CHEMICAL STABILITY OF
`PHARMACEUTICALS
`A HANDBOOK FOR PHARMACISTS·
`
`KENNETH A. CONNORS
`School of Pharmacy, The University of Wisconsin
`
`GORDON L. AMIDON
`School of Pharmacy, The University of Wisconsin
`
`LLOYD KENNON
`Formerly School of Pharmacy, .
`The University of Wiscorisin
`
`A WILEY·INTERSCIENCE PUBLICATION
`JOHN WILEY & SONS
`NEW YORK· CHICHESTER· BRISBANE . TORONTO
`
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`

`Copyright © 1979 by John Wiley & Sons, Inc.
`
`All rights reserved. Published simultaneously in Canada.
`
`Reproduction or translation of any part of this work
`beyond that permitted by Sections 107 or 108 of the
`1976 United States Copyright Act without the permission
`of the copyright owner is unlawful. Requests for
`permission or further information should be addressed to
`the Permissions Department, John Wiley & Sons, Inc.
`
`Library of Congress Cataloging in Publication Data:
`Connors, Kenneth Antonio, 1932-
`Chemical stability of pharmaceuticals .
`
`. "A Wiley-Interscience publication."
`Includes bibliographical references and index.
`I. Amidon, Gordon L., joint
`1. Drug stability.
`author.
`II. Kennon, Lloyd, 1929-
`joint author.
`ill. Title.
`[DNLM:
`1. Drug stability-Handbooks.
`2. Kinetics-Handbooks. QV38 C572cj
`
`615'.19
`RS189.C628
`ISBN 0-471-02653-0
`
`78-1759
`
`Printed in the United States of America.
`
`10 9 8 7 6 5 4 3 2 1
`
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`CHAPTER 5
`Oxidation
`
`On and within a few miles of the earth's surface,
`oxygen is the most abundant of elements. It makes up
`about 46% of the earth's crust and, of course, 89% of
`the water and over 20% of the air. It is the last com(cid:173)
`ponent that causes many of our pharmaceutical problems.
`with so much oxygen around, it is no wonder that oxida(cid:173)
`tion reactions, both completed and potential, are omni(cid:173)
`present.
`Ironically, virtually all of our useful drugs
`exist in a reduced, not their most oxidized, form; it
`is clear, then, th~t "the battle is on."
`Whereas in hydrolytic reactions temperature, pH,
`and the presence of water are the major factors that
`influence drug decomposition, oxidative reactions are
`strongly influenced by environmental factors such as
`light and metal ions, in addition to, of course, oxygen
`and oxidizing agents. For example, 0.0002 M copper has
`been shown to increase the rate of ascorbic-acid oxida(cid:173)
`tion by a factor of 10,000 over that in the absence of
`copper. One of the major problems encountered in
`dealing with oxidation reactions is that some reactants
`such as oxygen or metal ion need not be present in more
`than trace quantities to produce significant stability
`problems. Another interesting aspect of oxidative
`decomposition is the tendency of many drugs to form
`colored products and various other formulation compo(cid:173)
`nents to produce off-odors. Consequently, although
`only a very low level of oxidative degradation may have
`occurred, with drug decomposition being insignificant
`both chemically and therapeutically, the drug product
`may nevertheless be rejected and not used. Finally,
`note that oxidation can occur in both aqueous and non(cid:173)
`aqueous solutions as well as in the solid state to some
`extent.
`
`A. NATURE OF OXIDATION
`
`When one considers oxidation, it is important to
`
`80
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`88
`
`Oxidation
`
`stability problems will arise from light of the shorter
`wavelengths, in particular from the short visible and
`the UV.
`When electromagnetic radiation is absorbed, essen(cid:173)
`tially only one of four events occurs:
`
`1. The absorbing molecule decomposes.
`
`2. The energy is either retained until it can be used
`chemically or is transferred to another molecule,
`which mayor may not decompose.
`
`3. The energy is converted to heat, and no reaction
`ensues.
`
`4. The absorbing molecule emits light of a different
`wavelength (fluorescence or phosphorescence), and
`no decomposition occurs.
`
`The work to be described now illustrates by means
`of a specific example the very marked, explicit effect
`of UV light on an oxidative reaction. Solutions (5%)
`of two therapeutically useful phenothiazine salts,
`chlorpromazine hydrochloride and prochlorperazine
`ethanedisulfonate, were placed in a Warburg respiro(cid:173)
`meter to permit measurement of oxygen uptake and were
`then exposed to a sunlamp.
`[The structure of chlorpro(cid:173)
`mazine is given in Eq. (5.21); prochlorperazine is sim(cid:173)
`ilar, with the dimethylamino group being replaced by
`4-methyl-l-piperazinyl.] The solutions became colored
`shortly after the light was turned on, and they con(cid:173)
`tinued to darken. The data (1) are shown graphically
`in Figure 5.1.
