18TH
`
`EDITION
`
`Remington’s
`
`ALFONSO R GENNARO
`
`Editor, and Chairman
`of the Editorial Board
`
`AstraZeneca Exhibit 2132 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`
`

`

`Pharmaceutical
`
`Sciences
`
`1990
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`AstraZeneca Exhibit 2132 p. 2
`
`

`

`Entered unending to Actof Congress, in the year_1.885 by Joseph PRemington,.
`in the Office of the Librarian of Congresa', at Washington DC
`
`Copyright 1389, 1894, 1905. 1907. .1917, byJoeeph P Remington
`
`Copyright 1926, 1936. by Joseph P Remington Etate
`
`Copyright 1948. 1951, by The Philadelphia College of Pharmacy and Scheme
`
`Copyright 9 1.956, 1980. 1965. 1970,1975, 1930. 1985. 1990, 113* The Philadelphia college 01"
`Pharmacy and Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912me
`
`The use animate-a! famine from UEAN and the USP Dictionm offlmg Names is by
`permission-of The USP Convention. The Convention is not responsible for any inaccuracy
`con-mined ha-ein.
`
`NOTICE—This sex: is not intended to represent, nor shall it be interpreted to be. the equivalent
`of or a substitute for the official United States Hmmacopeia (USP) andfor theNatienai
`Formulary LNFJ. In the event of any difference or discrepancy between the current official
`USP or NFetnndarda of strength, quality. purity, paekaghIg-nnd labeling for drugs and
`representations of them herein. the center: and effect of the official campendia shall
`prevail.
`
`Printed in the United State; ofAmen’ca by the Mack Printing Company. EbstM.Pennsylnania
`
`AstraZeneca Exhibit 2132 p. 3
`
`

`

`Remington's Pharmaceutical Sciences .
`
`. . a treatise on the theory
`
`and practice of the pharmaceutical sciences, with essential
`
`information about pharmaceutical and medicinal agents: also a guide
`
`to the professional responsibilities of the pharmacist as the
`
`dmguinfonnation specialist of the health team. . . A textbook
`
`and reference work for pharmacists. physicians and other
`
`practitioners of the pharmaceutical and medical sciences.
`
`EDITORS
`
`_
`
`Alfonso R Gennaro, Chairman
`
`Thomas Medwick
`
`Grafton D Chase
`Ara Der Marderosion
`
`Stewart-C Howey
`
`Daniel A Hussar
`
`Edward G Ripple
`Joseph B Schwartz
`
`Ewart A Swinyard
`
`Gilbert L Zinls
`
`AUTHORS
`
`The 109 chapters of this edition of Remington's Pharmaceutical
`Sciences were written by the editors, by members of the
`
`Editorial Board. and by other authors listed on pages ix to" xi.
`
`Managing Editor
`
`John .E Hoover
`
`Editorial Assistaat
`
`Bonnie Brigham Packer
`
`Director
`
`Allen Mlsher 1965—1990
`
`Eighteenth Edition—1990
`
`Published in the 170th year of the
`
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`AstraZencca Exhibit 2132 p. 4
`
`

