M·OE>ERN
`PHARMACEUTICS
`
`-
`
`GILBERTS. BANKER
`Industrial and Physical Pharmacy Department
`Purdue University
`West Lafayette, Indiana
`CHRISTOPHER T. RHODES
`Department of Pharmacy
`University of Rhode Island
`Kingston, Rhode Island
`
`MARCEL DEKKER, INC. New York and Basel
`
`CLASS SEP.
`
`Ex. 1017
`
`Page 1 of 38
`
`

`

`Library of Congress Cataloging in Publication _Data
`Main entry under title:
`
`Modern pharmaceutics.
`(Drugs and the pharmaceutical sciences ; v. 7)
`Includes indexes •
`1. Drugs-Dosage forms. 2. Pharmacology.
`3. Drug trade-Quality control. I. Banker,
`GilbertS.
`[date]
`TI. Rhodes, Christopher T.
`[date]
`615 1.1
`RS201.A2M62
`ISBN 0-8247-6833-7
`
`79-18742
`
`COPYRIGHT© 1979 by MARCEL DEKKER, INC. ALL RIGHTS RESERVED
`
`Neither this book nor any part may be reproduced or transmitted
`in any form or by any means, electronic or mechanical, including
`photocopying, microfilming, and recording, or by any information
`storage and retrieval system, without permission in writing from
`the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`10 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMEIUCA
`
`Ex. 1017
`
`Page 2 of 38
`
`

`

`Chapter 7
`
`CHEMICAL KINE'l!CS AND DRUG STABIUTY
`
`Ho-Leung Fung
`
`Depa.:rtment of Pharmaceutics
`State University of New York at Buffalo
`Amherst, New York
`
`I. INTRODUCTION
`n. MODES OF PHARMACEUTICAL DEGRADATION
`A. Chemical Degradative Routes
`B. Physical Degradative Routes
`m. QUANTITATION OF RATE OF DEGRADATION
`A. Kinetic Equations
`B. Energetics of Reactions
`IV. THE ARRHENIUS EQUATION AND ACCELERATED
`STABILITY 'fESTING
`.
`V. FAC'fORS AFFECTING REACTION RATE
`A. pH
`B. Solvent
`c. Solubility
`D. Additives
`E. Other Factors
`REFERENCES
`
`227
`228
`229
`235
`238
`239
`244
`
`246
`219
`249
`253
`257
`257
`259
`259
`
`I. INTRODUCTION
`
`In any rational design and evaluation of dosage forms for drugs, the stability of the
`active component m.ust be a major criterion in determining acceptance or rejection
`of trial formulations. There are several forms of instability which can lead to
`rejection of a drug product. First, there may be extensive chemical degradation
`of the active drug, leading to a substantial lowering of the quantity of the therapeutic
`agent in the dosage form. With the rapid advari.ce of medicinal chemistry, drugs
`b.ave become increasingly more potent and a number of them now have very narrow
`l:b.erapeutic ranges. Drugs like nitroprusside, digoxin, theophylline, and others
`:teed to be carefully titrated in individual patients so that serum levels are neither
`i10 high as to be potentially toxic nor so low as to be ineffective.
`In these cases, it
`Jl of paramount importanc.e that the drug dosage form can reproducibly deiiver the
`lallle 8.lllOunt of drug. Second, although chemical degradation of the active·drug
`nay not be extensive, a very toxic product may be formed in the decomposition
`!rocess. Dearborn [1] described a number of examples in which the products of
`legra.da.tion· are significantly more toxic than the original therapeutic agent. Thus,
`he conversions of 'tetracycline to epianhydrotetraoycline, arsphenamine to
`
`227
`
`Ex. 1017
`
`Page 3 of 38
`
`

