16 TH
`
`EDITION
`
`Remington's
`
`ARTHUR OSOL
`Editor, and Chairman
`of the Editorial Board
`
`MYLAN Ex. 1016, Page 1
`
`

`
`TH
`
`Asa
`
`harma:
`Sciences
`
`UNIVERSITY of NORTH DRUM
`
`SEP 2 1982
`
`HEALTH SCIENCES LIBRARY
`
`1980
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`MYLAN Ex. 1016, Page 2
`
`

`
`for patients.
`icularly with
`
`9 and Their
`I., in addition
`Admixtures.
`ity, and Os-
`ic Solutions;
`indicated in
`and Chapter
`ng, evidence
`in evaluating
`icts than can
`is and stan-
`tctively, the
`pportunities
`xaining and
`Dmpounding
`ing or on an
`
`Lion editors,
`affiliations
`f the subject
`citing its 108
`thanks are
`had respon-
`se book but
`d Granberg,
`Dr. Alfred
`:rmaceutics;
`College of
`-al Chemis-
`,n D. Chase,
`ice, for Part
`Ewart A.
`niversity of
`Agents, 29
`r individual
`hia College
`'oducts; Dr.
`armacy and
`and Their
`igton State
`For metic-
`, from ap-
`Mrs. Ellen
`n Editorial
`
`Company
`ictor in the
`arly for the
`ter Kowal-
`
`ice extends
`thanks for
`he College,
`endow the
`macy.
`
`HUR OSOL
`rial Board
`
`Tables of Contents
`
`Part 1 (cid:9)
`
`Orientation
`
`1 Scope
`2 (cid:9) Evolution of Pharmacy
`
`3 Ethics (cid:9)
`4 Pharmacists in Practice
`5 (cid:9) Pharmacists in Industry
`6 (cid:9) Pharmacists in Government
`
`7 Literature
`8 Research
`
`
`Part 2 (cid:9)
`
`Pharmaceutics
`
`3 (cid:9)
`8 (cid:9)
`19 (cid:9)
`26 (cid:9)
`34 (cid:9)
`42 (cid:9)
`49 (cid:9)
`59 (cid:9)
`
`69
`104
`137
`148
`
`9 (cid:9) Metrology and Calculation
`10 Statistics (cid:9)
`11 (cid:9) Computer Science
`12 Calculus
`13 Atomic and Molecular Structure and the States of
`Matter (cid:9)
`14 Complexation
`15 Thermodynamics
`16 (cid:9) Solutions and Phase Equilibria (cid:9)
`Ionic Solutions and Electrolytic Equilibria
`17 (cid:9)
`18 (cid:9) Reaction Kinetics
`Interfacial Phenomena
`19 (cid:9)
`20 (cid:9) Colloidal Dispersions
`21 (cid:9) Particle Phenomena and Coarse Dispersions (cid:9)
`22 Rheology
`
` 160
`182
` 193
`202
`225
`244
`253
`266
`294
` 323
`
`Part 3 (cid:9)
`
`Pharmaceutical Chemistry
`
`Inorganic Pharmaceutical Chemistry
`23 (cid:9)
`24 (cid:9) Organic Pharmaceutical Chemistry
`
`25 (cid:9) Natural Products
`26 (cid:9) Drug Nomenclature—United States Adopted Names
`27 (cid:9) Structure-Activity Relationship and Drug Design .
`
`343
`364
`385
`413
`420
`
`Part 4 (cid:9)
`
`Radioisotopes in Pharmacy and Medicine
`
`28 (cid:9) Fundamentals of Radioisotopes °
`29 (cid:9) Medical Applications of Radioisotopes
`
`Part 5 (cid:9)
`
`Testing and Analysis
`
`30 (cid:9) Analysis of Medicinals
`31 (cid:9) Biological Testing
`32 (cid:9) Clinical Analysis
`33 Chromatography
`Instrumental Methods of Analysis
`34 (cid:9)
`
`
`
`
`
`
`
`
`
`
`439
`458
`
`487
`520
`532
`562
`585
`
`Part 6 (cid:9)
`
`Pharmaceutical and Medicinal Agents
`
`.