`

`Table of flantents
`
`Part1
`
`Orientation.
`
`1 Scope ......... . . . . . . .....................
`2 EvolutionotPharmacy ......................
`3 Ethics .....
`.
`. . .
`4 The ProcticeofCommunity Pharmacy
`5 Opportunities for Pharmacists in the Pharmaceuti-
`oailndusrry
`. . . .
`6 Pharmacists In Government
`
`. . . . . . ..
`
`7 Drug Information . . . . . . . . . . . . . . . . . ..........
`8 Research . . . . . . . . . . . . . . . .......... . . . . . . ..
`
`Part:
`
`Pharmaceutics
`
`. .
`9 Metrology and Calculation ......... . . . . . . . .
`10 Statistics
`. . . . . . . . . .
`. . . . ..
`. . . . . .
`11 ComputerScience
`12 Calculus ................ . . . . ..............
`13 Molecular Structure. Properties and States of
`Matter
`.. . . . . U... . . . . . . . ... . .
`. . u........
`(Sample): Formation . . . . . . . . .. . . . . . . . . . . . . . .
`14
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria
`. . . . ..
`17
`lonlc Solutions and Electrolytic Equilibria
`18 ReactionKinetics...........................
`19 DisperseSystems...........................
`20 Rheology ................ . .
`.
`. . . ...........
`
`Part I
`
`Pharmaceutical chemistry
`
`InorganlcPharn-raoeutioal Chemistry
`21
`22 Organic Pharmaceutical Chemistry . . . . . . . . . . . .
`23 NaturalPtoducts
`24 Drug Nomenclature—United States Adopted
`Names ......n...........................
`25 Structure-Amt! Relationship and Drug
`Design ............ . . . . . . ... . . . . . .........
`
`Part 4
`
`Testing and Analysis
`
`26 AnoiysisofMedictnais
`27 Biological'l'esting . . . . . . . . . . . . . . . . .
`26 CIinicalAnalvsis “...”... . . . . .............
`29 solute-Ist-natoo-elta-oaoos
`30 Instrumental Methods of Analysis . . . . . . . . . . . . .
`81 Dissolution . . . . . . .
`
`3
`6
`20
`28
`
`33
`36
`
`49
`60
`
`69
`10-1
`1:55
`145
`
`158
`1B2
`197
`207
`22B
`247
`257
`310
`
`329
`356
`360
`
`412
`
`422
`
`I135
`464
`495
`
`555
`589
`
`Part 5
`
`Radioisotope in Pharmacy and fledkine
`
`32 Fundamentalsailiadloisotapes ...............
`83 MedicolApplioatiansofRadioisotopes .........
`
`605
`624
`
`Part 6
`
`Pharmaceutical and Medicinal Agents
`
`34 Diseases: Manifestations and Parlia-
`
`physlolagy ...... . . . . . . . . . . . . . . . . . .........
`35 Drug Absorption. Action and Disposition ...“...
`36 Basic Pharmacokinetlcs . . . . . . . . . . . . . . . . . . . . . .
`37 Clinical Pharmaaoklnettcs . . . . . . . . . . . . . . . . . . . .
`
`06 TopiaalDtugs ....... . . . . . . . . . . . ... . . .
`39 Gastrointestinal Drugs
`. . . . . . . .
`40 Blood. Fluids. Electrolytes and Hematologic
`Drugs
`. . . . .
`. . . . . . . . . . . .
`. . . . . .
`41 Cardiovascular Drugs
`42 RespiratoryDrugs ......... . . . . . . . ..........
`43 Sympathomlmetlc Drugs . . . . . . . . .
`. . . . . . . . . . . .
`
`. . . ...
`. . . . ..
`
`655
`697
`72.5
`746
`
`757
`774
`
`600
`631
`660
`B70
`
`46
`45
`
`47
`
`49
`
`51
`52
`50
`
`55
`
`57
`56
`
`61
`62
`
`65
`
`67
`66
`69
`70
`
`71
`72
`
`73
`74
`
`75
`76
`77
`78
`79
`
`51
`
`65
`56
`67
`86
`69
`
`91
`92
`
`95
`94
`95
`96
`
`Cholinomimetic Drugs . . . . . . . . . . . . . . . . . .
`Adrenergic and Adrenergic Neuron [Hacking
`Drugs
`. . .
`. . . . .
`.
`. . . .
`. . . . . . . ..
`Antimuscarinic and Antispasmodic Drugs . . . .
`. . .
`Skeletal Muscle Relaxants . . . . . . . . . - . . . . . . . . .
`
`. . . .
`
`.
`
`. . . . .........
