`
`ALKERMES EXh. 2018
`
`Luye V. Alkermes
`IPR2016-1096
`
`ALKERMES Exh. 2018
`Luye v. Alkermes
`IPR2016-1096
`
`

`

`11TH
`
`EDITION
`
`Remington’s
`
`
`
`ALFONSO R GENNARO
`
`Editor, and Chairman
`of the Editorial Board
`
`

`

`. Pharmaceutical .
`
`Sciences
`
`e1985
`
`L:gMACK PUBLISHING COPMANY
`’Egs’ron, Pennsylvania 18042
`
`

`

`in the Office of the Librarian of Congress, at Washington, DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`Copyright 1948, 1951, by‘The Philadelphia College of. Pharmacy and Science
`Copyright © 1956, 1960,.11965,1970, 1975, 1980, 19:85, by The Philadelphia College ofPharrnacy and
`Science
`‘
`..
`'
`'
`‘
`.,
`_'
`.
`
`All Rights Reserved
`
` Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`
`Library of Congress Catalog Card No 60—53334
`ISBN 0-912734-03-5
`
`The use of portions of the text of USP XX, NF XV, and USAN and the USP Dictionary of Drug
`Names is by permission of the USP Convention. The Convention is not responsible for any
`inaccuracy of quotation or for any false or misleading implication that may arise from
`separation of excerpts from the original context or by obsolescence resulting from
`publication of a supplement.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia (USP) and/or the National
`Formulary (NF).
`In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`representations of them herein, the context and effect of the official compendia shall
`prevail.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`