`
`35 Diseases: (cid:9) Manifestations and Pathophysiology (cid:9)
`36 Drug Absorption, Action, and Disposition
`37 Basic Pharmacokinetics (cid:9)
`38 Principles of Clinical Pharmacokinetics (cid:9)
`39 Topical Drugs (cid:9)
`40 Gastrointestinal Drugs
`41 Blood, Fluids, Electrolytes, and Hematologic Drugs
`42 Cardiovascular Drugs (cid:9)
`43 Respiratory Drugs
`44 Sympathomimetic Drugs
`45 Cholinomimetic (Parasympathomimetic) Drugs
`46 Adrenergic Blocking Drugs
`47 Antimuscarinic and Antispasmodic Drugs
`48 Skeletal Muscle Relaxants (cid:9)
`Diuretic Drugs
`49
`Uterine and Antimigraine Drugs (cid:9)
`50
`51 Hormones
`52 Vitamins and Other Nutrients (cid:9)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`615
`656
`683
`702
`716734
`
`757
`
`788034
`815
`835
`844
`850
`861
`873
`886
`891
`945
`
`53 Enzymes
`54 General Anesthetics
`55 Local Anesthetics
`56 Sedatives and Hypnotics
`57 Antiepileptics
`58 Psychopharmacologic Agents
`59 Analgesics and Antipyretics
`60 Histamine and Antihistamines
`61 Central Nervous System Stimulants
`62 Antineoplastic and Immunosuppressive Drugs (cid:9)
`63 (cid:9) Antimicrobial Drugs
`64 Parasiticides
`65 Pesticides (cid:9)
`66 (cid:9) Diagnostic Drugs
`67 (cid:9) Pharmaceutical Necessities
`68 (cid:9) Adverse Effects of Drugs
`69 Pharmacogenetics (cid:9)
`70 (cid:9) Pharmacological Aspects of Drug Abuse
`Introduction of New Drugs
`71 (cid:9)
`
` 978
`982
`991
` 1004
`1020
` 1029
` 1043
` 1065
` 1075
`1081
` 1099
` 1179
` 1188
` 1212
` 1225
` 1268
` 1283
` 1287
` 1302
`
`Part 7 (cid:9)
`
`Biological Products
`
`72 (cid:9) Principles of Immunology
`Immunizing Agents and Diagnostic Antigens (cid:9)
`73 (cid:9)
`74 (cid:9) Allergenic Extracts (cid:9)
`
` 1315
`. (cid:9) 1324
` 1341
`
`Part 8 (cid:9)
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`75 Preformuiation
`76 (cid:9) Bioavailability and Bioequivalency Testing (cid:9)
`77 Separation (cid:9)
`78 Sterilization
`79 (cid:9) Tonicity, Osmoticity, Osmolality, and Osmolarity . (cid:9)
`80 (cid:9) Plastic Packaging Materials (cid:9)
`81 (cid:9) Stability of Pharmaceutical Products
`82 Control
`83 (cid:9) Solutions, Emulsions, Suspensions, and Extractives (cid:9)
`84 (cid:9) Parenteral Preparations (cid:9)
`Intravenous Admixtures (cid:9)
`85 (cid:9)
`86 (cid:9) Ophthalmic Preparations
`87 (cid:9) Medicated Applications (cid:9)
`88 Powders (cid:9)
`89 (cid:9) Tablets, Capsules, and Pills (cid:9)
`90 (cid:9) Coating of Pharmaceutical Dosage Forms (cid:9)
`91 (cid:9) Prolonged-Action Pharmaceuticals
`92 Aerosols (cid:9)
`
` 1355
` 1369
` 1378
` 1390
`1403
`1420
` 1425
` 1434
`1438
` 1463
` 1488
` 1498
` 1518
` 1535
`1553
` 1585
` 1594
`1614
`
`Part 9 (cid:9)
`
`Pharmaceutical Practice
`
`Ambulatory Patient Care
`93
`Institutional Patient Care
`94
`Long-Term Care Facilities
`95
`96 The Pharmacist and Public Health
`97 The Patient: (cid:9) Behavioral Determinants
`98 Patient Communication
`99 Patient Compliance
`110001
`The Prescription (cid:9)
`Drug Interactions
`102 Utilization and Evaluation of Clinical Drug Literature (cid:9)
`Health Accessories
`110034 Surgical Supplies
`105 Poison Control
`106 Laws. Governing Pharmacy (cid:9)
`107 Pharmaceutical Economics and Management (cid:9)
`108 Dental Services (cid:9)
`
`
`
`
`
`
`
`
`
`.