`

`228
`
`FUNG
`
`Mapharsen, and p-aminosalicylic acid to m-amirtophenol in dosage forms give rise
`to potentially toxic agents which, when hi.gested, can cause undesirable effects.
`Third, with the development of analytical methodologies which allow for precise
`measurements of·blood levels of drugs, we learn about the problem of bioavaila(cid:173)
`bility. (This topic has been extensively dealt with in Chapters 2 through 6.)
`Instability of a drug product can be exhibited by a decrease in its bioavailability,
`rather than by loss of drug or production of toxic degradation products. This
`reduction in bioavailability can lead to a substantial lowering in the therapeutic
`efficacy of the dosage form. This phenomenon can be brought about by physical
`and/or chemical changes of the diluents in the dosage form, independent of what(cid:173)
`ever changes the active drug may have undergone. A more detailed discussion of
`this phenomenon will be given later in Section IT. B. 3. Fourth, there may be sub(cid:173)
`stantial changes in the physical appearance of the dosage form. Examples of these
`physical changes include mottling of tablets, creaming of emulsions, o:r caking of
`suspensions. Although the therapeutic efficacy of the dosage form may be unaf(cid:173)
`fected by these changes, the patient will most likely lose confidenoe in the drug
`product, which then luis to be rejected.
`
`A drug product, therefore, has to satisfy stability criteria chemically, physi(cid:173)
`cally, therapeutically, and toxicologically. Basic principles in pharmaceutical
`kinetics can often be applied to anticipate and quantify the undesirable changes so
`that they can be ·circumvented by stabilization techniques.
`In the present chapter,
`stability problems and examples are discussed from the viewpoint of the t:esearch
`and development scientist. The presentation follows the following sequence: first,
`an overview of the potential routes of degradation that drug molecules can undergo;
`then, a discussion of the mathematics used to quantify drug degradation; and,
`finally, a discussion of the factors which can affect degradation rates, with an
`emphasis on stabilization techniques. It is not the intent of this chapter to docu(cid:173)
`ment stability data for the various drugs. Readers are referred to a classic
`chapter on stability of drugs by Garrett [2] and a more recent compilation by
`Lintner [3] for this information .
`
`. II. MODES OF PHARMACEUTICAL DEGRADATION
`
`Since most drugs are organic molecules, it is important to first recognize that
`most pharmaceutical degradations are, in principle, similar to reactions described
`for organic compounds in standard organic chemistry textbooks. On the other hand
`lt is also important to realize that different emphases are placed on the type of
`reactions which are commonly encountered in drug product stability as opposed to
`those seen in classical organic chemistry. In the latter case, reactions are gen(cid:173)
`erally described for the purpose of synthesis; thus the conditions under which they
`are carried out are most likely to be quite drastic. Reactive agents, e. g. , thionyl
`chloride or lithium aluminum hydride, are employed in relatively high conoent'ra(cid:173)
`tions (usually > 10%) and are treated at exaggerated conditions such as refluxing.
`Reactions are effected in relatively short periods of thne (hours or days). In con(cid:173)
`trast, pharmaceutical reactiona pertaining to drug produot stability usually involve
`the active drug components in relatively dilute concentrations. For example,
`dexamethasone sodium phosphate, a synthetic adrenocortical steroid salt, is
`
`Ex. 1017
`
`Page 4 of 38
`
`

`

`cHEMICAL KINETICS AND DRUQ STABILITY
`
`229
`
`present only to the extent of about 0.01% in its elixir, 0.4% in its injection, 0.1%
`in its cream, and 0. 05% in its ophthalmic ointment. The decomposition of a drug
`is more likely to be mediated not through reaction with another active ingredient
`but through reaction with comparatively inert en'Vi.ronmental ch6micals or stimuli
`such as water, oxygen, or light. Reaction conditions are usually ambient and
`sometimes even at refrigerated temperatures. The durations for pharmaceutical
`reactions are in terms of l;ll.Onths or years as opposed to hours or days in synthetic
`organic chemistry.
`
`Students need to refocus their experiences on chemical reactions learned from
`organic chemistry classes. Reactions such as the Diels-Alder reaction and aldol
`condensations, which are important in synthetic and mechanistic organic chemis(cid:173)
`try, are of only minor importance when drug degradation is concerned. On the
`other hand, hydrolysis, oxidation, and photolysis reactions constitute some of the
`most important modes of pharmaceutical degradation.
`
`Appreciation of reactions of particular functional groups is important if we
`are to gain a broader view of drug degradation. It is difficult, and perhaps impos(cid:173)
`sible, to remember degrada.tive pathways of all commonly used drugs. By utiliz(cid:173)
`ing some functional group chemistry, it is possible to anticipate the potential
`mode(s) of degradation which the drug molecule will likely undergo. The following
`discussion, therefore, is mainly oriented, where possible, to describing drug
`degrada.tive modes through indentification of the reactive functional groups in the
`drug molecule. The degradative routes are described, through the use of selected
`examples, as chemical, when new chemical entities are formed as a result of
`drug degradation, and as physical, when drug loss does not produce distinctly dif(cid:173)
`ferent chemical products.
`
`A. Chemical Degradative Routes
`
`1. Solvolysis
`
`This type of reaction involves the decomposition of the active drug through reac(cid:173)
`tion with the solvent present. In most instances the solvent is water; but in some
`cases the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or
`polyethylene glycol. These solvents act as nucleophilic agents, and they attack
`electropositive centers in the drug molecule. The commonest solvolysis reactions
`encountered in drug instability are those. involving "labile" carbonyl compounds
`such as esters, lactones, and lactams (Table 7. 1).
`
`Although all the functional groups cited are in principle subjected to solvolysis,
`the rates at which they undergo this reaction may be vastly different. For exam(cid:173)
`>le, the rate of hydrolysis of a fJ -lactam ring (a aycli~ed amide) is very much
`·aster than that of its linear analog. The half-life (the time needed for half the
`lrug to decompose) of the {j -lactam in potassium phenethicillin at 35"C and pH 1. 5
`s about 1 hr. A corresponding value for penicillin a is about 4 min [4]. By
`om.parison, the half-life of propionamide at 0.18 molal H2S04 and at 2s•c is
`lout 58 hr [5]. The extreme susceptibility of the penicillin group toward bydroly(cid:173)
`s is due to the high degree of steric strain in the 4-membered {j-lactam ring.
`
`Ex. 1017
`
`Page 5 of 38
`
`

