is sufficiently alkaline to cause its breakdown with the
`formation of ephedrine hydrochloride which will separate from a liquid
`It is only slightly soluble in water, hence alcohol
`petrolatum solution.
`must be used to dissolve the required amount in certain vehicles. A soft
`mass is produced by trituration with antip1..1ri:ne, menthol, pherwl and
`other substances.
`Uses-Topically, as a solution in clove oil as a dental analgesic.
`It
`has local anesthetic potency tb a mild degree and has been employed as an
`anesthetic dusting powder (1 to 5%) or ointment {10%).
`It has antibacte(cid:173)
`It is used chiefly as a preservative in
`rial and germicidal properties.
`solutions of epinephrine, posterior pituitary, etc. When administered
`orally, it has much the same therapeutic use as chloral hydrate. Hence, it
`has been employed as a sedative and hypnotic. It has been taken orally to
`allay vomiting due to gastritis.
`Dose--Topical, as a 25% solution in clove oil.
`Other Dose Jrifarmation-The oral dose is 300 mg to 1 g , given in
`tablets or capsules.
`
`Dehydroacetlc Acid
`
`Keto form: 2H-Pyran-2,4(3H)-dione, 3-acetyl-6-methyl-,
`
`H,ClloY o
`'-f"cocH,
`OH
`
`(~to form)
`
`Eno! form: 3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one [520-45-6
`(Keto) ], [771-03-9 (enol)] C8H8O4 (168.15).
`Preparation-By fractional distillation of a mixture. of ethyl acetoac(cid:173)
`etate and sodium bicarbonate, maintaining almost total reflux conditions,
`allowing only ethanol to be removed. The residue is distilled under
`vacuum. OrgSynCoUIIJ: 231, 1955.
`Description-White to creamy-white crystalline powder melting about
`I Io• with sublimation.
`·
`I g dissolves in 25 gacetone, 18 g benzene, 5 g methanol
`Solubility-
`or 3 g alcohol.
`Use,..._Preservative.
`
`Ethylenedlamlne
`
`1,2-Ethanediamine
`
`Ethylenediamine [ 107-15-3] C2H8N2 (60.10).
`Caution-Use care in handling because of its caustic nature and the
`irritating properties of its vapor.
`Note-It is strongly alkaline and may readily absorb carbon diox(cid:173)
`ide fmm the air to form a nonvolatile carbonate. Protect it against
`undue exposure.to the atmosphere.
`Preparation:...By reacting ethylene dichloride with ammonia, then
`adding NaOH and distilling.
`Descriptlon--Clear, colorless or only slightly yellow liquid, having an
`ammonia-like odor and strong alkaline reaction; miscible with water and;
`alcohol; anhydrous boils 116 to 11 7° and solidifies at about 8°; volatile
`with steam; a strong base and readily combines with acids to form salts
`with the evolution of much heat.
`Uses--A pharmaceutical necessity for AminophyUine Injection.
`It is irritating to skin and mucous membranes. It also may cause sensiti(cid:173)
`zation characterized by asthma and allergic dermatitis.
`Ethylparaben-see RPS-18, page 1171.
`Ethyl Vanillin-page 1386.
`Glycerin-pages 1041 and 1405.
`Hypophosphorus Acid-page 1410.
`Malic Acid BP-see RPS-18, page 1288.
`Methylparaben-see RPS-18, page 1171.
`Monothioglycerol-see RPS-18, page 1287.
`Phenol-page 1412.
`Phenylethyl Alcohol- page 1389.
`Phenylmercuric Nitrate-page 1270.
`
`PHARMACEUTICAL NECESSITIES
`
`1381
`
`Potassium Benzoate
`
`Benzoic acid, potassium salt
`
`[582-25-2) C7H5KO2 (160.21) {llllhydrous).
`Descriptlon--Crystalline powder.
`Solublllty--Soluble in water or alcohol.
`Uses--Preservative.
`
`Potassium Metablsulflte
`
`Dipotassium pyrosulfite
`
`,
`[16731-55-8 ] J<i82Os (222.31).
`Description-White crystals or crystalline powder with an odor ofSO2.
`Oxidizes in air to the sulfate. May ignite on powdering in a mortar if too
`much heat develops.
`Solubility-Freely soluble in water; insoluble in alcohol.
`Uses-Antioxidant.'
`
`Potassium Sorbate
`
`2,4-Hexadienoic acid, (E,E)·. potassium salt; 2,4-Hexadienoic acid,
`potassium salt; Potassium 2,4-Hexadienoate
`
`I
`
`.