`
`
`
`
`.
`
`
`INDEX
`
`Alphabetic Index
`
`xul
`
`1631
`1641
`1663
`1676
`1688
`1695
`1703
`1715
`1741
`1772
`1780
`1817
`1827
`1838
`1866
`1884
`
`1894
`
`MYLAN Ex. 1016, Page 3
`
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`(cid:9)
`

`
`Biological
`
`hermophilus,
`
`products being
`ci ally available
`•pecific methods
`characteristics.
`d for biological
`.ties can be em-
`the validity of
`•eq u fret-tie n ts of
`compared to
`oaintained,
`materials being
`by inoculation
`or convenience
`yed most often.
`n verifying ste-
`at are the most
`se of a syringe,
`es between the
`
`': 187, 1977.
`st for Determina-
`erospace Liquid,"
`
`ization in Health
`
`ization, Thomas,
`
`rieal Examination
`iington, DC, Oct
`
`z1 Conference on
`L.S.A, Washington,
`
`SterilizQtiun,
`
`p Pharm 29: 947.
`
`ndustrial Sterit.
`
`nination Control
`
`Controlled En-
`, DC, 4, April 24,
`
`a/ Control: Mi-
`I Spec. Publ. No,
`
`Chapter 79
`Tonicity, Osmoticity, osmolality,
`and Osmolarity
`
`Dwight L. Deardorff, PhD Emeritus Professor of Pharmacy, College of Pharmacy,
`University of Illinois, Chicago, IL 60612
`
`osmotic effects
`definitions
`osrnolarity
`computation
`abnormal
`osmoticity
`effects
`osmometry and
`the clinical
`laboratory
`
`osmoticity and
`enteral
`hyperalimen-
`tatlon
`osmolality
`determination
`freezing paint
`calculations
`
`It is generally accepted that osmotic effects have a major
`place in the maintenance of homeostasis (the state of equi-
`librium in the living body with respect to various functions
`and to the chemical composition of the fluids and tissues, e.g.,
`temperature, heart rate, blood pressure, water content, blood
`sugar, etc.). To a great extent these effects occur within or
`between cells and tissues where they cannot be measured.
`One of the most troublesome problems in clinical medicine
`is the maintenance of adequate body fluids and proper balance
`between extracellular and intracellular fluid volumes in se-
`riously ill patients. It should be kept in mind, however, that
`fluid and electrolyte abnormalities are not diseases, but are
`the manifestations of disease.
`The physiologic mechanisms which 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 antidiuretic hormone (ADH) and other
`factors in response to changes in serum osmoticity. Osmotic
`changes also serve as a stimulus to moderate thirst. This
`mechanism is sufficiently sensitive to limit variations in Os-
`moticity in the normal individual to less than about 1%. Body
`fluid continually oscillates within this narrow range. An in-
`crease of plasma osmoticity of 1% will stimulate ADH release,
`result in reduction of urine flow, and at the same time stim-
`ulate thirst that results in increased water intake. Both the
`increased renal reabsorption of water (without solute) stim-
`ulated by circulating 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 equilibrium between the two
`fluid compartments in any given tissue is usually corrected
`within a few seconds, and at most within a minute or so.
`However, this rapid transfer of water does not mean that
`complete equilibration occurs between the extracellular and
`intracellular compartments throughout the whole body within
`this same short period of time. The reason for this is that
`fluid usually enters the body through the gut and must then
`be transported by the circulatory system to all tissues before
`complete equilibration can occur. In the normal person it
`may require 30-60 minutes to achieve reasonably good
`equilibration throughout the body after drinking water.
`Osmoticity is the property that largely determines the phys-
`iologic acceptability of a variety of solutions used for thera-
`peutic and nutritional 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 ab-
`normal osmoticity, and to either formulating to avoid the side
`
`The author gratefully acknowledges suggestions received from Dr.
`Frederick P. Siegel, Professor of Pharmacy, and from Dr. John K. Siepler,
`Assistant Professor of Pharmacy Practice, College of Pharmacy, University
`of Illinois, Chicago, IL.