`DIureticDrugs 4...... . . . . . . . . .
`Uterine and Antimtgraine Drugs
`.. . . . . . . . . . . . .
`Hormones............ . . .
`.
`.
`. . . . . . . . .
`. ..
`Vitamins ondOtherliuirlents
`Enzymes
`. . . . . . . . .
`. . .
`. . . . . . . . .
`General Anesthetics . . .
`. . . . . . . .
`. . . . . . . . . . . . .
`LocaiAnesthetics.............. . . . .
`. . .
`. . . ...
`
`. . . . . . . . . . . . . . . . . ..
`.
`Sedatives and Hypnotlcs .
`Antleplieptlcs
`. . . . .
`. . . . . . . . . . . . . . .
`.
`. .
`.
`. . . . .
`Psychopharmocoiogic Agents
`.. . . . . . .
`. .. . . . .
`.
`Analgesics and Antlpyretics . . . . . . . . . . . . . .
`.
`. . .
`Histamine and Antihistamines . . .
`.
`. . . . . . . . . . . .
`Central Nervous System Stimulants . . .
`. . .
`. . . . . .
`Antlneaplastic and immunosuppressive Drugs . . .
`Antimicrobial Drugs .........................
`Parasiticides . . . . . . . . . .
`. . . .
`. . . . . . .
`. . . . . . . . . .
`Pesticides . . . . . . . . . . .
`.
`.
`. . . . . . . . .. .
`. . . . . . . . .
`
`. . . . . . . .
`. . .
`Diagnostic Drugs . . .
`Pharmaceutical Necessities
`
`. . . . . . . . . . . . .
`
`669
`
`893
`907
`916
`
`929
`943
`966
`1002
`1035
`10:39
`1046
`
`1057
`1072
`1062
`1097
`1123
`1132
`1 138
`1163
`1242
`1249
`
`1272
`1266
`
`1300
`Adverse Drugfieoctlons
`Pharmacogenetics . . . . ..u... . . . . . . . ..........1344
`Pharmacological Aspects of Drug Abuse . .. . . . .
`.
`13-49
`Introduction of New Drugs
`. . . . . . . . . . . .
`. . . . . . .
`1565
`
`Part 7
`
`Biological Products
`
`. . . . . . . .
`. . . . . . .
`Principles of immunology .
`immunizing Agents and Diagnostic Sitin
`. . . ..
`. . .
`.
`Antigens.. . . . . . . . . . . . .
`. . .
`AllergenicExtracts..........................
`Biotechnolon and Drugs . . . .. . . .
`.
`. . . . .. . . . . .
`
`. . .
`
`1379
`
`1069
`1405
`1416
`
`Part 0
`
`Pharmaceutical Preparations and Their
`manufacture
`
`Pretormulatian ... ...”..........u.........
`Bioovailabiliry and Bioequivalency Testing . . . . .
`Separation”... . . . . . ... . . . . . . .............
`Sterilization . . . . . . . .
`. . . . . . . . .
`. . . . . . . . . . . . . .
`TonicitY. Osmoticlty. Utmolaliiy and Osmalarlty .
`Plastic Packaging Materials . . . . . . . . . . . . . . . . . .
`Stability of Pharmaceutical Products
`. . . . .. . . . . .
`Quality Assurance and Control
`. . . . . . . . . . . . . . .
`Solutions. Emulsions. SUspenslons and
`Extractlves ........ . . . . . . . . . . ..... . . . . . . . ..
`
`. . . . .
`
`. . . . . . . . .. . . . .
`
`Parenteral Preparations . .
`lntravonousAdmixmres
`. . . . ..
`. .
`. . . .
`OphthalmlcPreparatlons .. . . . . . .
`.
`. . . . . .
`.
`. . . .
`Medicated Applications . . .. . . . . .
`Powders........ .
`. . . . . . . . . . . . . . . .
`. . . .
`.
`.
`Oral Solid Dosage Forms . . . . . t . . . . . . . . .
`Coating of Pharmaceutical Dosage Forms . . . . . . .
`Sustained-Release Drug Delivery Systems . . . .
`. .
`Aerosols . . . .
`. .
`.
`.
`. . .
`
`1435
`1451
`1459
`1470
`1461
`1499
`1504
`1515
`
`1519
`
`1545
`1570
`1561
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`AmbulatoryPatientCare
`. . . . . . . . . . . . .. . . . . . .
`Institutional Patient Care.
`Long-Term Care Facilities . . . . . . . . .
`. . . . . . . . . . .
`The Pharmacist and Public Health . . . . . . . . . . . . .
`
`1715
`1757
`1756
`1770
`
`AstraZeneca Exhibit 213 2 p. 5
`
`