`

`230
`
`FUNG
`
`Some Functional Groups Which Are Subjected to Hydrolysis
`
`TABLE 7.1
`
`Drug type
`
`A. Esters
`
`RGC=O
`
`RCON~2
`
`RG.C=O
`
`NH
`
`B. Lactones
`
`c. Amides
`
`D. Lactams
`
`E. Oximes
`
`F. lmides
`
`G. Malonic ure.as
`
`Examples
`
`Aspirin, alkaloids
`
`Dexamethasone sodium
`phosphate
`
`Estrone sulfate
`
`Nitroglycerin
`
`Pilocarpine
`
`Spironolactone
`
`Thiacinamide
`
`Chloramphenicol
`
`Penicillins
`
`Cephalosporins
`
`Steroid oximes
`
`Glutethimide
`
`EthoSUJ!,:imide
`
`Barbiturates
`
`The most frequently encountered hydrolysis reaction in drug instability is tba.t
`of the ester. Many formulators are reluctant to incorporate drugs which possess
`the ester functional group in liquid dosage forms because of the suspected high
`rates of hydrolysis. It is quite true that many esters are rapidly degraded in
`aqueous solutions, but a significant number of es~rs are also quite stable under
`conditions for drug storage. For example, at 25°C the methyl ester of p-hydroxy(cid:173)
`benzoic acid (methylparaben) has a half-life of 6, 675 days at pH 6. 0, 892 days at
`pH 8. 0, and 412 days at pH 9.0. When buffered at pB 3 and 6, it shows no
`
`Ex. 1017
`
`Page 6 of 38
`
`

`

`CHEMICAL KINETICS AND DRUG STABILITY
`
`231
`
`TABLE 7.2
`
`Relative Rate Constants of Hydrolysis of Esters
`
`H
`
`CH
`
`3
`
`C2H5
`
`iso-C
`
`H
`3
`
`7
`
`t-C
`
`H
`9
`
`4
`
`n-C
`
`H
`7
`
`3
`
`CH
`
`2
`
`=CH
`
`C6H5
`
`CH
`
`2
`
`C6H
`5
`HOCH
`
`CH
`2
`2
`
`CICH
`
`2
`
`CH
`
`CI
`
`2
`
`CH
`
`00C
`3
`-ooc
`
`CH
`
`00CCH
`3
`
`2
`
`-ooccH
`
`2
`
`CH
`
`3
`
`COOR
`
`1. 0
`
`0.601
`
`0.146
`
`o. 0084
`
`0.549
`
`57.7
`
`7.63
`
`1.10
`
`1. 52
`
`223
`
`1
`
`761
`
`16,000
`
`170,000
`
`8.4
`
`13.7
`
`0.19
`
`decomposition when heated for 2 hr at l00°C or for 30 min at l20°C [3). The
`stability of this ester is enhanced by the electron-donating (resonance) hydroxy
`group at the para position. However, even for the unstabilized methyl benzoate,
`the comparable half-life at pH 6. 0 can be estimated at 2, 870 days.
`The effect of substituent groups on reactio~ rates is a very important topic in
`the area of structure-reactivity relationships. The theories which deal.with the
`Prediction and rationalization of reaction rates as a function of structure belong to
`the exciting discipline of physical organic chemistry. Interested readers are
`
`Ex. 1017
`
`Page 7 of 38
`
`