`
`effects or finding methods of administration to minimize
`them. More recently this consideration has been extended
`to total (central) parenteral nutrition, to enteral hyperali-
`mentation ("tube" feeding), and to concentrated-fluid infant
`formulas.1 Also, in recent years the importance of osmometry
`of serum and urine in the diagnosis of many pathological
`conditions has been recognized.
`There are also instances of the direct therapeutic effect of
`osmotic action, such as the intravenous use of mannitol as a
`diuretic, which is filtered at the glomeruli and thus increases
`the osmoticity of tubular urine. Water must therefore be
`reabsorbed against a higher osmotic gradient than otherwise,
`so reabsorption is slower and a diuretic effect is observed.
`The same principle applies, for example, to cathartics such
`as magnesium sulfate, to plasma substitutes such as poly-
`vinylpyrrolidone, to 5% sodium chloride solution used topi-
`cally for corneal edema, and to the new drug-delivery system
`called an "Elementary Osmotic Pump."2
`Osmometry may be used also in such studies as determining
`the extent of binding of drugs to macromolecules, and in fol-
`lowing the course of chemical reactions in which a net change
`in the number of particles occurs.
`Many medicinal agents affect serum and urine osmoticity.
`They act either by increasing ADH release, or by inhibiting
`physiological responses induced by ADH. For example, re-
`lease of ADH is stimulated by barbiturates, carbamazepine,
`chlorpropamide, clofibrate, cyclophospharnide, vincristine,
`and by various tricyclic antidepressants .3
`If a solution is placed in contact with a membrane that is
`permeable 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 is often called semi-
`permeable. As the several types of membranes of the body
`vary in their permeability, it is well to note that they are se-
`lectively permeable. Most normal living-cell membranes
`maintain various solute concentration gradients. 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 concen-
`tration gradient across itself. Osmosis then is the diffusion
`of water through a membrane that maintains at least one so-
`lute concentration gradient across itself.
`Assume a solution A on one side of the membrane, and a
`solution B of the same solute but of a higher concentration on
`the other side; the solvent will tend to pass into the more
`concentrated solution until equilibrium has been established.
`The pressure required to prevent this movement is the os-
`motic pressure. It is defined as the excess pressure, or pres-
`sure greater than that above the pure solvent, which must be
`applied to solution B to prevent passage of solvent through
`a perfect semipermeable membrane from A to B. The con-
`centration of a solution with respect to effect on osmotic
`
`1403
`
`MYLAN Ex. 1016, Page 4
`
`

`
`(cid:9) (cid:9)
`
`f
`
`14%
`
`ip!,
`
`a.
`
`r
`
`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. Physiologic solutions with
`an osmotic pressure lower than that of body fluids, or of 0.9%
`sodium chloride solution, are commonly referred to as being
`hypotonic. Physiologic solutions having a greater osmotic
`pressure are termed hypertonic.
`
`Such qualitative terms are of limited value, and it has be-
`come necessary to state osmotic properties in quantitative
`terms. To do so a term must be used that will represent all
`particles that may be present in a given system. The term
`used is osmoi. (cid:9)
`osmol is defined as the weight in grams of
`a solute, existing in a solution as molecules (and/or ions,
`macromolecules, aggregates, etc.), that is osmotically equiv-
`alent to the gram-molecular-weight of an ideally behaving
`nonelectrolyte. Thus the osmol-weight of a nonelectrolyte,
`in a dilute solution, is generally equal to it,s gram-molecular-
`weight. A milliosmol, abbreviated mOsm, is the weight stated
`in milligrams.
`
`For a solute such as sodium chloride, which is completely
`ionized, the osmol weight in dilute solution will be about half
`its gram-molecular-weight. However, as concentration is
`increased, other factors enter. With strong electrolytes, in-
`terionic attraction causes a decrease in their effect on colli-
`gative properties. In addition, and in opposition, for all so-
`lutes, including nonelectrolytes, solvation and possibly other
`factors operate to intensify their colligative effect. Therefore
`it is very difficult and often impossible to predict accurately
`the osmoticity of a solution. It may be pOssible to do so for
`a dilute solution of a single, pure and well-characterized solute,
`but not for most parenteral and enteral medicinal and/or
`nutritional fluids; experimental determination is likely to be
`needed.