`

`97
`95
`
`100
`101
`102
`103
`104
`105
`
`. . . . . . .
`
`The Patient: Behavioral Determinants .. .
`Pafleanammunlcaiian
`Dngducailan
`PafleniCamplianoe
`ThePrescrlpflan
`Dmglnieracfions...........................
`ClinicalDrugLneraiure......................
`Health Accessories
`
`SurgioaISUppiies ...........................
`
`1768
`1796
`1800
`1613
`1825
`1642
`1859
`1864
`1895
`
`106
`107
`108
`
`109
`
`PaisanControl ..............................
`
`LawchwemingPhan-nacy ...........'..‘....
`Community Pharmacy Economics and
`.ulou-Iu..-o.-u.-I.o-uoo.-.-'
`Management
`DentalServiees ............................
`
`1905
`191d
`
`19m
`195?
`
`Index
`
`Alphabeflclndex ..........................
`
`1967
`
`xvi
`
`AstraZeneca Exhibit 213 2 p. 6
`
`

`

`Chapter 9
`
`Merrology and Calculation
`
`Werner lowerrthul. PhD
`Prol'mor of Phonnocy and Pnurmocourtcs and Praiesscr cl Educationol Development ond Flounan
`Salton] of Pharmacy. Medical-College of Virginie. Virginia Commonwealth University
`Richmond. VA 232950551.
`
`The first technical operation which the student of phar-
`macy must learn is the manipulation of balances. weights
`and measures of volume. This entails estudy of the various
`systems of weights and measures. their relationships and a
`mastery of the mathematics involved. This chapter consid-
`ers the fundamental principles of metrology underlying the
`testing. manufacturing and compounding of pharmaceutical
`preparations. under three headings:
`Weights and Measures—en accumulation of facts commuting the
`various systems. with tables of conversion factors and practical equiva-
`
`lents. The relationships among. the various systems of weights and
`measures are clarified.
`
`Weighing and Measuring—e discussion of the various types of huh
`snces, particularly preacription balances. and methods o! using. testing
`and protecting them: also of various devices and methods of their use for
`measuring large or small volumes of fluids.
`
`Density and Specific Gravity—e consideration of the massivolumc
`ratio of a substance {density}. and the ratio of the weight {mass} of one
`substance to the weight {mess-l or another substance telrcn as the stan-
`tlurd i specific gravity}.
`
`Weights and Measures
`
`Weight is a measure of the gravitational force acting on a
`body and is directly proportional to its mass. The latter.
`being a constant based on inertia, never varies, whereas
`weight varies slightly with latitude. altitude, temperature
`and pressure. The effect of these factors usually is not
`considered unless very precise weighings and large quanti-
`ties are involved
`Measure is the determination of the volume or extent of a
`body. Temperature and pressure have a pronounced effect.
`especially on gases or liquids. These factors therefore. are.
`considered when making precision measurements.
`All standard weights and measures in this country are
`derived from or based on the United States National Proto-
`type Standards of the Meter and the Kilogram. made of
`platinum—iridium. in the custody of the National Bureau of
`Standards at Washington. DC.
`
`History
`
`A brief outline of the origin of the many systems of weights
`and measures may help in remembering essential distinc-
`tions between them. The sense of the weight of a body
`cannot be conveyed intelliginy to themind unless a means
`of comparison is chosen. As weight is the measure of the
`gravitational force of a body. so this force is expressed in
`terms of standards of resistance. which exactly balance the
`body and keep it in equilibrium when used with a mechani-
`cal device constructed for this specific purpose. Such stan-
`dards are termed weights and the mechanical devices are
`called balances or scales.
`The standards which have been chosen by various nations
`are arbitrary. and instances are common where different
`standards are in use at the same time in the same country.
`Many of the ancient standards clearly are referable to vari-
`able parts of the human body. as nail. foot. span. pace. cubit
`(length of the forearm) and fathom or faction (stretch ofthe
`armsld.‘ In the history of metrology three periods may be
`trace '
`L The Ancient period. during which the old classical standards orig-
`inated. terminated with the decline ofthe Roman Empire.
`It is interest-
`ing to note that the unitof distance used at the present day by all nations
`
`in maritime measurements is the nautical or meridian mile or lie. of a
`degree of the earth's equatorial circumference. and that this is exactly
`equal to 1000 Egyptian fathoms or 4000 Egyptian cubits. These Egyp-
`tian measurements. which have persisted for more than 4000 yr. were
`based on astronomical or meridian measurements which were recorded
`lmperishahly in the great Pyramid of Ghizeh. whose perimeter is exactly
`500 of these fathom. or V: nautical mile.
`2. The Medieval period extended to the 16th century. During this
`period the old standards were lost. but their names were preserved. and
`European nations adopted various independent standards.
`3. The Modern period extends from the 18th century to the present.
`Since the 17th ccntury the effortsol’ rnosl. enlightened nations have been.
`directed toward scientific accuracy and simplicity. and during the
`present century toward international uniformity.
`
`Historical metrology is also referred to as Documentary
`Mctroiogy. which is concerned with the study of monuments
`and records of ancient periods. and Inductive Metrology.
`which is concerned With the accumulation of data concern-
`ing the measurementof large numbers of objects which have
`been referred to as standards but which have no exact mea-
`sure eacept by statutory regulation.
`The English Systems—In Great Britain, in 1266. the
`Slat Act of the reign of Henry III declared “that by the
`consent of the whole realm of England the measure of the
`King was made—that is to say. that an English silver penny
`called the sterling. round and without clipping. shall weigh
`thirty-two grains of wheat. well dried and gathered out of
`the middle of the ear; and twenty pence (pennyweights) do
`malts an ounce and twalve ounces a pound, and eight pounds
`do make a gallon of wine. and eight wine gallons do make a
`bushel, which is the eighth of a quarter."
`The 16-02 1h (aooirdupois pound}. undoubtedly of Roman
`origin. was introduced at the time of the first civilization of
`the British island. The word “haherdepois,” according to
`Gray. was, however. first used in English laws in 1303. A
`statute of Edward I {AD 1304] states “that every pound of
`mousy or of medicines is of twenty shillings weight. but the
`pound of all other things is twenty-five shillings weight.
`The ounce of medicines consists of twenty pence. and the
`pound contains twelve ounces (the Troy Pound}. but in
`other thingsthe pound contains fifteen ounces. in both cases
`the ounce weighing twanty pence."
`These laws unfold the theory of the ancient weights and
`
`Asnachcca Exhibit 2132 p. 7
`
`