`

`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`Scope
`1
`2 Evolution of Pharmacy
`3 Ethics
`.
`.
`.
`4 Pharmacists in Practice
`
`'5 Pharmacists in Industry
`6 Pharmacists in Government
`
`7 Drug Information .
`8 Research
`
`Part 2
`
`Pharmaceutics
`
`9 Metrology and Calculation .
`10 Statistics
`
`.
`
`11 Computer Science
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`12 Calculus
`13 Molecular Structure, Properties, and States of
`Matter
`.
`.
`"
`14 Complexation .
`,
`.
`.
`.
`15 , Thermodynamics .
`'16 Solutions and Phase Equilibria
`17
`Ionic Solutions and Electrolytic Equilibria
`18 Reaction Kinetics .
`19
`Interfacial Phenomena
`.
`.
`.
`.
`.
`20 Colloidal Dispersions
`21
`Particle Phenomena and Coarse Dispersions
`22 Rheology .
`'
`
`.
`
`Pharmaceutical Chemistry
`
`3
`8
`19
`27
`
`34
`42
`
`49
`59
`
`69
`104
`
`140
`148
`
`161
`186
`.198
`207
`230
`249
`258
`271
`301
`330
`
`’ 44
`45
`46
`47
`
`48
`49
`50
`51
`52
`53
`. 54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`7 1
`72
`
`.
`.
`.
`.
`.
`.
`.
`Respiratory Drugs
`.
`.
`.
`.
`.
`.
`.
`.
`Sympathomimetic Drugs .
`Cholinomimetic (Parasympathomimetic) Drugs
`Adrenergic and Adrenergic Neuron Blocking Drugs
`
`Antimuscarinic and Antispasmodic Drugs
`Skeletal Muscle Relaxants
`
`.
`
`.
`
`.
`
`.
`
`.
`
`,
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`.
`.
`Diuretic Drugs
`Uterine and Antimigraine Drugs
`Hormones .
`.
`.
`.
`.
`.
`.
`
`Vitamins and Other Nutrients .
`Enzymes
`.
`.
`.
`.
`.
`.
`.
`General Anesthetics
`Local Anesthetics .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`Sedatives and Hypnotics .
`.
`Antiepileptics
`.
`.
`.
`.
`.
`Psychopharmacologic Agent
`Analgesics and Antipyretics
`Histamine and Antihistamines
`.
`.
`Central Nervous System Stimulants
`Antineoplastic and Immunosuppressive Drugs .
`Antimicrobial Drugs .
`.
`Parasiticides .
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`Pesticides .
`.
`.
`Diagnostic Drugs
`Pharmaceutical Necessities
`.
`Adverse Effects of Drugs .
`.
`.
`.
`.
`.
`Pharmacogenetics
`Pharmacological Aspects of Drug Abuse
`Introduction of New Drugs
`
`.
`
`866
`876
`894
`
`911
`921
`
`933
`946
`951
`
`1002
`1035
`1039
`1048
`
`1059
`1075
`1084
`1099
`1124
`1133
`1139
`1158
`1234
`
`1241
`1264
`1278
`1321
`1336
`1341
`1357
`
`Part 3
`
`Inorganic Pharmaceutical Chemistry .
`23
`24 Organic Pharmaceutical Chemistry
`.
`.
`.
`.
`.
`.
`.
`25 Natural Products
`.
`.
`.
`.
`26 Drug Nomenclature—United States Adopted
`Names
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`27 Structure-Activity Relationship and Drug Design
`
`.
`
`349
`374
`397
`
`428
`
`435
`
`73
`74
`
`75
`
`Part 1
`
`Biological Products
`
`.
`.
`.
`.
`I.
`.
`Principles of Immunology
`Immunizing Agents and Diagnostic Skin Anti-
`gens........
`Allergenic Extracts .
`.
`
`1371
`
`1380
`1396
`
`Part 4
`
`Radioisotopes in Pharmacy and Medicine
`
`28 Fundamentals of Radioisotopes .
`29 Medical Applications of Radioisotopes
`
`Part 5
`
`Testing and Analysis
`
`30 Analysis of Medicinals
`31 Biological Testing .
`.
`.
`32 Clinical Analysis
`.
`.
`33 Chromatography .
`34
`Instrumental Methods of Analysis
`35 Dissolution
`
`.
`
`.
`
`.
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`Part 6
`
`Pharmaceutical and Medicinal Agents
`
`36 Diseases: Manifestations and Pathophysiology
`
`’\ 37 Drug Absorption, Action, and Disposition
`38 Basic Pharmacokinetics
`.
`.‘
`.
`.
`.
`.
`.
`39 Principles of Clinical Pharmacokinetics
`40 Topical Drugs
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`41 Gastrointestinal Drugs .
`.
`.
`42 Blood, Fluids, Electrolytes, and Hematologic
`Drugs
`.
`.
`.
`43 Cardiovascular Drugs
`
`453
`471
`
`503
`550
`559
`593
`619
`653
`
`713
`741
`762
`773
`792
`
`816
`843
`
`Part 8
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`\ 76
`77
`78
`79
`80
`81
`82
`83
`84
`
`85
`86
`87
`88
`89
`F3?
`‘3 92
`L93
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Preformulation .
`Bioavailability and Bioequivalency Testing .
`Separation
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Sterilization .
`.
`.
`.
`Tonicity, Osmoticity, Osmolality, and Osmolarity .
`Plastic Packaging Materials
`Stability of Pharmaceutical Products
`.
`.
`.
`.
`.
`.
`Quality Assurance and Control
`.
`.
`Solutions, Emulsions, Suspensions, and Extrac~
`tives..
`
`Parenteral Preparations .
`Intravenous Admixtures
`
`.
`
`.'
`
`.
`
`.
`
`Ophthalmic Preparations
`.
`Medicated Applications
`.
`.
`.
`Powders
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Oral Solid Dosage Forms .
`Coating of Pharmaceutical Dosage Forms .
`Sustained Release Drug Delivery Systems
`Aerosols
`
`.
`.
`
`Part 9
`
`Pharmaceutical Practice
`
`94
`95
`96
`
`Ambulatory Patient Care
`Institutional Patient Care
`Long-Term Care Facilities
`
`XV
`
`1409
`1424
`1432
`1443
`1455
`1473
`1478
`1487
`
`1492
`
`1518
`1542
`
`1553
`1567
`1585
`1603
`1633
`1644
`1662
`
`1681
`1702
`1723
`
`