`
`Osmoticity, Osmolality, Osmolarity
`
`T
`
`1
`
`1404 (cid:9)
`
`CHAPTER 79
`
`pressure is related to the number of particles (un-ionized
`molecules, ions, macromolecules, aggregates) of solute(s) in
`solution and thus is affected by the degree of ionization or
`aggregation of the solute. The osmotic pressure, as well as
`other colligative properties, is determined by the number of
`particles because they have, on the average, equal kinetic
`energy, regardless of size. As the effect does not depend on
`mass, concentration in this case should not be stated in terms
`of mass.
`
`Body fluids, including blood and lacrimal fluid, normally
`have an osmotic pressure which is often described as corre-
`sponding to that of a 0.9% solution of sodium chloride. The
`body also attempts to keep the osmotic pressure of the con-
`tents of the gastrointestinal 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 isoosmotic
`with physiologic fluids. The term isotonic, meaning equal
`tone, is in medical usage commonly used interchangeably with
`isoosmotic. However, terms such as isotonic and tonicity
`should be used only with reference to a physiologic fluid.
`Isoosmotic is actually a physical term which compares the
`osmotic pressure (or another colligative property, such as
`freezing point depression) of two liquids, neither of which may
`be a physiologic fluid, or which may be a physiologic fluid only
`under certain circumstances. For example, a solution of boric
`acid that is isoosmotic with both blood and lacrimal fluid is
`isotonic only with the lacrimal fluid. This solution causes
`hemolysis of red blood cells because molecules of boric acid
`pass freely through the erythrocyte membrane regardless of
`concentration. As another example, a "chemically defined
`elemental diet" or enteral nutritional fluid can be isoosmotic
`with the contents of the gastrointestinal tract; but would not
`be considered a physiologic fluid, or suitable for parenteral
`use.
`
`It is, moreover, necessary to use three additional terms to
`define the osmotic situation of solutions: osmoticity, osmol-
`ality, and osmolarity. They are all needed. Many profes-
`sional people, including authors of textbooks, who use the '
`terms do not have a clear understanding of their meaning.
`This applies especially to the terms osmolality and osmolarity,
`as the term osmoticity has been in less frequent use. The
`terms osmolality and osmolarity are often used interchange.
`ably. This is no doubt due, at least in part, to the circum-
`stance that until recent years most of the systems involved
`were body fluids, where the difference between the numerical
`values of the two quantities is small, perhaps 1%, and probably
`similar in magnitude to the error involved in their determi-
`nation. The confusion seems to have done no real harm up
`to this time. However, it can be a problem, in some cases a
`dangerous one, with certain fluids. This seems most likely
`to occur with the more concentrated solutions used in Total
`Parenteral Nutrition, Enteral Hyperalimentation, and oral
`nutritional fluids for infants.
`The reasons that all three terms are needed deserve a fairly
`lengthy explanation but can be summarized as follows:
`Osmolarity, which expresses a wt/vol relationship, is sim-
`pler to visualize, understand and use than osmolality, but is
`more difficult to determine with satisfactory accuracy. It is
`not measured experimentally, the values being approximated
`by computation from values of osmolality or from ingredient
`concentration. Osmolarity is affected by temperature
`changes; osmolality is not.
`Osrnolality, which expresses a wt/wt relationship, is, com-
`pared to osmolarity, more difficult to use in extemporaneous
`preparation of enteral nutritional fluids (oral or "tube"), and
`even more difficult to use in extemporaneous preparation of
`sterile intravenous medicinal and nutritional fluids. How-
`ever, it can be determined quite readily experimentally. It ,
`generally cannot be calculated. Examples of some approxi-
`mate methods of calculation for serum are given in a later
`section.
`Osmoticity is a more general term. It is useful when one
`wishes to refer to an osmotic state without stipulating whether
`one refers to osmolality or osmolarity. Much current confu-
`sion could be avoided if this term is used, except in the in-
`stances when one specifically means osmolality or osmolarity,
`as defined in the following section.
`As these concepts are coming with increasing frequency to
`the attention of physicians, nurses, dietitians, the clinical
`laboratory staff, and to some individuals of the general public,
`the pharmacist should be able to explain them when neces-
`sary.