`
`C.
`
`INHIBITION OF OXIDATION
`
`1. Protection from Light
`
`As previously described, many compounds undergo
`changes on receiving and absorbing radiant energy
`(light). When one is dealing with pharmaceutical pro(cid:173)
`ducts, any alterations, light-induced or otherwise,
`that result in losses in potency or in color or taste
`changes are detrimental. Therefore, the choice of a
`suitable container is very important. At the outset of
`this discussion it is stressed. that whatever container
`
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`Inhibition of Oxidation
`
`89
`
`;:- ::"
`
`140
`
`120
`
`100
`
`Light
`off
`
`'i
`.,
`
`-'" '" -c.
`=>
`c .,
`co >-x
`
`0
`
`80
`
`60
`
`40
`
`20
`
`~ a
`
`Exposure time (min)
`
`60
`
`FIGURE 5.1. Plot of oxygen-uptake data for chlorproma(cid:173)
`zine hydrochloride (A) and prochlorperazine ethanedi(cid:173)
`sulfonate (B) illustrating induction period, the
`linearity of the uptake with time, and the extreme
`light dependence of the oxidative degradation (1).
`
`is chosen, it must be tested with the formula it is to
`hold to ascertain the overall stability characteristics.
`Although most such testing is done in industrial labora(cid:173)
`tories, and although the community pharmacist certainly
`would not dispense a moisture-sensitive product in a
`cardboard box, he should appreciate this fact since he
`does do some repackaging. Note also that if a product
`is light-sensitive, it is important that this fact be
`stated on the label.
`To exclude light, four main techniques are avail(cid:173)
`able:
`Ca) wrap-around labels, (b) container coatings
`(some may incorporate ultraviolet absorbing materials),
`(c) various cartoning procedures, and (d) the use of
`so-called light-resistant containers. Since the latter
`are mentioned in the united States Pharmacopeia (2), we
`treat this area in some detail.
`The light-transmission limits of glass and plastic
`containers are specified by the USP (2). These limits
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`90
`
`Oxidation
`
`are given as the maximum percent transmission for any
`wavelength between 290 nm and 450 nm, for vessels of
`nominal capacities up to 50 mI. For containers larger
`than 50 ml, the limits for 50 ml apply. Light trans(cid:173)
`mission for containers of type NP glass and for plastic
`containers for products intended for oral or topical
`use must not exceed 10%.
`To understand the subject of light transmission
`through glass a bit more thoroughly, note that a beam
`of light falling on a flat transparent surface perpen(cid:173)
`dicularly loses some of its energy by reflection.
`If
`the beam impinges at an angle other than 90°, the ],.oss
`is even greater. The transparent material then absorbs
`part of. the energy entering it and transmits the
`remainder to the second surface, where a second loss by
`reflection takes place. The fraction of the light
`G
`transmitted is the ratio of the intensity of the light
`emerging to the incident intensity. The amount of
`.light energy absorbed is a function of the. physicochem(cid:173)
`ical nature and depth of the glass. The·losses from
`reflection depend on the refractive index of the glass.
`Fresnel showed that the fraction of light energy lost
`due to reflection, R, from a single surface is given by
`(n - 1)2/(n + 1)2, where n is the
`the expression R =
`index of refraction of the glass in the spectral region
`being considered. container glasses have refractive
`indices of approximately 1.5. Thus R = 0.04 for one
`surface or 0.08 for two. This means that 8% is lost by
`reflection, and the maximal transmission is about 92%;
`Samples of glass can be spectrophotometrically scanned
`in much the same way as a solution of an organic com(cid:173)
`pound; the procedure is given in the USP. Thus the
`actual transmission values for a specific piece of
`glass depend on its thickness and the absorption coef(cid:173)
`ficient of the glass. Figures 5.2 to 5.6 show the
`detailed character of the transmission of various
`colored glasses and illustrate that much variation
`exists. Except as noted, the spectra have been cor(cid:173)
`rected to a thickness of 2 rom to facilitate comparison.
`It is apparent that amber glasses afford the best
`protection.
`Theoretically, the use of plastic containers is
`essentially analogous to that of glass. There is one
`difference, however, in that oxygen can penetrate many
`plastic containers, so the packaging must have suffi(cid:173)
`cient wall thickness.
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`

`100
`
`90
`
`80
`
`70
`
`60
`
`c:
`,~ 50
`~ 'E
`~ c:
`'" j!: 40
`if'.
`
`\D
`f-'
`
`30
`
`20
`
`10
`
`0 1
`275
`
`/
`
`1
`300
`
`1
`
`1
`
`3~ 3~ ~5~ m %0
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`I.