`

`'105
`106
`107
`108
`109
`
`.
`
`.
`
`.
`
`,zsurgical Supplies .
`Poison Control
`.
`.
`.
`.
`.
`Laws Governing Pharmacy
`Pharmaceutical Economics and Management
`Dental Services
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`_.,
`
`.
`
`.
`
`1869
`1879
`1690
`1917
`1935
`
`Index
`
`Alphabetic Index
`
`1946
`
`.
`
`.
`
`.
`
`u-
`
`.
`
`.
`
`97
`98
`
`100
`101
`102
`100
`
`104
`
`
`
`.. I
`
`~—.--)
`L.-
`.ll
`i'l
`a
`
`1‘???”
`
`.
`The Pharmacist and Public Health .
`The Patient: Behavioral Determinants .
`Patient Communication
`.
`PatientCompliance .
`.
`*
`The Prescription
`.
`_
`_
`.
`.
`.
`.
`Drug Interactions .
`Utilization ,and Evaluation of Clinical Drug
`Literature .
`.
`Health Accessories
`
`.
`
`-
`
`..
`
`.
`
`.
`
`.
`
`_;
`
`u
`
`.
`
`-
`
`.
`
`.-.
`
`.
`
`.
`
`u
`
`. ~
`
`

`

`1306
`
`CHAPTER 68
`
`Polyethylene glycol monostearate [9004-99-3]; a mixture .of
`monostearate anddistearate esters of mixed polyoxyethylene diols
`and corresponding free glycols, the average polymer length being
`equivalent to about 40 oxyethylene units. Polyoxyethylene 50
`Stearate is a‘similar mixture in which the average polymer length is.
`equivalent to about 50 oxyethylene units.
`1
`'
`Preparation—Onemethod consists of heating the corresponding
`polyethylene glycol with an equimolar portion of stearic acid.
`Description—White to light-tan waxy solid; odorless or has a faint
`fat-like odor; congeals between 37° and 47°.
`_
`Solubility—Soluble in water, alcohol, ether, and acetone; insoluble in
`mineral and vegetable oils.
`Uses—Contains ester and alcohol functions that impart both
`lyophilic and hydrophilic characteristics to make polyoxyl 40 stearate
`useful as- a surfactant and emulsifier.
`It is an ingredient of some
`water-soluble ointment and~cream bases.
`
`Polysorbates
`
`Sorbitan esters, poly(oxy.1,2-ethanediyl) derivs., Monitans
`(Ives-Cameron); Sorlates (Abbott); Tweens (ICI Americas)
`HolczHaolw
`_.-(0C2H4)x 0“
`r
`.(|3(0C2H,)yOH
`HzcloceHalzR
`[Sum of w, my, and z is 20‘I
`a is (anumoo)
`
`9
`
`"
`
`Sorbitan esters, polyoxyethylene derivatives;-fatty acid esters of
`sorbitol and its anhydrides copolymerized with a varying number of
`
`moles of ethylene oxide. The NF recognizes: Polysorbate 20
`(structure given above), a laurate ester; Polysorbate 40, a palmitate
`ester; Polysorbate 60, a mixture of stearate and palmitate esters;
`Polysorbate 80, an cleate ester.
`Preparation—These important nonionic surfactants (page 267)
`are prepared starting with sorbitol by (1) elimination of water forming
`sorbitan (a cyclic sorbitol anhydride); (2) partial esterification of the
`sorbitan with a fatty acid such as oleic or stearic acid yielding a hexitan
`ester known commercially as a Span; and (3) chemical addition of
`ethylene oxide yielding a Tween (the polyoxyethylene derivative).
`Description—Polysorbate 80: Lemon- to amber-colored, oily liquid
`having a faint, characteristic odor, and a warm, somewhat bitter taste;
`specific gravity between 1.07 and 1.09; pH (1:20 aqueous solution) between
`6 and 8.
`Solubility—Polysorbate 80: Very soluble in water, producing an
`odorless and nearly colorless solution; soluble in alcohol, cottonseed: oil,
`corn oil, ethyl acetate, methanol, and toluene; insoluble in mineral oil.
`
`Uses—Because of their hydrophilic and lyophilic characteristics,
`these, nonionic surfactants are very useful as emulsifying agents
`forming o/w emulsions in pharmaceuticals, cosmetics, and other types
`of products. Polysorbate 80 is an ingredient in Cool Tar Ointment
`and Solution. See Glycol Ethers" (page 1305).
`
`Other Water-Soluble Ointment Base Component
`Polyethylene Glycol 400 Monostearate USP XVI—It is an ether,
`alcohol, and an ester. Semitransparent, whitish, odorless, or nearly
`odorless mass; melting range 30° to 34°. Freely soluble in carbon tetra-
`chloride, chloroform, ether, and petroleum benzin; slightly soluble in al-
`cohol; insoluble in water. Uses: Anonionicsurface-active agent in the
`preparation of creams, lotions, ointments, and similar pharmaceutical
`preparations, which are readily soluble in water.