`The unit of osmolality is "that mass of solute which, when
`dissolved in a kilogram of water, will exert an osmotic pressure
`equal to that exerted by a gram-molecular-weight of an ideal
`un-ionized substance dissolved in a kilogram of water," while
`the unit of osmolarity is "that mass of solute which, when
`dissolved in sufficient solvent to produce a liter of solution,
`will exert an osmotic pressure equal to that exerted by a gram I
`molecular weight of an ideal un-ionized substance dissolved
`in a liter of solution."
`In brief, osmolality represents the number of osmols of the
`solute in a kg of solvent, and osmolarity represents the num-
`ber of osmols in a liter of solution. For example, if one as-
`sumes the case of the kilogram of solvent measuring 1 liter,
`and assumes using the same weight of a given solute in the
`same solvent in both cases, the concentrations (in terms of
`wt/vol) would be slightly different because in the first case the
`total volume would be more than 1 liter due to the volume
`contribution of the solute. Therefore a one-molal solution
`will be slightly more dilute than a one-molar solution if other r
`factors are equal. It is important that these definitions be
`
`MYLAN Ex. 1016, Page 5
`
`

`
`TONICITY, OSMOTiCITY, OSMOLALITY, AND OSMOLARITY (cid:9)
`
`1405
`
`understood and that accurate terminology be used by the
`professional groups involved.
`Reference has been made to the terms hypertonic and by-
`potonic. Analogous terms are, hyperosmotic and hypoos-
`motic. The significance of hyper- and hypo-osmoticity for
`medicinal and nutritional fluids will be discussed in later
`sections. The values which correspond to those terms for
`serum may be approximately visualized from the following
`example. Assuming normal serum osmolality to be 285
`rnOsm/kg, as serum osmolality increases due to water deficit
`the following signs and symptoms usually are found to pro-
`gressively accumulate at approximately these values:
`294-298—thirst (if the patient is alert and communicative);
`299-313—dry mucous membranes; 314-329—weakness,
`doughy skin; above 330—disorientation, postural hypotension,
`severe weakness, fainting, CNS changes, stupor, coma. As
`serum osmolality decreases due to water excess the following
`may occur:, . 275-261—headache; 262-251—drowsiness,
`weakness; 250-233—disorientation, cramps; below 233—
`seizures, stupor, coma.
`As indicated previously, the body's mechanisms actively
`combat such major changes by limiting the variation in os-
`molality for normal individuals to less than about 1% (ap-
`proximately in the range 282-288 mOsm/kg, based on the
`above assumption).
`The value given for normal serum osmolality above was
`described as an assumption because of the variety of values
`found in the references. Serum osmolality is often loosely
`stated to be about 300 mOsm/1. Apart from that, and more
`specifically, two references state it as 280-295 mOsm/1; other
`references give it as 275-300 mOsm/1, 290 mOsm/1, 306
`mOsirdl, and 275-295 mOsm/kg. There is a strong tendency
`to call it osmolality but to state it as mOsm/1 (not as mOstn/
`kg). In the light of these varying values, one may ask about
`the reproducibility of the experimental measurements, as-
`suming that is their source. It has been stated that most os-
`mometers are accurate to 5 mOsm/1. With that type of re-
`producibility, the above variations may perhaps be expected.
`The difference between liter and kilogram is probably insig-
`nificant for serum and urine. It is difficult to measure kilo-
`grams of water in a solution, and easy to express body fluid
`quantities in liters. Perhaps no harm has been done to date
`by this practice for body fluids. However, loose terminology
`here may lead to loose terminology when dealing with the
`rather concentrated fluids used at times in parenteral and
`enteral nutrition.
`Reference has been made to confusion in the use of the
`terms osmolality and osmolarity, a distinction of special im-
`portance for nutritional fluids. Awareness of high concen-
`trations of formula should give warning as to possible risks.
`Unfortunately, the osmoticity of infant formulas, tube feed-
`ings, and total parenteral nutrition solutions is not adequately
`described either in textbooks or in the literature,5 and the
`labels of many commercial nutritional fluids do not in any way
`state their osmoticity. Often, when the term osmolarity is
`used, one cannot discern whether this is simply incorrect
`terminology, or if osmolarity has actually been calculated from
`osmolality. With concentrated infant formulas, tube feedings
`or parenteral fluids, the osmolarity may only be 80% of the
`osmolality.