`

`70
`
`CHAPTER 9
`
`measures of Great Britain. and reveal the standards. is. a
`natural object. grains of wheat: a difference axisted then
`between the Troy and the avoirdupois pound, but the
`weights now in use are If... heavier than those of Edward 1.
`due to the change subsequently made in the value of the coin
`by the sovereign.
`In addition. the true pennyweight stan-
`dard was lost and, in the next revision of the weights and
`measures. the present troy and avoirdupois standards were
`adopted.
`The troy weight is of still earlier origin. The great fairs of
`the 8th and 9th centuries were held at several French cities.
`including Troyes. the gathering place of traders from all
`countries. Coins frequently were mutilated so that they
`were sold by weight. and the standard weight of Troyes for
`selling coin was adopted for precious metals and medicines
`in all parts of Europe. The troy ounce and the avoirdupois
`ounce originally were intended to have the same weight. but
`after the revision it was found that the avoirdupois ounce
`was lighter by 421.5 gr than the troy ounce. The subsequent
`adoption of troy weight by the London College of Physicians
`in 1618. on the recommendation of Sir Theodore Turquet de
`la Mayerne. who compiled their first pharmacopoeia. has
`entailed upon all apothecarias who are goiter-nod by British
`customs. to this day. the very great inconvenience of buying
`and selling medicines by one system of weights (the ouoirdu-
`pair) and compounding them hyanother (the cpotheccry or
`troy).
`In the next century efforts were made toward reforming
`the standards. and the Royal Society. in 1736. began the
`work. which ended in the preparation. under the direction of
`the House of Commons. by Mr Bird. of the standard "yard"
`and standard “pound” troy in 1760. Copies of these were-
`prepared and no intentional deviation has been made since.
`In 1813. on account of the growing popularity of the French
`Metric System. and in View of the desirability of securing a
`standard which could he recovered easily in case of loss or
`destruction and which should be commensurable with a sim-
`ple unit. steps were taken in England to secure these advan-
`tages. The labors ofEnglish scientists led to the adoption of
`the Imperial measures and standards, which were legalized
`January 1. 1826. and are now in use in Great Britain, thus
`introducing another element of confusion into an already
`complicated subject.
`In this system the yard is equivalent to 36 in. and its
`length was determined by comparison with .a pendulum
`beating seconds of mean time. in a vacuum. at the tempera-
`ture of 62°F at the level of the sea in the latitude of London.
`which length was found to he 39.1393 in. The pound troy
`(containing 5760 gr) was determined by comparison with a
`given measure of distilled water under specified conditions.
`Thus. a cubic inch of distilled water was weighed with brass
`weights in air at 62°F, the barometer at 30 in. and it weighed
`252.458 gr. The standard for measures of capaci-twl in Great
`Britain (either dry or liquid} is the Imperial gallon. which
`contains 10 lb avoir (each 7000 gr) of distilled water weighed
`in air at 62°F. the barometer standing at 30 in. The bushel
`contains 8 such gal.
`Washington. in his first annual message to Congress. Jan~
`uary. 1790. recommended the-establishment of uniformity in
`currency. weights and measures. Action was taken. with
`reference to the currency. and recommendations were made
`by Jefferson. then Secretary of State. for the adoption of
`either of the currently used English systems or a decimal
`system. However. nothing was accomplished until in
`1819-1820 when efforts again were made in the US to secure
`uniformity in the standards which were in use by the several
`states. Finally. after a lengthy investigation. the Secretary
`of the Treasury. on June 14. 1-836. was directed by Congress-
`to furnish each state in the Union with a complete set of the
`revised standards. and thus the troy pound [5760 gr). the
`
`ouoirdupois pound (7000 grl and the yard [36 in) are all
`identical with the British standards; but the US gallon is
`quite different. the old wine gallon oil-131 cu in. containing
`58.3722 gr of distilled water at its maximum density.
