`
`Remingt;on
`
`The Science and Practice
`of Pharmacy
`
`'~ LIPPINCOTTWILLIAMS & WILKINS
`
`A Wolters Kluwer Company
`Philadelp~ia • Baltimore • New York • London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`•
`
`FlatWing Ex. 1023, p. 1
`
`
`
`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O'Brien
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`530 Walnut Street
`Philadelphia, PA 19106
`
`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 utili~ed by any information storage and retrieval system without written permission from the copy(cid:173)
`right 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. Manufacturer's 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 Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If they have 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 responsible 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 discrepancy between the
`current official USP or NF standards of strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
`
`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 should call (301) 714-2324.
`
`2345678910
`
`FlatWing Ex. 1023, p. 2
`
`
`
`CHAPTER 11: METROLOGY AND PHARMACEUTICAL CALCULATIONS
`
`119
`
`pretations of the different type percentages involving solutions
`and mixtures.
`The USP states
`
`Percentage concentrations of solutions are expressed as follows:
`
`Weight-in-Volume Percentages
`This is the type of percent problem most often encountered on
`prescriptions. The volume occupied by the solute and the vol(cid:173)
`ume of the solvent are not known because sufficient solvent is
`added to make a given or known final volume.
`
`Percent weight in weight-(w I w) expresses the number of
`g of a constituent in 100 g of product.
`
`Percent weight in volume-(w Iv) expresses the number of
`g of a constituent in 100 mL of product, and is used regardless
`of whether water or another liquid is the solvent.
`
`Percent volume in volume-(v Iv) expresses the number of
`mL of a constituent in 100 mL of product.
`
`The term percent used without qualification means, for mix•
`tures of solids, percent weight in weight; for solutions or sus(cid:173)
`pensions of solids in liquids, percent weight in volume; for solu- <.
`tions of liquids in liquids, percent volume in volume; and for
`solutions of gases in liquids, percent weight in volume. For ex(cid:173)
`ample, a one percent solution is prepared by dissolving one g of
`a solid or one mL of a liquid in sufficient of the solvent to make
`100 mL of the solution.
`
`Ratio Strength
`Ratio strength is another manner of expressing concentration.
`Such phrases as "1 in 10" are understood to mean that one part
`of a substance is to be diluted with a diluent to make 10 parts
`of the finished product. For example, a 1:10 solution means 1
`mL of a liquid or one g of a solid dissolved in sufficient solvent
`to make 10 mL of solution. Ratio strength can be converted to
`percent by:
`
`.
`1 g substance
`-~---- X 100 mL solution = 10 g substance
`10 mL solution
`
`10 g substance = lO%
`100 mL solution
`
`The expression "parts per thousand" (eg, 1:5000) always means
`parts weight in volume when dealing with solutions of solids in
`liquids and is similar to the above expression. A 1:5000 solution
`means 1 g of solute in sufficient solvent to make 5000 mL of so(cid:173)
`lution. This can be converted to percent by
`
`1 g substance
`. X 100 mL solution = 0.02 g substance
`500 mL 1 0 so utwn
`
`
`
`0.02 g substance = 0.02%
`100 mL solution
`
`The expression "trituration" has two different meanings in
`pharmacy. One refers to the process of particle-size reduction,
`commonly by grinding or rubbing in a mortar with the aid of a
`pestle. The other meaning refers to a dilution of a potent pow(cid:173)
`dered drug with a suitable powdered diluent in a definite pro(cid:173)
`portion by weight. It is the second meaning that is used in this
`chapter.
`When pharmacists refer to a "1 in 10 trituration" they mean
`a mixture of solids composed of 1 g of drug plus sufficient dilu(cid:173)
`ent (another solid) to make 10 g of mixture or dilution. In this
`case the "1in10 trituration" is actually a solid dilution of a drug
`with an inert solid. The strength of a trituration may also be
`stated as percent w I w. Thus, the term trituration has come to
`mean a solid dilution of a potent drug with a chemically and
`physiologically inert solid.
`·
`The meanings implied by the USP statements in the section
`on percentage are illustrated below with a few examples of the
`three types of percentages.
`
`EXAMPLES
`1. Prepare 1 f3 of a 10% solution.
`Since this is a solution of a solid in a liquid, this is aw Iv solution.
`
`X
`
`29.6 mL
`+>z
`1
`'.'.>
`
`10 g drug
`100 mL soln
`2.96 g is dissolved in sufficient purified water to make 29.6 mL of
`solution.
`.
`2. How much of a drug is required to compound 4 f3 of a 3% solution
`in alcohol?
`
`X 1 f3 = 2.96 g drug
`
`3 g drug
`100 mL soln
`3. How much 0.9% solution of sodium chloride can be made from X 3
`of NaCl?