`

`232
`
`FUNG
`
`referred to the classic texts of Hammett [6] and Leffler and Grunwald [7]. Sub(cid:173)
`stituent groups may exert electronic (inductive and resonance), steric, and/or
`hydrogen-bonding effects which can drastically affect the stability of the com(cid:173)
`pounds, The relative rates of hydrolysis for some simple alkyl esters have been
`compiled [8) and are listed in Table 7.2.
`
`Dramatic decrease in ester stability can be brought about by intramolecular
`catalysis. This type of facilitation is mostly effected by neighboring groups capa(cid:173)
`ble of acid-base properties, vis: -NHz, -OH, -COOH, etc. For example, bex:a.(cid:173)
`·chlo.rophene monosucc:ID.a.te hydrolyzes 1. 5 x 107 times faster than he.xa.chlorophene
`diaceta.te below pH 5 [9 ). The enhancement in the rate of decomposition of the
`monosuccinate is due partly to intramoleoular nucleopbllic catalysis and partly to
`steric factors [9 ,10 ).
`
`2. Oxidation
`
`Oxidation reactions, like solvolysis, are important degradative pathways in drug
`instability. In pharmaceutical dosage forms, oxidation is U.Sually mediated through
`reaction with atmospheric oxygen under ambient conditions, and this process is
`commonly referred to as autoxidation. Since the oxygen molecule is itself a di(cid:173)
`radical (a free radical is a molecule or atom with one or more unpaired electrons),
`most autoxida.tions .are free radical reactions [llJ involving numerous chain
`reactions. The complexity of aJltoxidation reactions ca.n be gleaned from the reac(cid:173)
`tion mechanism proposed for the copper-catalyzed, alcohol-inhibited autoxidation
`of the biSU:lfite ion [~]:
`
`(1]
`
`(chain initiating)
`
`(2)
`
`(3)
`
`(4)
`
`(chain propagating)
`
`(5)
`
`(6)
`
`HSo; + Cu2+
`
`o
`
`2
`
`+
`0 + Cu
`+ H
`2
`
`cu+ + HSo
`3
`- + H0
`+ OH
`
`2+
`...... Cu
`
`2
`
`0 +
`2
`
`H
`
`o + HS0
`2
`
`-H
`2
`
`so
`4
`
`3
`
`+ H<\
`
`.
`H02
`.
`
`OH
`
`+ HSo;
`
`+ HSO;
`
`...... HSO-
`4
`
`+ OH
`
`-
`- H80 + OH
`3
`
`2HS0
`
`3
`
`- H2S206
`
`2H02 -HO+
`2
`
`3
`2°2
`
`(7)
`
`(chain breaking)
`
`H02
`
`+ ROH
`
`... Cl\OOH + H
`
`0J
`2
`
`(8)
`
`Ex. 1017
`
`Page 8 of 38
`
`

