20 TH EDITION
`
`--~------'-
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`SENJU EXHIBIT 2009
`MYLAN v. SENJU
`IPR2016-00626
`
`Page 1 of 23
`
`

`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
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`Baltimore, Maryland 21201-2436 USA
`
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`
`All rights reserved. This book is protected by copyright. No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers' product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`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, 1905, 1907, 1917, by Joseph P Remington
`
`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 Phila(cid:173)
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-3064 72
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they haue inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon(cid:173)
`sible for any inaccuracy contained herein.
`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 discrep(cid:173)
`ancy 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.
`
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
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`
`02 03 04
`2 3 4 56 7 8 9 10
`
`Page 2 of 23
`
`

`
`Remington: The Science and Practice of Pharmacy . . . A treatise on the theory
`and practice of rhe pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health ream . . . A texrbool~ and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medico/ sciences.
`
`EDITORS
`
`Alfonso P. Gennaro, Choir
`
`Nicholas G Popovich
`
`Ara H Der Marderosian
`
`Glen P. Hanson
`
`Thomas Medwicl~
`
`P.oger L Schnaore
`
`Joseph [5 Schwartz
`
`H Steve White
`
`AUTHORS
`
`The 119 chapters of this edition of Remington were written by the
`
`editors, by members of the Editorial r5oord, and by the authors
`
`listed on pages viii to x.
`
`Managing Editor
`
`John E Hoover, GSc (Phorm)
`
`Editorial Assistant
`
`r5onnie Grighom Pad~er, P.NC, GA
`
`Director
`
`Philip P Gerbino 1995-2000
`
`Twentieth Edition- 2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`Page 3 of 23
`
`

`
`Preface to the First Edition
`
`The rapid and substantial progress made in Phaxmacy within
`the la<;t decade has created a necessity for a work treating of the
`imp,·ovcd apparatus, the revised processes, and the recently
`introduced preparations of the age.
`The vast advances made in theoretical and applied chemistry
`and p hysics have much to do with the development of pharma(cid:173)
`ceutical science, and these have been reflected in all the revised
`editions of the Phannacopoeias which have been recently pub(cid:173)
`lishe·d.When the author was elected in 1874 to the chair of
`Theory and Practice of Pharmacy in the Philadelphia College of
`Phannacy, the outlines of study which had been so carefully
`prepared for the classes by his eminent predecessors, Professor
`William Proctor, Jr, and Professor Edward Parrish, were found
`to be not strictly in accord, either in their arrangement of the
`subjects or in their method of treatment. Desiring to preserve the
`distinctive characterisi..ics of each, an effort was at once made to
`frame a system which should embody their valuable features,
`eml)l·ace new subjects, and still retain that harmony of plan and
`proper sequence which are absolutely essential to the success of
`any system.
`The strictly alphabetical classi.fication of subjects which is
`now universally adopted by phannacopocias and dispensato1ies,
`although admirable in works of reference, presents an effectual
`stumbling block to the acquisition of pharmaceutical knowledge
`through systematic study; the vast accumulation of facts col(cid:173)
`lected under each head arranged lexically, they necessarily have
`no connection with one another, and thus the saving of labor
`effected by considering similar groups together, and the value of
`the association of kindred subjects, are lost to the student.In the
`method of grouping the subjects which is herein adopted, the
`constant aim has been to arrange the latter in such a manner that
`the reader shall be gradually led from the consideration of ele(cid:173)
`ment.ary subjects to those which involve more advanced knowl(cid:173)
`edge, whilst the groups themselves are so placed a..'> to follow one
`another in a natural sequence.
`The work is divided into six parts. Part I is devoted to detailed
`descriptiom of apparatus and definitions and comments on gen(cid:173)
`eral phannaceulical processes.
`The Official Preparations alone are considered in Part II.
`Due weight and prominence are thus given to the Pharma(cid:173)
`copoeia, the National authority, which is now so thoroughly
`recognized.