`
`X
`
`29.6 mL
`+>z
`1
`'.'.>
`
`X 4 f3 = 3.55 g drug
`
`L
`31.1 g
`100 mL soln
`- - - - -x - - -X . 3=
`m son
`1730
`1
`0 5
`0.9 gNaCl
`13
`4. How many grams of a drug are required to make 120 mL of a 25%
`solution?
`
`25 g drug
`-~-~- x 120 mL = 30 g drug
`100 mL soln
`5. How would you prepare 480 mL of a 1 in 750 solution of an
`antiseptic?
`Remember: percent w Iv is indicated.
`1 in 750 means 1 g of the antiseptic dissolved in sufficient sol(cid:173)
`vent to make 750 mL solution.
`
`- 1--=g'--dr---'ug=--- X 480 mL = 0. 64 g drug
`750mL soln
`Dissolve 0.64 g of antiseptic in sufficient solvent to make 480 mL
`solution.
`6. How much of a substance is needed to prepare 1 L of a 1:10,000
`solution?
`The ratio 1:10,000 means 1 g of a substance in 10,000 mL of solu(cid:173)
`tion.
`
`1000 mL
`1 g substance
`-~---- X - - - - X 1 L = 0.1 g substance
`10,000 mL soln
`1 L
`7. How would you prepare 120 mL of 0.25% solution of neomycin
`sulfate? The source of neomycin sulfate is a solution which con(cid:173)
`tains 1 g neomycin sulfate/10 mL.
`
`10 mL stock soln
`- - - - - - - X
`1 g drug
`
`0.25 g drug
`100 mL soln
`
`X 120 mL soln =
`
`= 3 mL stock soln
`Add sufficient purified water to 3 mL of stock solution to make
`120mL.
`
`Problems
`1. How would you make 3 f3 of a 12.5% solution?
`2. How many liters of a 4% solution can be made from 43 of a solid?
`3. How many liters of an 8% solution can be made from 500 g of a
`solid?
`4. How many grams of a drug are needed to make 4 L of a 1 in 500
`solution?
`
`FlatWing Ex. 1023, p. 3
`
`
`
`dipole moment or polarizability. In charge-transfer complexing,
`substituent effects that increase electron density in the donor
`or decrease it in the acceptor (Structures 5, 6, and 7 are exam-
`ples of the latter type) may be expected to increase complex
`stability. Such effects have been observed. 30'81
`If the hydrophobic interaction makes an important contri-
`bution to complex stability, the incorporation of organic sol-
`vents will reduce the stability. According to the cavity theory of
`the hydrophobic effect, complex stability is related to the
`change in surface area upon complex formation, so it may be
`anticipated that, for such systems, complex stability is related
`to the size of the interactants. Such a dependence has been
`seen, but it is complicated by the presence of additional ef-
`fects.' Another prediction of the cavity model is that, for a
`given complex, stability should be determined primarily by the
`solvent surface tension, and there is some experimental sup-
`port for this prediction.''''"
`
`COMPLEXES IN PHARMACY
`
`APPLICATION TO DRUG DELWERY—Some of the prop-
`erties of a drug are so pertinent to dosage forms and drug
`delivery that it is reasonable to identify them as pharmaceuti-
`cal or biopharmaceutical properties. Complex formation may
`affect these properties, sometimes to advantage and sometimes
`adversely. Many of these properties, with corresponding exam-
`ples of drug complexes, are given in Table 14-9. 34
`A dosage form might be prepared either with the separate
`components S (the substrate or drug) and L (the ligand or
`complexing agent), or with the preformed solid complex.
`In a solution dosage form the method of preparation makes no
`difference, because the complexation equilibrium immediately es-
`tablishes the equilibrium composition. It must be remembered
`that the fraction of drug in the complexed form is given by Equa-
`tion 11, so that the free-ligand concentration is a critical variable,
`and excess ligand may have to be added in order to "drive the
`equilibrium" in favor of the bound (complexed) form.
`In a solid dosage form it may be preferable to incorporate
`the solid complex rather than a physical mixture of the drug
`and complexing agent. For many systems it has been shown
`that the complex provides faster dissolution and greater bio-
`availability than does the physical mixture. The processing
`characteristics (physical state, stability, flowability, etc) of the
`complex also may be better than those of the free drug.
`Not all complexation is intentional or desirable, and some
`dosage-form incompatibilities may be the result of unwanted
`complexation reactions. For example, some widely used poly-
`ethers (Tweens, Carbowaxes, or PEGs) can form precipitates
`with H-bond donors such as phenols and carboxylic acids.
`A substance used widely in liquid dosage forms as a corn-
`plexer of metal ions is EDTA (ethylenediaminetetraacetic acid).