`weighed in air at 62°F. the barometer standing at 30 in.
`being retained. while the bushel contained 77.274 lb of water
`under the same-conditions, thus making the dry quart about
`16% greater in volume than the liquid quart.
`In 1364 the use of the metric measures was legalized in
`Great Britain. but not made compulsory. and in 1866 the US
`followed the same course. By the US Law of July 28. 1866.
`all lengths. areas and cubic measures are derived from the
`international meter equivalent to 39.37 in. Since 1893 the
`US Office of Standard Weights and Measures has been au-
`thorized to derive the yard from. the meter. 1 yd equals
`3509/3537 m. and the customary weights are referred to the
`kilogram. by Executive order approved April 5. 1393'. Ca-
`pacities were to be based on the equivalent. I cu dm equals 1
`L. the dosimeter being equal to 3.937 in. The gallon still
`remains at 231 cu in and the bushel contains 2150.42 cu in.
`This makes the liquid quart equal to 0.946 L and the dry
`quart 1.1013 L. while the Imperial quart is 1.1359 L. The
`customary weights are derived from the international kilo-
`gram. based on the value that 1 avo'ir lb = 4535924277 3 and
`that “when avoir- 1h equals 1 troy lb.
`Avoirdupcis weight is used in general in the US for com-
`mercial purposes. including the buying and selling of drugs
`on the large scale and occasionally on prescription orders.
`The Metric System-me idea of adopting a scientific
`standard for the basis of metrology. which could be reveri-
`fied accurately. Was suggested by a number of individuals
`after the Renaissance. Jean Pi'card. the French astronomer.
`in the 17th century. proposed to take as a unit the length of a
`pendulum heating 1 sea of time at sea level. at a latitude of
`45".
`James Watt. the English inventor. in 1783 first suggested
`the application of decimal notation. and the commensurahil-
`ity of weight. length and volume. The French National
`Assembly in 1-790 appointed a committee to decide the pref-
`erability of the pendulum standard or a terrestrial measure
`of some kind as a basis for the new system. The committee
`reported in 1791 in favor of the letter. and commissions were
`appointed to measure an arc of meridian and to perfect the
`details of the commensurahility of the units and of nomen—
`clature. However. certain inaccuracies were inherent in the
`early standards and they do not hear to each other the
`intended exact relationships. The present accepted stan-
`dards are defined in publiCations of the National Bureau of
`Standards.
`
`in its original conception the meter was the fundamental unit of the
`metric system. and all units of length and capacity were to be derived
`directly from the ureter which was intended to be equal to one ton-
`millionth of the earth's quadrant. Furthermore.
`it originally was
`planned that the unit of mass. the kilogram. should be identical with the
`mass of a cubic decimeter of water at its maxhnum density. At present.
`however. the units of length and mass are defined independently of these
`conceptions.
`For all practical purposes calibration of length standards in indusz
`and scientific laboratories is accomplished by comparison with the mate-
`rial standard of length:
`the distance between two engraved lines on a
`platlntun-iridium bar. the international prototype meter. which is kept
`at the international Bureau of Weights and Measures.
`The kilogram is defined independently as the mass ore definite pinto
`cum-iridium standard.the international Prototype Kilogram. which is
`also inept at the International Bureau of Weights and Measures. The
`Liter is defined as the volume of a kilogram of water. at standard atmo.
`spherio pressure. and at the temperature of its maximum density. op.-
`roximstely 4‘0. The meter is thus the fundamean unit on which are
`used all metric standards and measurements of length and urea. and of
`volumes derived from linear measurements.
`or basic scientific interest is that on October 14. 1960. the 11th Gen—
`eral Conference on Weights and Measures. meeting in Paris. adopted a
`new interimtional definition for the standard of length:
`the meter is-
`now defined as the length equal to 1.650.763.73 wavelengths of the
`
`AstraZencca Exhibit 2132 p. 8
`
`