`In order to suit the convenience ofpham1acists who prefer to
`weigh solids and measu1·e liq~tids, the official formulas are
`expressed, in addition to parts by weight, in avoir·dupois weight
`and apoth.ecari,es' mea.sm·e.These equivalents are printed in bold
`
`type near the margin, and ananged so as to fit them for quick and
`accurate reference.
`Part ID treats of Inorganic Chemical Substances.Precedence is
`of course given to official preparation in these.The descliptions,
`solubilities, and tests for identity and impw-ities of each s ubstance
`are systematically tabulated under its proper title.lt is confidently
`believed that by this method of arrangement the valuable desclip(cid:173)
`tivc features of the Pharmacopoeia will be more prominently de(cid:173)
`veloped, ready reference facilitated, and close study of the details
`rendered easy. Each chemical operation is accompanied by equa(cid:173)
`tions, whilst the reaction is, in addition, explained in words.
`The Carbon Compounds, or Organic Chemical Substances,
`are considered in Part IV.These are naturally grouped according
`to the physical and medical properties of their principal constit(cid:173)
`uenl<;, l>eg•nning ..,vith simple bodies like cellulin, gum, etc, and
`progressing to the most highly organized alkaloids, etc.
`Pa1t V is devoted to Extemporaneous Phannacy.Care ha<;
`been taken to treat. of the practice which would be best adapted
`for the needs of the many phannacists who conduct operations
`upon a moderate scale, rather than for those of the few who
`manage very large establishments.ln this, as well as in other
`parts of the work, operations are illustrated which are conducted
`by manufacturing pharmacists.
`Part VI contains a formulary of Pharmaceutical Preparations
`which have not heen recognized by the Pharn1acopoeia.The rec(cid:173)
`ipes selected are d1iefly those which have been heretofore rather
`difficult of access to most pharmacists, yet such as are likely to
`be in request. Many private formulas are embraced in the collec(cid:173)
`tion; and such of the preparations of the old Pharmacopoeias as
`have not been inducted in the new edition, but are still in use,
`have been inserted.
`In conclusion, tthe author ventures to express the hope that
`the work will prove an efficient help to the pharmaceutical
`student as well as to the pharmacist and the physician.
`Although the labor ha<; been mainly performed amidst the ha(cid:173)
`rassing cares of active professional duties, and perfection is
`known to be unattainable, no pains have been spared to discover
`and correct errors and omissions in the text. The author's wann(cid:173)
`est acknowledgments, are tendered to Mr A B Taylor, Mr Joseph
`McCreery, and Mr George M Smith for their valuable assistance
`in revising the proof sheets, and to the latter especially for his
`work on the index.The outline illustrations, by i.\1r John Collins,
`were drawn eithe1· from the actual objects or from photographs
`taken by the author.
`
`Philadelphia, October, 1885
`
`JPR.
`
`xiii
`
`Page 4 of 23
`
`

`
`Table of Contents
`
`Port 1 Orientation
`
`1 Scope of Pharmacy ... . ...... . .. .
`2 Evolution of Pharmacy . . ..... . . ... . ... . .
`J Ethics and Professionalism . . ....... .. ... . .
`4 The Practice of Community Pharmacy . . . ....... .
`5 Pharmacists in Industry . .
`6 Pharmacists in Government
`7 Pharmacists and Public Health .... . . .
`8 Information Resources in Pharmacy and rhe
`Pharmaceurical Sciences. . . .
`. . . . . . . ... .... .
`9 Clinical Drug Literature . . .
`1 0 Research.
`
`Port 2 Pharmaceutics
`
`11 Pharmaceurical Calculations .. . . . ..... .
`12 Statistics. . . .
`. . . . . . . . . . . . . . .
`1 J Molecular Structure, Properties, and Stores of Motter. .
`14 Complex FormaTion . ..... . . ..... . . ... ... . . .
`15 Thermodynamics . .
`. . ..... . . .. . ..... . .. .
`16 Solutions and Phose Equilibria .. . ............ . .
`17 Ionic Solutions and Electrolytic Equilibria ..... . .. . .
`18 Tonicity. Osmoticity. Osmola lity, and Osmolarity ... .