`
`~5 ~ m
`A (nm)
`
`1
`1
`1
`1
`1
`~O 575 ~ 6~ 6~ ~5 ~ rn
`
`750
`
`FIGURE 5.2. Spectral transmission curves of two amber
`glasses representative of commercial lots.
`
`____ .• =~,-,..;.c,=sjj.,
`
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`

`~ -
`
`1 mm
`
`100
`
`90
`
`BOr
`
`70
`
`\.0
`N
`
`c 60
`0
`'in
`V>
`.~ 50
`c
`'" ~ I-
`*- 40
`
`30
`
`20
`
`10
`
`01
`·1
`275 D
`
`'/1.-
`~5 B
`
`:r I-~
`
`~5 ~ ~5 ~ ~5 ~ ~5 ~ ~5~ 6~ 650
`11 (nml
`
`675
`
`700
`
`725
`
`7W
`
`FIGURE 5.3. Spectral transmission curves showing effect
`of thickness on transmission of an amber glass.
`
`, =me "=:t~
`
`..,.,
`
`"""'''''''n
`
`W:8;;;md!Liili:i~
`
`9~P:m.
`
`.I,ll'" ~!l!\'j§jlit
`
`X'eW"
`
`S.,
`
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`

`100rl --~---'--~r-~r---~--~--'----r---r--~---'----r---r---.---.-~-r---r--~--~
`
`90
`
`80
`
`70
`
`60
`
`" o
`'Bi
`.~ 50
`"
`~
`~ 40
`
`30,
`
`20
`
`10
`
`\0
`W
`
`·01
`/1 /
`1
`1
`1
`1
`1
`1
`1
`1
`1 ~ 1
`V5 ~ m
`3~ ~5 400 4~ 4~ 475r~ ~ ~O 575 B
`A (nm)
`
`--"]
`
`!
`
`1
`1
`6~ 650
`
`1
`1
`1
`1
`~5 ~ 7~ 750
`
`FIGURE 5.4. Spectral transmission curves of four com(cid:173)
`mercial green glasses.
`
`..~-;.--
`
`._ . ......;"""
`
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`

`100·
`
`90
`
`80
`
`70
`
`c: 60
`
`0
`'<;;
`
`~ 'E 50
`~ c:
`'" ~ I-
`.... 40
`
`I I
`, ,
`
`,
`30
`
`20
`
`10
`
`~
`~
`
`......
`
`/
`
`'\
`
`,
`
`--C
`
`I
`,
`
`(
`
`, ( '
`
`( !
`
`4~ ~5 ~ ~5 5~ ~5 ~ ~5 6~ ~5 700 7~ 7~
`A (nm)
`
`.£ {
`
`(
`
`0.1
`~5 ~ ~5 3~ 3~ ~ 425
`
`( ( ! (
`
`FIGURE 5.5. Spectral transmission curves of commercial
`blue glasses. (A, light blue; B, dark blue; C, copper'
`blue) .
`
`Zlu:t&
`
`... MW"''"'W
`
`u ; ! !S
`
`· .......... wtt'tn '!'WT'.f!S
`
`£
`
`ffl •
`
`. :iI:jpj" $ Z"
`.
`
`. .. :~
`
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`

`"
`
`100"
`
`90
`
`80
`
`70
`
`60
`
`c:
`0
`';;;
`
`'" '~ 50
`c: e
`'r-*' 40
`
`ID
`U1
`
`30
`
`20
`
`10
`
`01
`275
`
`r
`300
`
`325
`
`350
`
`375
`
`1
`400
`
`425
`
`450
`
`475
`
`525
`500
`11 (nml
`
`550
`
`575
`
`600
`
`625
`
`650
`
`675
`
`700
`
`725
`
`750
`
`spectral transmission curve of a 6.7-mm
`FIGURE 5.6.
`clear, colorless milk bottle.
`
`'-------'------~~---:--~--'-
`
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`96
`
`oxidation
`
`2. Exclusion of Oxygen
`
`To remove oxygen from a formulation is an obvious
`way to prevent oxidation. This can be done in several
`,ways. Oxygen may be expelled from aqueous preparations
`by boiling the water beforehand, although some oxygen
`will redissolve during the cooling process. A better
`way is to bubble nitrogen through the solvent to' flush
`the oxygen out of solution. Another way is to flush
`the headspace of the container with nitrogen just prior
`to sealing or capping. This is done mostly with ampuls
`and bulk powders that are reconstituted at the time of
`dispensing.
`
`3. Addition of Antoxidants
`
`Antoxidants are materials that act by being more
`readily oxidized than the agents they are to protect.