`

`Int-angered light of the krypton-'30 isotope. This standard will he used
`in actual measurements only when extreme accuracy is needed.
`The kilogram is the fundamental unit on which are based all metric
`standards of mass. The llter is aaecondary or derived unit of capacity or
`volume. The L is larger by about 2'? ppm than the cube of the tenth of
`the meter. is. the co din—that is l l. = 1.00002? cu tire.
`The Immersion tables in this publication which involve the relative
`length of the yard and meter are based upon the relation:
`1 m = 30.3?
`in. contained in the act of Congress of 1066. From this relation it
`{allows that 1 in. = 25.40005 mm {nearly}.
`In recent years engineering and industrial interests the world ever
`have urged the adoption nfthe simpler relation. 1 in. = 25.4 mm exactly.
`which differs from the preceding value by only 2 ppm. This simpler
`relation has not as yet been adopted officially by either Great Britain or
`the US but is in wide industrial use.
`
`In the US. the abbreviation cc still persists in general use
`and is taken as synonymous for the more correct term ml..
`The USP IX and NF IV adopted the term milliliter with its
`abbreviated form mil. but it proved so unpopular in practice
`that the following phermacopeie] convtlon directed the
`return to the older term cubic centimeter {cc}.
`In 1955 USP
`XV and NF X. however. once again adopted the term millili-
`ter with the abbreviation ml.
`Nationaljealoueies and the natural antipathy to changing
`established customs interfered greatly with the adoption of
`the metric system during the early part of the 19th century.
`At present the metric system is in use in every maior country
`of the world. In the US and and Great Britain it is legalized
`for reference to and-definition nfntherstsndatds. is in exclu-
`sive use by nearly all scientists. and by inch segments
`of industry and the public.
`In the US the metric system was
`legalized in 1866. but not made compulsory, and in the same
`year the international prototype meter and kilogram were
`adopted as fundamental standards. As corporations be-
`come more international. the need for a universal standard
`increases.
`The US silver coinage was based upon the metric system.
`the half dollar being exactly 12% g and the quarter and the
`dime being of the proportionate weights.
`Since 1875 there has been established and maintained an
`International Bureau of Weights and Measures. with head-
`quarters at Paris. This Bureau is managed by an interna-
`tional committee on which all civilized countries are repre-
`sented. One object of the committee is to make and provide
`prototypes of the meter and kilogram for the subscribing
`nations: approximately 40 such copies have been prepared.
`The US prototype standards of both the meter and the
`kilogram mass. constructed of a platinum-iridium alloy.
`were brought from Paris in 1890 and are now in the custody
`of the Bureau of Standards at Washington DC. They have
`been reproduced and distributed by our own government to
`the various states having bureaus needing such replicas.
`The original US prototype meter was taken back to Paris in
`195? for reverification and was found to have altered only 3
`parts in 100,000.000 after 67 years of use. Thus. there was
`no demonstrable change within the limits of experimental
`error.
`
`Adoption of the krypton-06 wavelength of light definition
`for the meter gives the different countries the means to
`check their prototype meter bars without returning them to
`Paris at periodic intervals for comparison with the interna-
`tional meter bar.
`
`Orthography and Reading
`
`Orthogranhy—There are two methods of orthography of
`the metric units in use.
`In one of these, the original French,
`the units are spelled metre. litre. gramme; in the other.
`proposed by the American Metric Bureau, the units are
`spelled meter. liter and gram.
`In the USP and NF for three
`decades after the original adoption of the metric system,
`meter and liter were adopted but the French gramme was
`need. Now these official compendia use the spelling gram.
`
`METROLOGY AND CALCLLATHDN
`
`71
`
`Reading—Some difficulty usually is experienced by
`those unfamiliar with the metric system in reading the Quart -
`titles.
`In the linear measures, in pharmacy. centimeters and
`millimeters are used almoot exclusively; thus. 0.05 it: would