`19 Chem ical Kinetics . . . . . . .
`. .. . .. . .... .
`20 Interfacial Phenomena.
`_ . . . . _ . . . . . .... . . _
`21 Colloidal DispersiOns ... . .. .. .. . . . . . . ....... .
`22 Coarse Dispersions ..... ......... .... . .. . .. .
`2.3 Rheology ... . . . ... . ... .... ........ . .
`
`Port 3 Phormaceuticol Chemistry
`
`24 Inorganic Pharmaceutical Chemistry . . . _ .. .
`25 Organic Pharmaceutical Chemistry
`_ . .... . . .. .
`26 Natural Products ... . . . . . ....... . ... . .
`27 Drug Nomenclature-United States Adopted
`Names .... . . .
`.... . . . ........... .
`28 Strucrure-Acrivity Relationship and Drug Design .. .. .
`29 Fundamentals of Rodionuclides
`. ... . . . . .
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`JO Analysis of Medicinals . . ...... . ... . ... .
`J1 Oiologica l Testing
`. ..... ... ... .. . ... . . .. . . .
`J2 Clinical Analysis . .. . ... . . . ... . . .. • . . .
`JJ Chromatography .... ... . ... ....... . ..... . .
`J4 Instrumenta l Methods of Ana lysis . . . . . . .. . .... . .
`J5 Dissolutio n .
`. . . . . . . . . . .
`. _ . . . . . . . . . .
`
`Part 5 Pharmaceutical Manufacturing
`
`_ . _ . _ . . .
`J6 Seporarion .. _ . . . _ . . . . .
`J7 Powders ...... . ........... . . . . . . . .
`J8 ?reformulation .. ... . .. _ . . ... . . . . ... .
`J9 Solutions. Emulsions. Suspensions. and Extracts ... . .
`40 Sterilization . . . . . . . . . . . .
`. .... .... .
`41 Parenteral Preparations ... ...... .. . ...... .. .
`42 Intravenous Admixtures
`. _ .. __ .. . .
`4J Ophthalmic Preparations . . . _
`_ _ . .. . . .. .
`44 Medicated Topicols . . . . . . . .
`. ... . ... ... . .
`45 Oral Solid Dosoge Forms . . . . . . ... . . . . . ..... .
`46 Coating o f Pharmaceutical Dosage Forms . . ... . . .
`47 Contro lled-Release Drug -Delivery Systems _
`48 The Introduction of New Drugs
`... . . . . .
`
`J
`7
`19
`28
`JJ
`J8
`47
`
`60
`70
`81
`
`9 1
`124
`159
`18J
`198
`208
`227
`246
`26J
`275
`288
`J16
`JJ5
`
`J59
`J85
`409
`
`44 1
`458
`469
`
`485
`540
`552
`587
`61 4
`654
`
`669
`681
`700
`721
`75J
`780
`807
`821
`8J6
`858
`894
`90J
`9JO
`
`4 9 Oiorechno logy and Drugs . ... ... . .. . .. .. . ... .
`50 Aerosols . . .......... . . .......... • .. . . . . .
`51 Q ua lity Assurance and Control
`. . ... . .... .
`52 Stability of Pharmaceutical Products . . . .. .. _ . . . . _
`5J Dioavailability a nd Oioequivolency Testing .... . .. .
`54 Plasric Pocl1oging Materials . ...... .... _ ..... . .
`55 Pharmaceutical Necessities ....... . . . . . . .
`
`Port 6 Pharmacodynamics
`
`56 Diseases Manifestations and Pathophysiology
`57 Drug Absorption. Action. and Disposition
`58 Oosic Pharmocol~inetics .... . . . ..... . . . .. .. . . .
`59 Clinical Pharmacollinetics . ....... . . ... . ... . . .
`60 Principles of Immunology .
`. • .. . .. . . . . . . .
`6 1 Adverse Drug Reactions ... . . . . ....... . ... . . .
`62 Pharmacogenetics .
`. . ....... . . .