`

`CHEMICAL KINETICS AND DRUG STABILITY
`
`238
`
`TABLE 7.3
`Some Functional Groups Which Are Subjected to Autoxidation
`
`Functional group
`
`Phenols
`
`Catechols
`
`Ethers
`
`Thiols
`
`Thioethers
`
`Carboxylic acids
`
`Nitrites
`
`Aldehydes
`
`HO~R
`
`R-0-R'
`
`RCH
`
`SH
`2
`
`R-8-R'
`
`RCOOH
`
`RCHO
`
`Examples
`
`Phenols in steroids
`
`Catecholamines (dopamine,
`isoproterenol)
`
`Diethylether
`
`Dimercaprol (BAL)
`
`Phenothi.az.ines (chlorpromazine)
`
`Fatty acids
`
`Amyl nitrite
`
`Paraldehyde
`
`A list of some functional groups which are subjected to autoxidation is shown
`in Table 7. 3. The products of oxidation are usually more conjugated electron(cid:173)
`ically; thus, the appearance of, or a change in, color in a dosage form. is sug(cid:173)
`gestive of the occurrence of an oxidative degraCiation.
`
`1. Photolysis
`
`qormal sunlight or room light may cause substantial degradation of cltug molecules.
`>ne of the most dramatic examples of photolysis is the photodegra.dation of sodium
`.itroprusside in aqueous solution. SodiUm. nitroprusside, Na2Fe(CN)sNO • 2R20•
`9 used in an intravenous (i. v.) infusion for the management of acute hypertension.
`'be infusion, if exposed to normal room light, has a "shelf-life" of only 4 hr [13].
`owever, if the solution is protected from light, it is stable for at least a year.
`
`Photolysis reactions are usually associated with oxidation because the latter
`.ass of reaction is often initiated by light. However, photolysis reactions are not
`1strtcted to oxidation. In the case of sodium nitroprusside, it is believed that
`•gradation results from loss of the nitro ligand from the molecule, followed by
`ectronic rearrangement and hydration. Photo-ind-q.ced rearn.ugement reactions
`e common in steroids [14], an example is the formation of 2-benzoylcholestan(cid:173)
`one from irradiation of cholest-2-en-3-ol benzoate. Photoadditions of steroids
`
`Ex. 1017
`
`Page 9 of 38
`
`

`

`·234
`
`FUNG
`
`can also occur by addition of solvent molecules, such as alcohols or water, to the
`electronically excited state of the steroid [14].
`
`4. Dehydration
`
`The elimination of a water molecule from their structures is the favored mode of
`degradation for prostaglandin E2 and tetracycline. The driving force for this type
`of covalent dehydration is the formation of a double bond which can then form elec(cid:173)
`tronic resonance with existing delocalized functional groups.
`In physical dehydra(cid:173)
`tion reactions, such as those occurring with theophylline hydrate and ampicillin
`trlhydrate [15 J, water removal, does not create new bonds but often changes the
`crystalline structure of the drug. Since it is well known that anhydrous compounds
`may have very different dissolution rates as compared to their hydrates [16 J,
`dehydration reactions involvjng water of crystallization may potentially affect the
`absorption rates of the dosage form.
`
`5. Racemization
`
`The change in optical activity of a drug may result in substantial decrease in its
`biological activity. As a route of drug degradation~ the most well-known racemiza(cid:173)
`tion reactions are those which involve epinephrine, pilocarpine, and tetracycline.
`In all these cases, the reaction mechanism appears to involve an intermediate
`carbonium ion or carbanion which is stabilized electronically by the neighboring
`substituent group. For example, in the racemization of pilocarpine [17], a car(cid:173)
`banion is produced which is stabilized by delocalization to the enolate.
`It is worthwhile to point out that in addition to the racemization reaction, pilo(cid:173)
`carpine is also degraded ~rough hydr<;>lysis of the lactone ring.
`
`6. Incompatibilities
`
`Chemical interactions between two or more drugs components in the same dosage
`form or between the active ingredient and a pharmaceutical adjuvant can frequently
`occur. A notable example of drug-drug incompatibility is the inactivation of
`aminoglycoside antibiotics, such as kanamycin and genta.mycin, by penicillins in
`i. v. admixtures. The formation of an inactive complex between these two classes
`of antibiotics occurs not only in. vitro, but apparently also in vivo in patients with
`severe renal failure [lSJ. Thus, when gentamyain sulfate was given alone to
`patients on long-term hemodialysis, the biological half-life of gentamycin was
`greater than 6·o hr. However, when carbenicillin disodium (CD) was given together
`with gentamycin sulfate (GS) in the dose ratio of CD:GS = 80:1, the.gentam.ycin
`half-life was reduced to about 24 hr.
`
`Most pharmaceutical incompatibilities are generated by compounds with the
`amine functional group. A summary of some of the potential interactions which
`can occur between various functional groups is given in Table 7. 4.
`
`7. Other Chemical Degradation Reactions
`
`Other chemical reactions such as hydration, decarboxylation, or pyrolysis are
`also potential routes ~or drug degradation. Thus, cyanocobalamin may absorb
`
`Ex. 1017
`
`Page 10 of 38
`
`