`not be read five hundredths of a meter. but 5 centimeters. (5
`cm); if the millimeter column contains a unit. as in 0.05:3 m. it
`is read fifty—five millimeters [55 mm). in preference to fifty-
`five thousandths of a meter.
`Fractions of a millimeter roost he read decimally. as.
`0.0555 to. fifty-five and five-tenths millimeter (55.5 mm)..
`in measures of capacity. cubic centimeters (cc) or milliliters
`lmLJ. are used exclusively for quantities of less than a liter.
`The terms half liter. quarter liter, 100 milliliters and one
`are denoted by 500 mL. 250 ml... 100 mL and 1 mL;
`with water the milliliter is considered equivalent to a gram.
`In weight. when the quantity is relatively large. and in com-
`mercial transactions. the kilogram is abbreviated to kilo.
`when less than a kilogram and not less than a grant. the
`quantity is read with the gram for the unit: 2000 g would be
`read either as two thousand grams or as two kilos. and 543 1;
`would be read five hundred and forty-three grams, while
`2543 g is sometimes read two kilos and five hundred and
`forty-three grams, although twenty-five hundred and forty-
`three grams usually is preferred. For quantities below the
`gram, decigram and centigram usually are not used. but
`milligram has been regarded as the most convenient unit.
`With the increase in the use of extremely small doses of very
`potent drugs and the wide application of more delicate ana-
`lytical procedures. the term microgram (meg. pg. 0r Tl. for
`thousandths of a milligram. is used frequently to designate
`quantities up to 099 ug (less than 1.000 mg).
`Both the metric and English systems of weights and mea-
`sures are in use in the US. even though the metric system
`nearly has replaced the English system; the pharmacist must
`have a practical knowledge of both.
`
`Weights
`
`The Metric System
`
`The USP of 1800 adopted the metric system of weights
`and measures to the exclusion ofall others except for equiva-
`lent dosage statements, and the British Pharmacopoeia of
`191-1 did likewise.
`In 1944 the Council on Pharmacy and
`Chemistry of the American Medical Association adopted the
`metric system exclusively. The advantages of the metric or
`decimal system, and its simplicity. brevity and adaptability
`to everyday needs are now conceded universally.
`Fractional and Multiple Prefixes—In many experi-
`mental procedures, including some in the pharmaceutical
`sciences, very small (and occasionally very large} Quantities
`of weight, length. volume. time, radioactivity. etc are mea-
`sured To avoid the use of numbers with many zeros in such
`cases. the National Bureau of Standards recognises prefixes
`to be used to express fractions or multiples of the Interna-
`tional System of Units (SI) established in 1960 by th Gener-
`al Conference on Weights and Measures {see foregoing dis-
`cussion). The recognized prefixes. which in use are adioined
`to an appropriate unit (as, for example. in such quantities as
`nanogram, picomole. microcurie, microsecond or megavolt)
`are defined in Table I.
`Table ll lists some metric weights. The prefixes. which
`indicate multiples. are of Greek derivation—delta. 10: hecto,
`100; kilo. 1000. Fractions of the units are expressed by
`Latin prefixes—dad, Elm; centi. lime; milli, Ilium.
`Only a few of the most. convenient denominations are
`employed in practical work. Whole numbers from 1 to 1000
`usually are expressed in terms of grams while the kilogram is
`used as the unit for larger quantities. Quantities bemoan l
`milligram and 1 gram usually are referred to in terms of
`
`AstraZencca Exhibit 213 2 p. 9
`
`

`

`72
`
`censure 9
`
`Table l—Prellses lor Fractions and Multiples ol 3| Units
`
`Table \l—-Troy Weight
`
`Fraction
`
`Prone
`
`Symbol
`
`Multiple
`
`Prefix
`
`Symbol
`
`Poms
`
`unless
`
`Pomvwelghlsll’wu
`
`anion
`
`5'100
`400
`gr 24
`
`=
`=
`=
`
`lb 1
`
`=
`
`12
`3 1
`
`=
`=
`
`240
`20
`val. l
`
`Note—The abbreviation It: refers to the swiftlqu [round ul 7000 3|
`Lulless further qualified. as in the headings of Tables IV and V. The soothe-
`canr pound is sometimes abbreviated In.
`
`Table til—Metric Linear Measure
`
`10"
`10"
`10-3
`10‘“
`10"
`'10—“
`10"5
`10'18
`
`deci
`centi
`milli
`micro
`nano
`pica
`femto
`alto
`
`d
`c
`m
`u
`n
`p
`1‘
`a
`
`10
`10E
`1.03
`10°
`10”
`101*
`10'5
`1.015
`
`ticks
`heoto
`kilo
`megs
`giga
`tors
`pets