`6J Pharmacologica l Aspecrs of Subsra nce Abuse .
`
`Port 7 Pharmaceutical and Medicinal Agents
`
`64 Diagnostic Drugs and Reagents.
`65 Topical Drugs . . .
`_ ..... .
`66 Gastrointestinal and Liver Drugs.
`67 1!31ood. Fluids. Elecrrolyres. and Hemorolog:col Drugs .. .
`68 Cordiovosculor Drugs . . .
`. ..... . _ .. . ... .
`69 Respiratory Drugs . . . . . . _ _ . .. _ . ... ...... . .. .
`70 Symporhomimetic Drvgs . . . , .......... , , ... ,
`71 Cholinomimetic Drugs . .
`_ . . ........ . _
`72 Adrenergic and Adrenergic Neuron Olocl1ing Drugs . .
`7J Antim uscorinic and Antispasmodic Drugs . .
`74 Sl~eletal Muscle Relaxants . ..
`7 5 Diureric Drugs . . . _ . . . . . . . _ . . _ . . . . .
`76 Urenne ond Antim igraine Drugs . . . . ... . . . . . .. .
`77 Hormones and Hormone Anragonists
`7 8 General Anesthetics . . . _ . . . _
`79 Local Anesthetics . . .
`. .
`80 Sedative and Hypnotic Drugs .. . .
`81 Antiepileptic Drugs . . . . . . . . . . . ... . . .. . ..... .
`82 PsychophormocologiC Agenrs.
`8J Analgesic. Antipyretic, and Anti-Inflammatory
`Drugs . _ . . . . . . . .
`84 Histamine and Ami histaminic Drugs _ ..... . ..... .
`85 Centra l NeNous System Stimulants. .
`. . . . . . . . .
`86 A ntineoplasric ond lmmunoacrive Drugs . . . ... .. .
`87 Anri-lnfecrives .. ... . . . .... . . . . .... . ... ... .
`88 Parosiricides . .
`89 Immunizing Agents and Allergenic Exrracts
`
`944
`96J
`980
`986
`995
`1005
`1015
`
`105J
`1098
`1127
`1145
`1 156
`1165
`1169
`1175
`
`1185
`1200
`1219
`124J
`1274
`1297
`1J05
`1J14
`1J22
`1J28
`1JJJ
`1J44
`1J54
`1J58
`1J95
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`Port 8 Pharmacy Practice
`
`Port 8A Pharmacy Administration
`
`90 l ows Governing Pharmacy
`. . . _ ... . . . _
`91 Pharmocoeconomics .
`. .. . .. ...... .
`Q2 Marl~eting Pharmaceutical Core SeNices . . . ..... _
`9J Documenting ond Oilling for Phormaceurical Core
`SeNices . ... _.. ... ...
`. . ......
`94 Community Pharmacy Economics and
`Management .
`95 'Producr Recalls and Withdrawals
`
`1595
`1625
`1604
`
`1640
`
`1650
`1666
`
`Port 8D Fundamentals of Pharmacy Practice
`
`96 Drug Education _ . ... . . . . . . ....... . .. ... . . .
`
`1677
`
`xiv
`
`Page 5 of 23
`
`

`
`97
`98
`99
`100
`101
`102
`103
`
`104
`105
`106
`107
`108
`109
`
`The Prescription . . . . . . _ _ ..... . . .. _ . . .. ... .
`Extemporaneous Prescription Compounding
`Poison Conrrol .. ... __ . _ . _ ... _ . . .
`. . _ .... .
`Nurririon 1n Pharmacy Practice
`. . ........ .. ... .
`Self-Core/Diagnostic Producr:s . .. . .... . ........ .
`_ . _ . _ .. .
`Drug Interactions . _ . _ . _ . _
`Complementary and Alternative Medical Health
`Core.
`__ __ _____ ..
`Nuclear Pharmacy Practice _ . ............... .
`Enzymes
`_ ... _ . __ . __ _ _ __ . .. ... .. .. . . . . .
`Vitamins and Other Nutriems
`. .. .. . __ _ . .