`

`CHEMICAL KINETICS AND DRUG STABILITY
`
`235
`
`TABLE 7.4
`
`Some Potential Drug Incompatibilities
`
`Schiff's base formation
`
`(e. g. , aminophylline + glucose
`penicillamine + acetaldehyde)
`
`Racemization
`
`(e. g., epinephrine + HSO;)
`
`Amine
`
`I
`I
`
`Precipitation
`
`(e. g., neomycin sulfate+ steroid
`phosphate sodium)
`
`1. Amide formation
`(e. g. , benzocaine + citric acid)
`2. Salt/complex formation
`(e. g. , gentamycin + carbencillin)
`
`Aminolysis
`
`(e. g., aspirin + phenylephrine)
`
`Aldehyde
`
`t
`Bisulfite adduct
`I
`
`Bisulfite
`
`Large anions
`
`Carboxylic acid
`
`Ester
`
`Alcoholysis
`(e.g., aspirin+ peg)
`
`I AIL! I
`
`lhout 12% of water when exposed to air, p-aminosalicylic acid decomposes with
`~volution of carbon dioxide to form m-aminophenol when subjected to temperatures
`Lbove 40"C, and potassium permanganate decomposes at about 240"C with evolu(cid:173)
`:ion of oxygen.
`
`B. Physical Degradative Routes
`
`;. Polymorphism
`
`~review of the pharmaceutical applications of polymorphism has been given by
`ialeblian and McCrone [19]. Po1ymorphs .are different crystal forms of the same
`
`Ex. 1017
`
`Page 11 of 38
`
`

`

`236
`
`FUNG
`
`compound. They are usually prepared by crystallization of the drug from different
`solvents under diverse oonditiDns. Steroids, sulfona.mides, and barbiturates are
`notol'iDUs in their propensity to form polymorphs (2oJ. Yang and Guillory C21J
`carried out a. worthwhile attempt to correlate the frequency of occurrence of poly(cid:173)
`morphism in sulfonamides with certain aspects of chemiaal structure. They found
`that sulfona.mides which did not exhibit pol,ymorphism have somewhat higher melt(cid:173)
`ing points and heats of fusion than those which were polymorphic. The lack of
`polymorphism in sulfacetamide was attributed to the stronger hydrogen bonds
`formed by the amide hydrogen in this molecule. These stronger hydrogen bonds
`were not readily stretched or broken to form. alternate crystalline structures.
`
`Since polymorphs differ from one another in their crystal energies, the more
`energetic ones will seek to revert to the most stable (and the least energetic)
`crystal form. When a number of polymorPhs and solvates (drug plus different
`molecules of recrystallizing solvent) are present, the conditions under which they
`may interconvert can become quite complex, as is seen in the case of flupredniso(cid:173)
`lone (Fig. 7. l).
`
`Polymorphs may exhibit significant differences in important physicochemical
`parameters such as solubility and melting point. Thus, the conversion of one
`polymorph to anDtber in a pharmaceutical dosage form may lead to a f4"astic
`change in the physical characteristics of the drug. A well-kn,own example o.f this
`
`Fo mii:
`
`d
`
`a
`
`F~mi~ /Form:
`/mon:h'
`
`amorph~ /monohydrate
`
`tert-butylamine
`solvate
`
`Figure 7 .l. Phase interconversions of the various polymorphs of fiupredniso(cid:173)
`lone. Key: a, suspension in water; b, 1as•c under vacuum (2 mm Hg~; c, pres(cid:173)
`sure; d, 1so•c for 5 min; e, standing in air; f, aqueous suspension at sooc and
`seeded with ~-monohydrate. [From J. Baleblian et al., J. Pha.rm.. Sci. !Q_, 1485
`(1971). Reproduced with permission of the copyright Dwner. J
`
`Ex. 1017
`
`Page 12 of 38
`
`