`
`Table 14-9. Pharmaceutical Properties Affected
`by Complexation
`
`PROPERTY
`
`Physical state
`Volatility
`Solid-state stability
`Chemical stability
`Solubility
`Dissolution rate
`Partition coefficient
`Permeability
`Absorption rate
`Bioavailability
`Biological activity
`
`EXAMPLE"
`
`Nitroglycerin-cyclodextrin
`lodine-PVP
`Vitamin A-cyclodextrin
`Benzocaine-caffeine
`Aspirin-caffeine
`Phenobarbital-cyclodextrin
`Benzoic acid-caffeine
`Prednisone-dialkylamides
`Salicylamide-caffeine
`Digoxin-cyclodextrin
`lndomethacin-cyclodextrin
`
`Listed in order of drug-complexing agent.
`b Citations of the original literature will be found in Ref 34.
`
`COMPLEX FORMATION (cid:9)
`
`195
`
`The purpose of this application of complexation is to improve
`drug stability by inhibiting reactions (usually oxidations) that
`are catalyzed by metal ions, the complexed form of the metal
`ion being catalytically inactive. Citric acid (in the form of the
`citrate anion) also is used for this purpose.'
`The cyclodextrins have been shown to have effects on all of
`the properties listed in Table 14-9, and many pharmaceutical
`applications have been proposed. 19,20,36,37
`COMPLEMES IN PHARMACEUTICAL ANALYSIS-
`The formation of metal-ion coordination complexes provides
`the basis of many analytical methods for the determination of
`metals. Titration of divalent and trivalent metal ions with a
`solution of EDTA is a standard procedure called complexomet-
`ric or chelatometric titration.' The theoretical titration curve
`is calculated readily, and it can be shown that the very large
`endpoint "break" is the result of the 1:1 stoichiometry between
`the metal ion and the multidentate EDTA tetraanion. The end-
`point can be detected visually with metallochromic indicators
`or, potentiometrically, with ion-selective membrane electrodes.
`Very low concentrations of metal ions can be determined
`spectrometrically by complexation with a ligand that produces
`a spectral change. If the complex absorbs in the visible region
`of the spectrum, this is called colorimetric analysis. Thou-
`sands of such methods have been developed.' Two examples
`are the determination of Fe(III) by complexation with 1,10-
`phenanthroline (see Table 14-1), and of Hg(II) by complexation
`with dithizone (diphenylthiocarbazone), S=C(NHNHC 6H5)2.
`Gravimetric analysis of metal ions can be accomplished via
`their precipitation as insoluble coordination complexes. For
`example, Ni(II) forms an insoluble square planar bis(dimeth-
`ylglyoxime) complex, and many metal ions yield insoluble com-
`plexes with 8-hydroxyquinoline (see Table 14-1 for the struc-
`tures of these ligands).
`In some instances the analytical situation can be reversed to
`make the metal ion serve as the analytical reagent and the
`organic ligand as the sample. The ferric hydroxamate method
`for the detection and determination of carboxylic acid deriva-
`tives is a good example, in which a carboxylic acid derivative
`such as an ester, amide, or anhydride is reacted with hydroxyl-
`amine to form the corresponding hydroxamic acid.
`
`0 (cid:9)
`
`0
`
`R—C—X + NH2OH (cid:9)
`
`R—C—NHOH + HX
`
`An excess of Fe(III) is added, and this forms a red-violet coor-
`dination complex with the hydroxamic acid; the concentration
`of the complex is determined spectrometrically.
`Colorimetric analyses also can be based on molecular com-
`plex formation. Recall that charge-transfer complexation often
`is accompanied by the development of an intense charge-trans-
`fer absorption band, and this can be put to analytical use. For
`example, tertiary amines can be determined spectrometrically
`by complexation with tetracyanoethylene (Structure 5).
`Many complex formation reactions are used in conjunction
`with, or as the basis for, a separation, either by liquid—liquid
`extraction or chromatography. A classical method for amines,
`the acid-dye method, is based upon complex formation between
`an amine and a dye molecule. The complex is extracted from
`the aqueous phase in which it is formed into an organic solvent,
`where the dye concentration is measured spectrometrically.
`The success of the method is based on the condition that
`only the complexed form of the dye is extractable, so each
`molecule of amine results in the complexation of one molecule
`of dye, and this is extracted into the organic phase, where its
`concentration is an indirect measure of the amount of amine. In
`order to ensure the nonextractability of the excess (uncom-
`plexed) dye, a dye is used that is a neutral weak acid, and the
`aqueous pH is controlled at a level above the pKc, of the dye,
`thus converting it to its anionic form. 4° The principle can be
`reversed to determine acidic compounds with basic dyes.' In a
`similar way metal ions may be extracted into organic solvents
`upon complexation with hydrophobic ligands.
`
`FlatWing Ex. 1023, p. 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`