`
`Potassium (E,E)-sorbate; potassium sorbate [590-00-1 )·(24634- 61-5]
`C6H1KO2 (150.2 2).
`Preparatlon--Sorbic Acid is reacted. with an equimolar portion of
`KOH. The resulting potassium sorbate may be cry~tallized from aqueous.
`·
`ethanol. US Pat3,l 73,948.
`Description-White crystals or powder with a characteristic odor;
`melts about 2 70° with decomposition.
`Solublllty-1 gin 4 .5 mL water, 35 mL alcohol, > 1000 mL chloroform
`or> l000mLether.
`Uses-A water-soluble salt of sorbic acid used in pharmaceuticals to
`inhibit tmi growth of molds and yeasts.
`Its toxicity is low, but it r:nay
`irritate the skin.
`Propyl Gallate BP-see RPS-18, page 1288.
`Propylparaben-see RPS-18, page 1171.
`Sassafras OIi-page 1392.
`Sodium Benzoate-page 1271.
`
`.,
`
`Sodium Blsulflte
`
`Sulfurous acid, monosodium salt; Sodium Hydrogen Sulfite; Sodium
`Acid Sulfite; Leucogen
`
`Mono$odium sulfite (7631-90-5) NaHSO3 and sodium metabisulfite
`(Nai8iO5) in varying proportions; yields 5 8.5--6 7.4% of SO2•
`Description-White or yellowish white crystals or granular powder
`having the odor of sulfur dioxide; unstable in air.
`Solubility-I g in 4 mL water; s lightly soluble in alC!)hOI.
`Use,..._An ·antioxidant and stabilizing agent. Epinephrine hydro(cid:173)
`chloride solutions may be staoilized by the addition of small quantities of
`the salt. It also is used to help solubilize kidney stones. It is useful for
`removing permanganate stains and for solubilizing certain dyes and other
`chemicals (see Menadione Sodium BisuYi,te, RPS-1 7, page 10 11 ).
`
`Slayback Exhibit 1064, Page 10 of 59
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`
`

`

`1382
`
`CHAPTER 80
`
`Sodium Metablsulftte
`
`Disulfurous acid, disodium salt
`
`Disodium pyrosulfite (7681-57-4 ]Na:iS20 5 (190.10).
`Pre paratio n-Formed when sodium bisulfite undergoes thermal
`It also may be prepared by passing sulfur dioxide over
`dehydration.
`sodium carbonate.
`Description-White crystals or white to yellowish crystalline powder
`having an odor of sulfur dioxide; on exposure to air and moisture, it is
`slowly oxidized to sulfate.
`Solubility-I gin 2 mL water; slightly soluble in alcohol; freely soluble
`in glycerin.
`It is used in easily oxidized pharmaceuti(cid:173)
`Uses--A reduci'l1{} agent.
`cals, such as epinephrine hydrochloride and phenylephrine hydrochloride
`iajections, to retard oxidation.
`
`Sodium Propionate-see RPS-18, page 1236.
`
`SorblcAcid
`2,4-Hexadienoic acid, (E,E)-, 2,4-Hexadienoic acid
`
`(E,E}Sorbic acid; Sorbic acid I 22500-92-1 I I 110-4 4-1 J C6Ha02 ( 112.13).
`Pre paration-By various processes. Refer to US Pat 2,921,090.
`Description-Free-flowing, white, crystalline powder, having a charac-
`teristic odor; melts about 133°.
`Solubility-
`I gin 1000 mL water, 10 mL alcohol, 15 mL c hloroform,
`30 mL ether or 19 mL propylene glycol.
`Uses--A mold and yeast inhibitor.
`agent for foods, especially cheeses.
`Sulfur Dioxide-see RPS-18, page 1288.
`Thimerosal-pag1e 1271 .
`
`It also is used as a fungistatic
`
`Coloring, Flavoring and Diluting Agents
`
`The use of properly colored and flavored medicinal sub(cid:173)
`stances, although offering no particular therapeutic advan(cid:173)
`tage, is of considerable importance psychologically. A water(cid:173)
`clear medicine is not particularly acceptable to most patients,
`and, in general, is thought to be inert. Many very active
`medicinal substances are quite unpalatable, and the patient
`may fail to take the medicine simply because the taste or
`
`appearance is objectionable. Disagreeable medication can
`be made both pleasing to the taste and attractive by careful
`selection of the appropriate coloring, flavoring and diluting
`agents. Therefore,judicious use of these substances is impor(cid:173)
`tant in securing patient cooperation in taking or using the
`prescribed medication and continued compliance with the
`prescriber's intent.