`
`Pharmaceutical Solvents
`
`The remarkable growth of the solvent industry is attested
`by the more than 300 solvents now being produced on an in—
`dustrial scale. Chemically, these include a great Variety of
`organic compounds, ranging from hydrocarbons through al-
`cohols, esters, ethers, and acids to nitroparaffins. Their main
`applications are in industry and the synthesis of organic
`chemicals. Comparativer few, hOWever, are used as solvents
`in pharmacy, because of their toxicity, volatility, instability,
`and/or flammability. Those commonly used as pharmaceu-
`tical solvents are described in this section.
`
`Acetone
`
`2-Propanone; Dimethyl Ketone; fi-Ketopropane
`CH3COCH3
`
`Acetone [67—64-11 CgHso (58.08).
`Caution—Acetone is very flammable. Do not use where it may
`be ignited.
`'
`”
`Preparation—Formerly obtained exclusively from the destructive
`distillation of wood. ‘The distillate, consisting principally of meth-
`anol, acetic acid, and acetone was neutralized with lime and the ace-
`tone was separated from the methyl alcohol by fractional distillation.
`Additional quantities of aCetone were obtained by pyrolysis of the.
`calcium. acetate formed in the neutralization of the distillate.
`Acetone is nowlargely obtained as a by-product of the butyl alcohol
`industry. This alcohol is formed in the fermentation of carbohydrates
`such as, corri starch, molasses, etc, by the action of the bacterium
`Clostridium acetobutylicum (Weizmann fermentation) and acetone
`is always one of the products formed in the process. It is also obtained
`by the catalytic oxidation of isopropyl alcohol, which is prepared from
`propylene resulting from the "cracking" of crude petroleum.
`Des_cription~—Transparent, colorless, mobile, volatile, flammable liquid
`with a characteristic odor‘; specific gravity not more than 0.789; distils
`between 555° and 57°; congeals at about -95°; aqueous solution is neutral
`‘ to litmus.
`-
`Solubility-Miscible with water, alcohol, ether, chloroform, and with
`most volatile oils.
`
`In combi-
`Uses—As an antiseptic in concentrations above 80%.
`nation with alcohol it is used as an antiseptic cleansing solution. It
`is employed as a menstruum in the preparation of oleoresins in place
`of ether.
`It is used asa solvent for dissolving fatty bodies, resins,
`pyroxylin, mercurials, etc., and also in the manufacture of many or-
`ganic compounds such as chloroform, chlorobutanol, and ascorbic
`acid.
`v
`
`Alcohol
`
`Ethanol; Spiritus Vini Rectificatus; S. V. R.; Spirit of Wine;
`Methylcarbinol
`
`Ethyl alcohol [64-17-5]; contains 92.3—93.8%, by weight (94.9—96.0%,
`by volume), at 15.56° (60°F) of C2H5OH (46.07).
`Preparation—Alcohol has been made for centuries by fermenta-
`tion of certain carbohydrates in the presence of zymase, an enzyme
`present in yeast cells. Utilizable carbohydrate-containing materials
`include molasses, sugar cane, fruitjuices, corn, barley, wheat, potato,
`wood, and waste sulfite liquors. As yeast is capable of fermenting only
`D-glucose, D-fructo'se, D-mannose, and D-galactose it is essential that
`more complex carbohydrates, such as starch, be converted to one or
`more of these simple sugars before they can be fermented. This is.
`variously accomplished, commonly by enzyme- or acid—catalyzed
`hydrolysis.
`,
`_
`g The net reaction that occurs when a hexose, glucose for example,
`is fermented to alcohol may be represented as
`
`CeHmOs —’ 202H50H + 2C02
`
`but the mechanism of the process is very complex. The fermented
`liquid, containing about 15% of alcohol, is distilled to obtain a distillate
`containing 94.9% of 02H50H, by volume. To produce absolute al-
`cohol, the 95% product is dehydrated by various processes.
`Alcohol may be produced also by hydration of ethylene, abundant
`supplies of which are available from natural and coke oven gases, from
`waste gases of the petroleum industry, and other sources.
`In another
`synthesis acetylene is catalytically hydrated to acetaldehyde, which
`is then catalytically hydrogenated to ethyl alcohol.
`
`sligl
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