`Pesticides . . . _ . . . _
`Surgical Supplies ... . . . _
`Health Accessories _
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`Port 8C Patient Core
`
`11 0 Ambulatory Por,enr Core ..........•.........
`11 1 Institutional Potiem Core .... .......... •. . _ ..
`112 Long-Term Core Focil1t1es .. ..... _ ..•..... _ .. .
`
`189J
`1911
`1932
`
`113
`11 4
`115
`116
`117
`118
`119
`
`The Patient: Qehoviorol Dererminonrs .
`Patient Communication . _ . .. _ . . _ .
`Patient Compliance
`.
`. . ... _ .
`Phormocoepidemiology . . . . .
`. . . .. . . .
`lnregrored Healrh-Care Delivery Systems . . . . . ... .
`Home Heolrh Patient Core .. _ . _ . . . . . . _ ... _ . .
`Aseptic Technology for Home-Core
`Pharmaceuticals . _ . . . . . . . . . . . . . _ . . . _ . . . _
`
`Appendixes
`
`Dose Equivalents .
`Periodic Chart ...
`Logarithms __ _
`
`Glossary ond Index
`
`Glossary . . . . .. ..•......
`Index . . . _ . . . _ . . .
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`2037
`2039
`
`XV
`
`Page 6 of 23
`
`

`
`CHAPTER 18
`Tonicity, Osmoticity, Osmolality, and Osmolarity
`
`Irwin Reich, BSc
`Instructor and Manager, Pharmacy Laboratory
`Philadelphia College of Pharmacy
`University of the Sciences in Philadelphia
`Philadelphia, PA 19104
`
`Cat hy Y Poon, PharmD
`Assistant Professor of Clinical Pharmacy
`Philadelphia College of Pharmacy
`University of the Sciences in Philadelphia
`Philadelphia, PA 19104
`
`Edwin T Sugita, PhD
`Professor and Chairman, Pharmaceutics
`Department
`Philadelphia College of Pharmacy
`University of the Sciences in Ph1ladelphia
`Philadelphia, PA 19104
`
`BASIC DEFINITIONS
`
`If a solution is placed in contact with a membrane that is perme(cid:173)
`able to molecules of the solvent, but not to molecules of the solute,
`the movement of solvent through the membrane is called osmosis.
`Such a membrane often is called semi-permeable. As the several
`types of membranes of the body vary in their permeability, it is
`well to note that they are selectively permeable. Most normal
`living-cell membranes maintain various solute concentration gra(cid:173)
`dients. A selectively permeable membrane may be defined either
`as one that does not permit free, unhampered diffusion of all the
`solutes present, or as one that maintains at least one solute
`concentration gradient across itself. Osmosis, then, is the diffu(cid:173)
`sion of water through a membrane that maintains at least one
`solute concentration gradient across itself.
`Assume that Solution II. is on one side of the membrane, and
`Solution B of the same solute but of a higher concentration is on
`the other side; the solvent will tend to pass into the more
`concentrated sol ution until equilibrium has been established.
`The pressure required to prevent this movement is the osmotic
`pressure. It is defined as the excess pressure, or pressure
`greater than that above the pure solvent, that must be applied
`to Solution B to prevent passage of solvent through a perfect
`semipermeable membrane from A to B. The concentration of a
`solution with respect to effect on osmotic pressure is related to
`the number of particles (unionized molecules, ions, macromol(cid:173)
`ecules, aggregates) of solute(s) in solution and t hus is affected
`by the degree of ionization or aggregation of the solute. See
`Chapter 16 for review of colligative properties of solutions.