`

`CHEMICAL KINETICS AND DRUG STABILITY
`
`237
`
`phenomenon is the conversion of a mote soluble crystal form (Form II) of corti(cid:173)
`sone acetate to a less soluble form (Form V) when the drug is formulated in an
`aqueous suspension (22]. This phase change leads to caking of the cortisone
`acetate suspension.
`
`2. Vaporization
`
`Some drugs and pharmaceutical adjuvants possess sufficiently high vapor pres(cid:173)
`sures at room temperature that their volatilization through the container consti(cid:173)
`tutes a major route of drug loss. Flavors (mostly ketones, aldehydes, and esters)
`and cosolvents (low-molecular-weight alcohols) may be lost from the formulation
`in this manner. The most notable drug which "degrades" through this route is
`nitroglycerin, which has a vapor pressure of o. 00026 mm at 2o•c and 0. 31 mm at
`93•c [23]. Significant drug loss to the environment can occur during patient
`In 1972, the Food and Drug Administration (FDA) instituted
`storage and use.
`special regulations governing the dispensing and the types of container which may
`be used for sublingual nitroglycerin tablets [24].
`
`Reduction of vapor pressure, and hence of volatility, of drugs such as nitro(cid:173)
`glycerin can be achieved through dispersion of the volatile drug in macromolecules
`which can provide physicochemical interactions. The addition of macromolecules
`such as polyethylene glycol, polyvinylpyrrolidone, and microcrystalline cellulose
`allows for preparation of "stabilized" nitroglycerin sublingual tablets 1:25-27].
`
`Another aspect of nitroglycerin instability has been observed by Fusari (27).
`When conventional (unstabilized) nitroglycerin sublingual tablets are stored in
`enclosed glass containers, the high volatility of the drug gives rise to redistribu(cid:173)
`tion of nitroglycerin among the stored tablets. Interestingly, this redistribution
`leads to an increase in the standard deviation of the drug contents of the tablets,
`rather than the reverse. This migration phenomenon results in a deterioration in
`the uniformit;y of the tablets upon storage.
`
`3. "Aging"
`
`The most interesting and perhaps also the least-reported area of concern as
`regards the physical instability of pharmaceutical dosage forms is generally clas(cid:173)
`sified under "aging." This is a process through which changes in the disintegra(cid:173)
`ti.on and/or dissolution characteristics of the dosage form were brought about by
`subtle, and sometimes Wlexplained, alterations in the physicochemical properties
`of the inert ingredients or the active drug in the dosage form. Since the disinte(cid:173)
`gration and dissolution step may be the rate-detennining step in the absorption of
`the drug, changes in these processes as a function of the "age" of the dosage form
`may result in corresponding changes in the bioavailability of the drug product.
`Feinberg [28] cited an example of this phenomenon: 13 lots of reserpine tablets
`from one company were tested with respect to the disintegration time. Initially,
`all lots met the disintegration specification of 30 min. On storage, 8 out of 13
`l~ts lost their disintegration characteristics. For example, one of the lots. bad a
`fivefold increase in disintegration time after only 3 months of storage.
`Tingstad [29] gave a number of interesting examples of "aging" in pharma(cid:173)
`ceutical dosage forms. One such instance concerned the comparative stability (in
`
`Ex. 1017
`
`Page 13 of 38
`
`

`

`238
`
`FUNG
`
`terms of disintegration of the dosage form.) of the tablet as compared with the cap(cid:173)
`sule dosage fsrm of a drug with a low melting point. Both dosage forms disinte(cid:173)
`grated very well after manufacture. Upon storage, however, the tablet gave poor
`disintegration and became clinically inactive. On the other hand, the capsule dis(cid:173)
`integrated quickly and was fully active after ~;~torage. The increase in disintegra(cid:173)
`tion time in the tablet was rationalized in terms o! an increase in the vapor
`pressure of the drug because of distortion of the crystals on tablet compaction.
`The increase in vapor pressure led to sublimation of the drug, fUling up all the
`interstices of the tablet.
`
`It is evident from these examples that in order to assure drug quality after
`storage, specifications will have to be set up so that those physical properties
`which are relevap.t to drug absorption are also monitored.
`
`4. Adsorption
`
`Chemicals which have higher affinity for the surfaces of the container and enclo(cid:173)
`sure than for the bulk solution will tend to adsorb onto such surfaces. The extent
`of adsorption will depend on the relative thermodynamic activity of the molecular
`species in solution as compared to that on the surface. Marcus [30} has shown
`that when preservatives such as the parabens, phenol, and p-hydroxybenzoic acid
`are stored for 1 week at 30"C in the nylon barrel of a disposable syringe, more
`than 60% of the preservative is bound. No adsorption was o'bserved when the same
`preservatives were stored in polyethylene and polystyrene barrels.
`
`5. Particle Sedimentation
`
`The stability of suspensiOilj:l, emulsions, creams, and ointments is dealt with in
`other chapters.
`
`m. QUANTITA TION OF. RATE OF DEGRADATION
`
`Before a discussion af the mathematics involved in rate determination is com(cid:173)
`menced, it is necessary to point out the importance of proper data acquisition in
`stability testiDg. Applications of rate equations and predictions are only meaning(cid:173)
`ful if the data utilized in such processes are collected using valid statistical and
`analytical procedures. It is beyond the scope of this chapter to discuss in detail
`the proper statisticlil treatments which must be used in· a stability study. The
`reader is referred to standard statistics texts, as well as to a manual which out(cid:173)
`lines the statistical approaches used in pharmaceutical formulation [31]. Due
`caution must be exercised to include considerations of assay errors, batch-to(cid:173)
`batch variability, and sampling errors in the processing of stability data. Atten(cid:173)
`tion is now turned to the importance of analytical specificity in stability studies.
`
`When a drug degrades in a dosage form, the latter is now contaminated with
`degradation products the structure of which, in many cases, is quite similar to
`those of the parent compounds. Quantitative determination of intact drug concen(cid:173)
`tration left in the dosage form at any one time must be specific enough so that it is
`certain that only undegraded drug is selectively assayed. Such a quantitative
`
`Ex. 1017
`
`Page 14 of 38
`
`