`Thus in a closed system (e.g., an ampUl) they may con(cid:173)
`sume essentially all of the oxygen present and thereby
`protect the drug. Open systems may require higher
`antoxidant concentrations than closed systems. Antoxi(cid:173)
`dants may also function by being inhibitors of free
`radicals, that is, they provide an H' or an electron to
`break the chain reaction as discussed earlier.
`To enhance the effectiveness of the antoxidant
`approach, it is sometimes useful to uS~,more than one
`antoxidant.
`It has been found that a combination of
`two antoxidants along with a chelating agent to complex
`meta'ls (thus inhibiting their catalysis of the autoxi(cid:173)
`dation) often works well. Emulsions may need two
`antoxidant systems, a water-soluble one and an oil(cid:173)
`soluble one.
`The following lists are self-explanatory and
`illustrate the wide range of compounds that have seen
`use in the categories indicated. The concentrations
`used generally vary between 0.01% and 1.0%; 0,1% is a
`good place to start when formulating.
`Chelating agents are citric acid, dihydroxyethyl(cid:173)
`glycine, ethylenediaminetetraacetic acid, glycerin,
`phenylalanine, phosphoric acid, sorbitol, tartaric
`acid and tryptophan. Oil-'soluble antoxidants a:re
`ascorbyl palmitate, butylated hydroxyanisole (BHA),
`butylated hydroxy toluene (BHT), hydroquinone, lecithin,
`nordihydroguaiaretic acid, phenyl a-naphthylamine,
`propyl gallate (and octyl and dodecyl gallates), and
`a-tocopherol. Water-soluble antoxidants are acetone
`
`',:,' j I
`~ §
`
`!
`
`til
`
`I ~ i il
`
`~ I
`I
`
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`f···' .,' .
`
`. i
`
`Inhibition of Oxidation
`
`97
`
`sodium bisulfite, ascorbic acid, cysteine hydrochloride,
`isoascorbic acid, sodium bisulfite, sodium formaldehyde
`sulfoxylate, sodium .metabisulfite, sodium sulfite,
`thioglycerol, thioglycolic acid, and thiosorbi tol.
`The sulfites are very commonly used, and"a word of
`caution is in order.
`In the process of acting as antox(cid:173)
`idants, sulfites yield acid sulfates, which cause a
`drop in pH values. Also, sulfites can readily form
`inactive addition compounds as with, for example,
`epinephrine. They react with compounds such as alkenes,
`alkyl halides, and aromatic nitro and carbonyl compounds.
`Sometimes, as with thiamine, they may cleave molecules.
`Thus not all antoxidants can be used with all drugs.
`The correct choice is usually based on extensive sta(cid:173)
`bility testing, as is done in industrial product(cid:173)
`development laboratories.
`At the beginning' of this section, both closed and
`open systems were mentioned.
`It is possible to calcu(cid:173)
`late the approximate amount of antoxidant needed in
`closed systems. Air is, by volume, 78.1% N2, 21.0% 02,
`and 0.9% Ar. Multiplying by the molecular weights to
`convert the figures to a weight basis and then calcu(cid:173)
`lating the percent of oxygen produces these figures:
`
`78.1 x 28.0 = 2186.8
`21. 0 x 32.0 =
`672.0
`0.9 x 39.9 =
`35.9
`
`2894.7
`"
`lQO(672.0/2894.7) = 23.2% oxygen by weight
`
`The density of air at 760 mm and 25° is 0.001185 g/m1.
`Thus if 23.2% is oxygen, there is 2.749 x 10- 4 g of
`oxygen per ml of air. Dividing by 32 (the molecular
`weight of oxygen) gives 8.59 x 10- 6 mol ml- l
`• Hence,
`knowing the headspace and the antoxidant reaction
`stoichiometry, the moles of antoxidant needed may be
`calculated. As an example, in the bisulfite case the
`reaction is
`
`equals
`This shows that the moles of bisulfite needed
`In prac(cid:173)
`twice the moles of oxygen in the headspace.
`tice, some excess would be added since minor
`amounts
`adsorbed
`of oxygen may enter the system through being
`
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`98
`
`Oxidation
`
`on the raw materials or being dissolved in the solvent.
`
`4. Control of pH
`
`The reasons behind the principle of lowering the
`pH were given on p. 82. For purposes of pharmaceutical
`products, the pH range of 3 to 4 is generally ·found
`most useful. Obviously, this technique is not for use
`with drugs that precipitate out at lower pH values.
`
`D.
`
`REFERENCES
`
`1.
`
`2.
`
`L. J. Ravin, L. Kennon, and J. V. Swintosky, J.
`Amer. Pharm. Assoc., Sci. Ed., 47, 760 (1958)-
`
`The united States Pharmacopeia, Nineteenth
`Revision,
`(USP XIX), 1975, p. 643.
`
`ii
`
`I
`
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