`
`Coloring Agents or Colorants
`
`Coloring agents may be defined as compounds employed in
`pharmacy solely for the purpose of imparting color. They
`may be classified in various ways, eg, inorganic or organic.
`For the purpose of this discussion two subdivisions are used:
`Natural Colaring Principles and Synthetic Coloring
`Principles. The members of these groups are used as colors
`for pharmaceutical preparations, cosmetics, foods and as bac(cid:173)
`teriological stains and diagnostic agents.
`
`purple, once a sign of royalty, was prepared by air oxidation
`of a colorless secretion obtained from the glands of a snail
`(Murex brandari.s). This dye now is known to be 6,6'(cid:173)
`dibromoindigo, and has been synthesized, but cheaper dyes of
`the same color are available. Cochineal from the insect Coc(cid:173)
`cus cacti contains the bright-red coloring principle carminic
`acid, a derivative of anthraquinone. This dye is no longer
`used in foods and pharmaceuticals due to Salmonella contami(cid:173)
`nation.
`
`Natural Coloring Principles
`
`Natural coloring principles are obtained from mineral, plant
`and animal sources. They are used primarily for artistic
`purposes, as symbolic adornments of natives, as colors for
`foods, drugs and cosmetics and for other psychological ef(cid:173)
`fects.
`Mineral colors frequently are termed pigments and are
`used to color lotions, cosmetics and other preparations, usu(cid:173)
`ally for external application. Examples are Red Ferric Ox(cid:173)
`ide (page 1416) and Yellow Ferric Oxide (page 1416),
`titanium dioxide (page 884) and carlion black.
`The term pigment also is applied generically to plant colors
`by phytochemists. Many plants contain coloring principles
`that may be extracted and used as colorants, eg, chlorophyll.
`Anattenes are obtained from annatto seeds and give yellow to
`orange water-soluble dyes. Natural beta-carotene is a yellow
`color extracted from carrots and used to color margarine.
`Alizarin is a reddish-yellow dye obtained from the madder
`plant. The indigo plant is the source of a blue pigment called
`indigo. Flavones, such as riboflavin, rutin, hesperidin and
`quercetin, are yellow pigments. Saffron is a glycoside that
`gives a yellow color to drugs and foods. Cudbear and red
`saunders are two other dyes obtained from plants. Most
`plant colors now have been characterized and synthesized,
`however, and those with the desirable qualities of stability,
`fastness and pleasing hue are available commercially as syn(cid:173)
`thetic products.
`Animals have been a source of coloring principles from the
`earliest periods of recorded history. For example, Tyrian
`
`Synthetic Coloring Principles
`
`Synthetic colo,ring principles date from 1856 when WH
`Perkin accidentally discovered mauveine, also known as a
`Perkin's purple,. while engaged in unsuccessful attempts to
`synthesize quinine. He obtained the dye by oxidizing aniline
`containing o- andl p-toluidines as impurities. Other discover(cid:173)
`ies of this kind followed soon after, and a major industry grew
`up in the field of coal-tar chemistry.
`The earliest colors were prepared from aniline and for many
`years all coal-tar dyes were called aniline colors, irrespective
`of their origin. The coal-tar dyes include more than a dozen
`well-defined groups among which are nitroso-dyes, nitro(cid:173)
`dyes, azo-dyes, oxazines, thiazines, pyrazolones, xan(cid:173)
`thenes, indigoids, anthraquinanes, acridines, rosanilines,
`phthaleins, quinolines and others. These in tum are classi(cid:173)
`fied, according to their method of use, as acid dyes and basic
`dyes, or direct dyes and rrwrdant dyes.
`Certain structural elements in organic molecules, called
`chrorruYphore groups, give color to the molecules, eg, azo
`(-N=N-
`), nitroso (-N==O), nitro (-N02), azoxy
`(- N=N-0-), carbonyl
`(>C-0) and ethylene
`( > C=C < ). Other such combinations augment the chromo(cid:173)
`phore groups, eg, methoxy, hydroxy and amino groups and
`are known as auxochromes.
`Stability-Most dyes are relatively unstable chemicals due
`to their unsaturated structures. They are subject to fading
`due to light, metals, heat, microorganisms, oxidizing and re-
`
`Slayback Exhibit 1064, Page 11 of 59
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`PHARMACEUTICAL NECESSITIES
`
`1383
`
`In tablets, fading
`
`ducing agents plus strong acids and bases.
`may appear as spotting and specking.
`Uses--Most synthetic coloring principles are used in color(cid:173)
`ing fabrics and for various artistic purposes. They also find
`application as indicators, bacteriological stains, diagnostic
`aids, reagents in microscopy, etc.