`

`CHEMICAL KINETICS AND DRUG STABILITY
`
`239
`
`analysis is known as a "stability-indicating assay." A review of this topic has been
`given by Chafetz [32]. An example is given here to illustrate the importance of
`such a stability-indicating assay in drug stability monitoring. The degradation of
`an alkaloid ester such as atropine can be suspected to proceed mainly through the
`hydrolysis route:
`
`Atropine + OH- - t tropine + tropic acid
`
`(9)
`
`Direot spectrophotometric measurements of such a system will not give 1Dlam(cid:173)
`biguous concentrations of the m1changed drug because both atropine and the tropiC
`acid formed have similar ultraviolet spectral characteristics. ' If hydrolysis is the
`only degradative pathway, then a stability-indicating assay can be obtained by:
`(1) separation of atropine and tropic acid through selective extraction of atropine
`into an organic phase under alkaline conditions (tropic acid will be completely
`ionized at high pH and will remain in the aqueous phase); (2) back-extraction of
`atropine m1der acidic conditions; and then (3) spectrophotometric determination
`of atropine. Unfortunately, however, the hydrolysis route is not the only route of
`degradation. Dehydration of atropine to form apoa.tropine also takes place. The
`latter degradation product will not be separated from atropine by the above proce(cid:173)
`dure, which, if used, will produce an overestimate of. the amom1t of atropine
`present in the system, leading in tu,rn to an overestimate of the stability of the
`drug,
`
`A. Kinetic Equations
`
`Consider the reaction
`
`aA + bB-.mM + nN
`
`(10)
`
`where A and Bare the reactants; M and N, the products; a, b, m, and :a., the
`>toichiometric coefficiEints descr.ibing the reaction. The rate of change of the
`:oncentration, C, of any of the species can be expressed by the differential nota(cid:173)
`:ions -dCA/dt, -dCB/dt, dCM/dt and dCN/dt. Note that the rates of change for the
`:eactants are preceded by a negative sign, denoting a decrease in concentration
`vith respect to time (rate of disappearance). In contrast, the differential terms
`or the products are positive in sign; indicating an increase in concentration of
`hese species as time increases (rate of appearance).
`
`The rates of disappearance of A and B and the rates of appearance of M and N
`re interrelated by equations which take into account the stoichiometry of the
`eaction:
`
`The Rate Expression
`
`18 rate expression is a mathematical description of the rate of the reaction at
`Y tirne, t, in terms of the concentration(s) of the molecular species present at
`
`(11)
`
`Ex. 1017
`
`Page 15 of 38
`
`

`

`240
`
`FUNG
`
`that ti:nle. Using the hypothetical reaction aA + bB- products, the rate expression
`can be written as
`
`b
`a
`dCB
`- dt .. C A(t) 0B(t)
`
`(12)
`
`Equation (12) in essence states that the rate of change of the concentration of A at
`timet is equal to that of B, and that each of these rate changes at timet is pro(cid:173)
`portional to the product of the concentrations of the reactants raised to the respec(cid:173)
`tive powers. It should be noted that C.Alt) and CB(t) are time-dependent variables.
`As the reaction proceeds, both CA(t) and CBlt) will decrease in magnitude. For
`simplicity, these concentrations can be simply denoted by CA and CB, respec