`Body fluids, including blood and lacrimal fluid, normally have
`an osmotic pressure that often is described as corresponding to
`that of a 0.9% solution of sodium chloride. The body also attempts
`to keep the osmotic pressw-e of the contents of the gastrointestinal
`(Gl) tract at about this level, but there the normal range is much
`wider than that of most body fluids. The 0.9% sodium chloride
`solution is said to be iso-osmotic with physiological fluids. In
`medicine, the term isotonic, meaning equal tone, is commonly
`used interchangeably with iso-osmotic. However, terms such as
`isotonic and tonicity should be used only with reference to a
`physiological fluid . !so-osmotic actually is a physical tenu that
`compares the osmotic pressure (or another colligative property,
`such as freezing-point depression) of two liquids, neither of which
`may be a physiological fluid, or which may be a physiological fluid
`only under certain circumstances. For example, a solution of boric
`acid that is iso-osmotic with both blood and lacrimal fluid is
`isotonic only with the lacrimal flu id. This solution causes hemo(cid:173)
`lysis of red blood cells because molecules of boric acid pass freely
`through the erythrocyte membrane regardless of concentration.
`Thus, isotonicity infers a sense of physiological compatibility
`
`246
`
`where isoosmoticity need not. As another example, a chemically
`defined elemental diet or enteral nutritional fluid can be iso(cid:173)
`osmotic with the content s of the GI tract, but would not be con(cid:173)
`sidered a physiological fluid, or suitable for parenteral use.
`A solution is isotonic with a living cell if there is no net gain
`or loss of water by the cell, or other change in the cell, when it
`is in contact with that solution. Physiological solutions with an
`osmotiic pressure lower than that of body fluids, or of 0.9%
`sodium chloride solution, are referred to commonly as being
`hypotonic. Physiological solutions having a greater osmotic
`pressure a re termed hypertonic.
`Such qualitative terms are oflimited value, and it has become
`necessary to state osmotic properties in quantitative terms. To do
`so, a term must be used that will represent all the particles that
`may be present in a given system. The term used is osmoL the
`weight, in grams, of a solute, existing in a solution as molecules
`(and/or ions, macromolecules, aggregates, etc), which is osmoti(cid:173)
`cally equivalent to a mole of an ideally behaving nonelectrolyte.
`Thus, the osmol weight of a nonelectrolyte, in a dilute solution,
`generally is equal to its gram molecular weight. A milliosmol,
`abbreviated mOsm, is the weight stated in milligrams.
`If one extrapolates thiis concept of relating an osmol and a mole
`of a nonelectrolyte as being equivalent, then one also may define
`an osmol in the following ways. It is the amount of solute that will
`provide 1 Avogadro's number (6.02 X 1023 ) of particles in solution
`and it is the amount of solute that, on dissolution in 1 kg of water,
`will result in an osmotic pressure increase of 17,000 torr at oo or
`19,300 torr at 37°. One mOsmol is lJlOOO of an osmol. For exam(cid:173)
`ple, 1 mol of anhydrous dextrose is equal to 180 g. One osmol of
`this nonelectrolyte is also 180 grams. One mOsmol would be 180
`mg. Thus, 180 mg of this solute dissolved in 1 kg of water will
`produce an increase in osmotic pressure of 19.3 torr at body
`temperature.
`For a solution of an electrolyte such as sodium chloride, one
`moleciUle of sodium chloride represents one sodium and one
`chloride ion. Hence, 1 mol will represent 2 osmol of sodium
`chloride theoretically. Accordingly, 1 osmol NaCl = 58.5 g/2 or
`29.25 g. This quantity r epresents the sum total of 6.02 X 1023
`ions as the total number of particles. Ideal solutions infer very
`dilute solutions or infinite dilution.
`However, as the concentration is increased, other factors enter.
`With s trong electrolytes, interionic attraction causes a decrease in
`their effect on colligative properties. In addition, and in opposi(cid:173)
`tion, for all solutes, including nonelectrolytes, solvation and pos(cid:173)
`sibly other factors operate to intensify their colligative effect.
`Therefore, it is very difficult and often impossible to predict accu(cid:173)
`rately the osmoticity of a solution. It may be possible to do so for
`a dilute solution of a single pw-e and weU-characterized solute,
`but not for most parenteral and enteral medicinal and/or nutri(cid:173)
`tional fluids; experimental determination likely is required.