`Another current practice that can cause confusion is the use
`of the terms normal and/or physiological Tor isotonic sodium
`chloride solution (0.9%). The solution is surely isoosmotic.
`However, as to being physiological, the ions are each of 154
`mEq/1 concentration while serum contains about 140 mEq of
`sodium and about 103 mEq of chloride.
`The range of mOsm values found for serum raises the
`question as to what is really meant by the terms hypotonic and
`hypertonic for medicinal and nutritional fluids. One can find
`the statement that fluids with an osmolality of 50 mOsm or
`
`more above normal are hypertonic, and if 50 mOsm or more
`below normal are hypotonic. One can also find the statement
`that peripheral infusions should not have an osmolarity ex-
`ceeding 700-800 mOsm/1.6 Examples of osmol concentrations
`of solutions used in peripheral infusions are: D5W-252
`mOsm/l; D1OW —505 mOsin11; Freamine II (8.5%)-850
`mOsm/l; Lactated Ringer's 5% Dextrose-525 mOsm/1.
`When a fluid is hypertonic, undesirable effects can often be
`decreased by using relatively slow rates of infusion, and/or
`relatively short periods of infusion. It has been stated that
`when osmolal loading is needed, a maximum safe tolerance
`for a normally hydrated subject would be an approximate
`increase of 25 mOsm per kg of water over 4 hours.5
`Computation of Osmolarity
`Several methods are used to obtain numerical values of
`osmolarity. The osmolar concentration sometimes referred
`to as the "theoretical osmolarity" is calculated from the wt/vol
`concentration using one of the following equations:
`(1) For a nonelectrolyte
`grams/liter
`X 1000 = mOsm/liter
`mol wt
`(2) For a strong electrolyte
` number of ions
`grams/liter
`X 1000 = mOsm/liter
` X
`formed
`wt
`(3) (cid:9) For individual ions, if desired
`(3)
`grams of ion/liter
` X 1000 = mOsm (of ion)/liter
`ionic wt
`These are simple calculations; however, they omit consider-
`ation of factors such as solvation and interionic forces. By
`this method of calculation 0.9% sodium chloride has an os-
`molar concentration of 308 mOsm/l.
`Two other methods compute osmolarity from values of
`osmolality. The determination of osmolality will be discussed
`in a later section. One method has a strong theoretical basis
`of physical-chemical principles;4 it uses values of the partial
`molal volume(s) of the solute(s). A 0.9% sodium chloride
`solution, found experimentally to have an osmolality of 286
`mOsm/kg, was calculated to have an osmolarity of 280
`mOsm/1, rather different from the value of 308 mOsm/1 cal-
`culated as above. The method using partial molal volumes
`is relatively rigorous, but many systems appear to be too
`complex and/or too poorly defined to be dealt with by this
`method.
`The other method is based on the following relationship:7S
`actual osmolarity = measured osmolality X (density - g so-
`lute/m1). This expression can be written:
`mOsm/1 solution = mOsm/1000 g water
`X g water/ml solution
`
`The experimental value for the osmolality of 0.9% sodium
`chloride solution was 292.7 mOsm/kg; the value computed for
`osmolarity was 291.4 mOsm/1. This method does not have
`as firm a theoretical basis as the preceding method but it has
`the advantage that it uses easily obtained values of density of
`the solution and of its solute content. Apparently it can be
`used with all systems. For example, the osmolality of a nu-
`tritional product (Sustacal), was determined by the freezing
`point depression method to be 625 mOsm/kg;5 its osmolarity
`was calculated as 625 X 0.839 = 524 mOsm/1.