`Many coal-tar dyes originally were used in foodstuffs and
`beverages without cai;eful selection or discrimination be(cid:173)
`tween those that were harmless and those that were toxic and
`without any supervision as to purity or freedom from poison-
`ous constituents derived from their manufacture.
`,
`After the passage of the Food and Drugs Act in 1906, the US
`Department of Agriculture established regulations by which a
`few colors came to be known as permitted colors. Certain
`of these colors may be used in foods, drugs and cosmetics, but
`only after certification by the FDA that they meet certain
`specifications. From this list of permitted colors may be
`produced, by skillful blending and mixing, other colors that
`may be used in foods, beverages and pharmaceutical
`preparations. Blends of certified dyes must be recertified.
`The word "permitted" is used in a restricted sense. It does
`not carry with it the right to use colors for purposes of decep(cid:173)
`tion, even though they are "permitted" colors, for all food
`la)VS have clauses prohibiting the coloring of foods and bever(cid:173)
`ages in a manner so as to conceal inferiority or to give a false
`appearance of value.
`The certified colors are classified into three groups: FD&C
`dyes which legally may be used in foods, drugs and cosmetics,
`D&C ·dyes which legally may be used in drugs and cosmetics
`and External D&C dyes which legally may be used only in
`externally applied drugs and cosmetics. There are specific
`limits for the pure dye, sulfated ash, ether extractives, soluble
`and insoluble matter, uncombined intermediates, oxides , chlo(cid:173)
`rides and sulfates. As the use status of these colors is subject
`to change, the latest regulations of the FDA should be con(cid:173)
`sulted to determine how they may be used~specially since
`several FD&C dyes formerly widely used have been found to
`be carcinogenic even when "pure" and, therefore, have been
`banned from use.
`The Coal-Tar Color Regulations specify that the term '' exter(cid:173)
`nally applied drugs and cosmetics" means drugs and cosmet(cid:173)
`ics which are applied only to external parts of the body and not
`to the lips or any body surface covered by mucous membrane.
`No certified dye, regardless of its category, legally may be
`useq in any article which is to be applied to the area of the eye.
`Lakes are calcium or aluminum salts of certified dyes ex(cid:173)
`tended on a substrate of alumina. They are insoluble in water
`and organic solvents, hence are used to color powders, phar(cid:173)
`maceuticals, foods, hard candies and food packaging.
`
`The application of dyes to pharmaceut ical preparations is
`an art that can be acquired only after an understanding of the
`characteristics of dyes and knowledge of the composition of
`the products to be colored has been obtained. Specific rules
`for the choice or application of dyes to pharmaceutical prepa(cid:173)
`rations are difficult to formulate. Each preparation may pre(cid:173)
`sent unique problems.
`Preparations which may be colored include most liquid
`pharmaceuticals, powders, ointments and emulsions. Some
`general hints may be offered in connection with solutions and
`powders, but desired results usually can be obtained only by a
`series of trials.
`In general, an inexperienced operator tends
`to use a much higher concentration of the dye than is neces(cid:173)
`sary, resulting in a dull color. The amount of dye present in
`any pharmaceutical preparation should be of a concentration
`high enough to give the desired color and low enough to
`prevent toxic reactions and permanent staining of fabrics and
`tissues.
`Liquids (Solutions)--The dye concentration in liquid preparations
`andsolutionsusuallyshouldcomewithinarange of0.0005%(1 in200,000)
`and0.001% (1 in 100,000), dependinguponthedepthofcolorwantedand
`the thickness of column to be viewed in the container. With some dyes,
`concentrations as low as 0.0001% (I in 1,000,000) may have a distinct
`tinting effect. Dyes are used mos t conveniently in the form of stock
`solutions.
`Powders-White powders usually require the incorporation of 0.1 % ( I
`in 1000) of a dye to impart a pastel color. The dyes may be incorporated
`into the powder by dry-blending in a ball rpill or, on a small scale, with a
`mortar and pestle. The dye is incorporated by trituration and geometric
`dilution. Powders also may be colored evenly by adding a solution of the
`dye in alcohol or some other volatile solvent having only a slight solve nt
`action on the powder being colored. When this procedure is employed,
`the solution is added in portions, with thorough mixing after each addition,
`after which the solvent is allowed to evaporate from the mixture.
`Many of the syrups and elixirs used as flavoring and diluting
`agents are colored. When such agents are used no further
`coloring matter is necessary. The use of colored flavoring
`agents is discussed in a subsequent section. However, when
`it is desired to add color to an otherwise colorless mixture, one
`of the,