`
`Page 7 of 23
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`
`THERAPEUTIC CONSIDERATIONS
`
`It generally :is accepted that osmotic effects have a major place
`in the maintenance of homeostasis (the state of equilibrium in
`the living body with respect to various functions and to the
`chemical composition of the fluids and tissues, eg, temperature,
`heart rate, blood pressure, water content, or blood sugar). To a
`great extent these effects occur within or between cells and
`tissues where they cannot be measured. One of Lhe most trou(cid:173)
`blesome problems in clinical medicine is the maintenance of
`adequate body fluids and proper balance between extracellular
`and intracellular fluid volumes in seriously ill patients. It
`should be kept in mind, however, that fluid and electrolyte
`abnormalities are not diseases, but are the manifestations of
`disease.
`The physiological mecharnisms that control water intake
`and output appear to respond primarily to serum osmoticity.
`Renal regulation of output is influenced by variation in rate of
`release of pituitary anLidiuretic hormone (ADH) and other fac(cid:173)
`tors in response to changes in serum osmoticity. Osmotic
`changes also serve as a stimulus to moderate thirst. This mech(cid:173)
`anism is sufficiently sensitive to limit variations in osmoticity
`in the normal individual to less than about 1%. Body fluid
`continually oscillates within this narrow range. An increase of
`plasma osmoticity of 1% will stimulate ADH rel.ease, result in
`reduction of urine flow, and, at the same time, stimulate thirst
`that results in increased water intake. Both the increased renal
`reabsorption of water (without solute) stimulated by circu lat(cid:173)
`ing ADH and the increased water intake tend to lower serum
`osmoticity.
`The transfer of water through the cell membrane occurs so
`rapidly that any lack of osmotic equi.librium between the two
`fluid compartments in any given tissue usually is corrected
`within a few seconds and, a t most, within a minute or so.
`However, this rapid transfer of water does not mean that
`complete eq_uilibration occurs between the extracellular and
`intracellular compartments throughout the entire body within
`this same s hort period of time. The reason is that fluid usually
`enters the body through the gut and then must be transported
`by the circulatory system to all tissues before complete equili(cid:173)
`bration can occur. In the normal person it may require 30 to 60
`min to achieve reasonably good equilibration throughout the
`body after drinking water. Osmoticity is th(! property that
`largely determines the physiological acceptability of a variety
`of solutions used for therapeutic and nut1-itional purposes.
`Pharmaceutical and therapeutic consideration of osmotic
`effects has been, to a great extent, directed toward the side
`effects of ophthalmic and parenteral medicinals due to abnor(cid:173)
`mal osmoticity, and either to formulating to avoid the side
`effects or to finding methods of administration to minimize
`them. More recently this consideration has been extended to
`total (centraD parenteral nutrition, to enteral hyperalimenta(cid:173)
`tion ("tube" feeding), and to concentrated-fluid infant formu(cid:173)
`las.1 Also, in recent years, the importance of osmometry of
`serum and urine in the diagnosis of many pathological condi(cid:173)
`tions has been recognized.
`There are a number of examples of the direct therapeutic
`effect of osmotic action, suclh as the intravenous (IV) use of
`mannitol as a diuretic that is filtered at the glomeruli and thus
`increases the osmotic pressure of tubular urine. Water must
`then be reabsorbed against a higher osmotic gradient than
`otherwise, so reabsorption is slower and diuresis is observed.
`The same fundamental principle applies to the IV administra(cid:173)
`tion of 30% urea used to affect intr acranial pressure in the
`control of cerebral edema. Peritoneal dialysis fluids tend to be
`somewhat hyperosmotic to withdraw water and nitrogenous
`metabolites. Two to five percent sodium chioride solutions or
`dispersions in an oleaginous base (Muro, Bausch & Lomb) and
`a 40% glucose ointment are used topically for corneal edema.
`Ophthalgan (Wyeth-Ayerst) is ophthalmic glycerin employed for
`its osmotic effect to clear edematous cornea to facilitate an
`
`TONICITY, OSMOTICITY, OSMOLALITY, AND OSMOLARITY
`
`247
`
`ophthalmoscopic or gonioscopic examination. Glycerin solu(cid:173)
`tions in 50% concentration Osmoglyn (Alcon) and isosorbide
`solution Ismotic (Alcon) are oral osmotic agents for reducing
`intraocular pressure.