`The USP requires that labels of Pharmacopeial solutions
`that provide intravenous replenishment of fluid, nutrient(s),
`or electrolyte(s), as well as of the osmotic diuretic Mannitol
`Injection, state the osmolar concentration, in milliosmols per
`liter, except that where the contents are less than 100 ml, or
`where the label states the article is not for direct injection but
`is to be diluted before use, the label may alternatively state
`
`Tonal terms to
`)ticity, osmol-
`Many proles-
`, who use the
`heir meaning,
`nd osmolarity,
`not use. The
`interchange-
`o the circum-
`ems involved
`the numerical
`and probably
`heir determi-
`real harm up
`some cases a
`is most likely
`used in Total
`ion, and oral
`
`3serve a fairly
`follows:
`nship, is sim-
`olality, but is
`curacy. It is
`pproximated
`m ingredient
`temperature
`
`ship, is, corn-
`emporaneous
`• "tube"), and
`reparation of
`I uids. How.
`mentally. It
`ame approxi-
`'en in a later
`
`ful when one
`sting whether
`rrent confu-
`,pt in the in-
`ir osmolarity,
`
`frequency to
`, the clinical
`?neral public,
`when neces-
`
`which, when
`iotic pressure
`ht of an ideal
`Niter," while
`which, when
`r of solution,
`ed by a gram
`ice dissolved
`
`ismoLs of the
`its the num-
`le, if one as-
`iring 1 liter,
`;olute in the
`(in terms of
`first case the
`the volume
`solution
`tion if other
`!finitions be
`
`MYLAN Ex. 1016, Page 6
`
`

`
`1406 (cid:9)
`
`CHAPTER 79
`
`the total osmolar concentration in milliosmols per ml. This
`is a reasonable request from several standpoints, and intra-
`venous fluids are being labeled in accordance with this stip-
`ulation, as shown in the next section.
`An example of the use of the first method described above is the com-
`putation of the approximate osmolar concentration ("theoretical osmo-
`larity") of a Lactated Ringer's 5% Dextrose Solution (Travenol Solution),
`which is labeled to contain, per liter, dextrose (hydrous) 50 g, sodium
`chloride 6 g, potassium chloride 300 mg, calcium chloride 200 mg, sodium
`lactate 3.1 g. Also stated is that the total osmolar concentration of the
`solution is approximately 524 mOsm per liter, in part contributed by 130
`mEq of Nat, 109 mEq of Cl-, 4 mEq of K4, 3 mEq of Ca2+, and 28 mEq
`of lactate ion.
`The derivation of the osmolar concentrations from the stated compo-
`sition of the solution may be verified by calculations using equation (1)
`above for the nonelectrolyte dextrose, and equation (2) for the electro-
`lytes.
`Dextrose
`
`50 g X 1000
`198.17
`
`- 252.3 mOsm/liter
`
`Sodium Chloride
`6 g X 2 X 1000
`58.44 (cid:9) - 205.33 mOsm/liter
`
`(102.66 mOsm Nu+)
`(102.66 mOsm Cl-)
`ll
`
`Potassium Chloride
`0.3 g X 2X 1000
`(4.02 mOsm K+)
`74.55
`- 8.04 mOsm/liter
`(4.02 mOsm Cl-)
`1
`
`Calcium Chloride
`0.2 g X 3 X 1000
`(1.8 mOsm Ca2+)
`110.99
`- 5.4 mOsm/liter
`(3.6 mOsm Cl-)
`1
`
`.
`- 55.32 Itiostah
`
`Sodium Lactate
`3.1 g X 2 X 1000
`1(27.66 mOsm Na+)
`ter
`112.06 (cid:9)
`(27.66 mOsm lactate)
`The total osmolar concentration of the Fve solutes in the solution is
`526.4, in good agreement with the labeled total osmolar concentration of
`approximately 524 mOsm/liter.
`The mOsm of sodium in one liter of the solution is the sum of the mOsm
`of the ion from sodium chloride and sodium lactate, i.e., 102.66 + 27.66
`= 130.32 mOsm. Chloride ions come from the sodium chloride, potassium
`chloride, and calcium chloride, the total osmolar concentration being
`102.66 + 4.02 + 3.6 = 110.3 mOsm. The mOsm values of potassium, cal-
`cium, and lactate are calculated to be 4.02, 1.8, and 27.66, respectively.
`Thus, with the possible exception of calcium, there is close agreement with
`the labeled mEq content of each of these ions.
`
`The osmolarity of a mixture of complex composition, such
`as Protein Hydrolysate Injection or an enthral hyperalimen-
`tation fluid, probably cannot be calculated with any acc