`The osmotic principle also applies to plasma extenders such
`as polyvinylpyrrolidone and to saline laxatives such as magne(cid:173)
`sium sulfate, magnesium citrate solution, magnesium hydrox(cid:173)
`ide (via gastric neutralization), sodium sulfate, sodium phos(cid:173)
`phate, and sodium biphosphate oral. solution and enema (Fleet).
`An interesting osmotic laxative that is a nonelectrolyte is a
`lactulose solution. Lactulose is a nonabsorbable disaccharide
`that is colon-specific, wherein colonic bacteria degrade some of
`the disaccharide to lactic and other simple organic acids. These,
`in toto, lead to an osmotic effect and laxation. An extension of
`this therapy is illustrated by Cephulac (Marion Merrell Dow)
`solution, which uses the acidification of the colon via lactulose
`degradation to serve as a trap for ammonia migrating from the
`blood to the colon. The conversion of ammonia of blood to the
`ammonium ion in the colon ultimately is coupled with the
`osmotic effect and laxation, thus expelling undesirable levels of
`blood ammonia. This product is employed to prevent and treat
`frontal systemic encephalopathy.
`Osmotic laxation is observed with the oral or rectal use of
`glycerin and sorbitol. Epsom salt has been used in baths and
`compresses to reduce edema associated with sprains. Another
`approach is the indirect application of the osmotic effect in
`therapy via osmotic pump drug delivery systems.2
`
`OSMOLALITY AND OSMOLARITY
`
`It is necessary to use several additional terms to define expres(cid:173)
`sions of concentration in reflecting the osmoticity of solutions.
`The terms include osmolality, the expression of osmolal
`concentration, and osmolarity, the expression of osmolar
`concentration.
`OSMOLALITY- A solution has an osmolal concentration
`of one when it contains 1 osmol of solute/kg of water. A solution
`has an osmolality of n when it contains n osmol/kg of water.
`Osmolal solutions, like their counterpart molal solutions, re(cid:173)
`flect a weight-to-weight relationship between the solute and
`the solvent. Because an osmol of any nonelectrolyte is equiva(cid:173)
`lent ito 1 mol of that compound, then a 1 osmolal solution is
`synonymous to a 1 mol.al solution for a typical nonelectrolyte.
`With a typical electrolyte like sodium chloride, 1 osmol is
`approximately 0.5 mol of sodium chloride. Thus, it follows that
`a 1 osmolal solution of sodium chloride essentially is equivalent
`to a 0.5 molal solution. Recall that a 1 osmolal solution of
`dextrose or sodium chloride each will co.ntain the same particle
`concentration. In ihe dextrose solution there will be 6.02 X 1023
`molecules/kg of water and in the sodium chloride solution one
`will have 6.02 X 1023 total ions/kg of water, one-half of which
`are Na + ions and the other half CJ- ions.
`A.<:. in molal solutions, osmolal solutions usually are em(cid:173)
`ployed where quantitative precision is required, as in the mea(cid:173)
`surement of physical and chemical properties of solutions (ie,
`colligative properties). The advantage of the wlw relationship
`is that the concentration of the system is not influenced by
`temperature.
`OSMOLARITY- The relationship observed betwee.n mo(cid:173)
`lality and osmolality is shared similarly between molarity and
`osmolarity. A solution has an osmolar concentration of 1 when
`it contains 1 osmol of solute per liter of solution. Likewise, a
`solution has an osmolarity of n when it contains n osmols!L of
`solution. Osmolar solutions, unlike osmolal solution, reflect a
`weight in volume relationship between the solute and final
`solution. A 1 molar and 1 osmolar solution would be identical
`for nonelectrolytes. For sodium chloride a 1 osmolar solution
`would contain 1 osmol of sodium chloride per liter which ap(cid:173)
`proximates a 0.5 molar solution. T