JOURNAL OF
`PHARMACEUTICAL
`SCIENCES @
`
`APRIL 1978
`VOLUME 67 NUMBER 4
`
`REVIEW ARTICLE
`
`Stability of Pharmaceuticals
`
`JOSEPH A. MOLLICAx, SATINDER AHUJA, and JEROLD COHEN
`Keceived from the Rrararrh and Development Department, Pharmaceuticals Division, Ciba-Geigy Corporation, Suffern, N Y 10901.
`
`formulations, degradation
`Keyphrases Stability-pharmaceutical
`mechanisms. rates, and pathways, evaluation methods, regulatory con-
`formulations, rates,
`siderat ions, review 0 Degradation-pharmaceutical
`mechanisms, and pathways, review 0 Dosage forms, various-stahility,
`review
`
`CONTENTS
`Rates, Mechanisms, and Pathways of Degradation . . . . . . . . . . . . .444
`.....................
`. . . .
`Kinetics . . . .
`444
`Physical Organic Chemistry .............................
`,445
`Hydrolysis .................................
`447
`....................................
`447
`............................
`.448
`............................. 448
`Preformulation ........................................
`.448
`Solutions .............................................
`.448
`....................................... 449
`Solids ................................................. 450
`Stability-Indicating Methods ..............................
`.451
`Electrometric Methods .........................
`. . . .451
`... ,452
`Solvent Extraction Methods ....................
`Spectrophotometric Methods ............................
`.452
`Chromatographic Methods ..............................
`.453
`Marketed Product Stability .........
`............... 454
`............... 454
`Manufacturer's Container: Selection
`g .............. 455
`Package Stability: Dispensing and Re
`Storage Conditions .....................................
`.456
`Predictive (Accelerated Testing) ..........................
`,457
`Expiration Dating/Shelflife ..............................
`.457
`Regulatory co
`ns .................................
`458
`....................................
`IND/NDA
`458
`..................................... 458
`GMP Requi
`PPA: Child Resistant Closures ...........................
`,459
`Formulation Changes ....................
`GLP Requirements .....................................
`.459
`Cornputerization/Records/Reports ........................
`.460
`Failure of Drug Product to Meet Required Specifications ..... .460
`Refrrences ..............................................
`.460
`Many in-depth articles and seminar proceedings have
`appeared in the past 2 decades on various aspects of sta-
`bility (1-lo), but no single report has treated the overall
`subject in an integrated fashion. Investigations into the
`stability of pharmaceuticals have ranged from funda-
`mental studies on the rates and mechanisms of reactions
`
`of the active substance, through evaluation of the influence
`of the formulation and production processes on the drug
`and drug product, to, finally, the role of the container and
`the effect of storage and distribution of the finished
`packaged article on the integrity of the product.
`The objectives of this .article are to review the many
`facets of stability and to outline what a present-day sta-
`bility program does and should include. We hope to in-
`terrelate scientific considerations with regulatory re-
`quirements.
`It has been recognized that there are legal, moral, eco-
`nomic, and competitive reasons, as well as those of safety
`and efficacy, to monitor, predict, and evaluate drug
`product stability (7). However, stability can and does mean
`different things to different people or to the same people
`at different times, even those in pharmaceutical science
`and industry. Although unified nomenclature has been
`proposed, various terminology is still employed to en-
`compass the what and the how and the why of stability:
`stability study, kinetic study, compatibility study, stability
`evaluation, stability-indicating assay, expiration dating,
`outdating, shelflife, storage legend, preformulation studies,
`failures of a batch to meet specifications, microbiological
`stability, stability of the active ingredient, stability of the
`formulation, stability in the marketed package, stability
`in sample packages, stability in the dispensing package,
`and stability in the hands of the consumer. All of these
`areas have been referred to as stability.
`In the pharmaceutical industry, the disciplines primarily
`involved with stability are pharmaceutical analysis and
`product development. However, physical and organic
`chemistry, mathematics, physics, microbiology, toxicology,
`production, packaging, engineering, quality control, and
`distribution are all included. Basic subjects for consider-
`ation are physical organic chemistry-the
`evaluation of
`rates and mechanisms of reactions, kinetics and thermo-
`dynamics, and, importantly, organic analysis.
`One cannot monitor stability, determine the reaction
`rate, or investigate any mechanism without an analytical
`measurement. Hence, the pharmaceutical analyst is pri-
`
`vol. 67, No. 4, April 1978 I 443
`
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`Page 1
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`

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`marily involved in stability, because he or she must develop
`a method that will quantitatively determine the drug in
`the presence of, or separate from, the transformation
`product(s). This determination is required to assure that
`the drug has not undergone change. To select the appro-
`priate method(s), the analyst should have a thorough
`knowledge of the physicochemical properties of the drug,
`including an understanding of the routes by which a drug
`can be degraded or transformed.
`The knowledge of the physicochemical properties of the
`drug is equally important to the development pharmacist
`in efforts to achieve the optimum drug formulation.
`Likewise, this knowledge is needed by the package devel-
`opment group so that an appropriate container can be
`provided.
`The stability of this resultant product in various chan-
`nels of commerce is of concern to the marketing and dis-
`tribution departments and to the physician, pharmacist,
`and patient. This concern is manifested by the use of
`storage legends, expiration dates, protective packaging,
`and dispensing directions. Furthermore, from a regulatory
`viewpoint, one should assure that the product is of the
`“quality, strength, purity, and identity” that it is purported
`to be throughout the time it is held or offered for sale.
`An in-depth discussion on all aspects of this topic is
`beyond the scope of this review. We intend, however, to
`highlight the areas involved, with particular attention to
`recent literature, and to present an integrated overview of
`a total stability program.
`
`RATES, MECHANISMS, AND PATHWAYS OF
`DEGRADATION
`Kinetics-Two of the main contributors to an under-
`standing of kinetic principles as applied to drug develop-
`ment are T. Higuchi and Garrett (7,ll-13); they brought
`the principles of chemical kinetics to the evaluation of drug
`stability. Although the theory was well understood and
`groundwork in chemical reaction kinetics was underway,
`only a few papers on drugs appeared in the literature
`through the 1940’s. Detailed studies on drugs were not
`undertaken until the 1950’s. The classical concepts brought
`to bear were the consideration of factors influencing re-
`actions in solution (14-19), as summarized below.
`Most degradation reactions of pharmaceuticals occur
`at finite rates and are chemical in nature. These reactions
`are affected by conditions such as solvent, concentration
`of reactants, temperature, pH of the medium, radiation
`energy, and presence of catalysts. The manner in which the
`reaction rate depends on the concentration of reactants
`describes the order of the reaction. The degradation of
`most pharmaceuticals can be classified as zero order, first
`order, or pseudo-first order, even though they may degrade
`by complicated mechanisms and the true expression may
`be of higher order or be complex and noninteger.
`The quantitative relationship of the specific reaction
`rate and temperature is the Arrhenius expression:
`k = A ~ - A H . / R T
`(Eq. 1)
`where k is the specific rate constant; T is temperature in
`degrees Kelvin; R is the gas constant; A , the preexponen-
`tial factor, is a constant associated with the entropy of the
`reaction and/or collision factors; and AH,, is defined as the
`
`444 / Journal of Pharmaceutical Sciences
`
`heat of activation. The equation is usually employed in its
`logarithmic form:
`log k = -(AHa/2.303RT) + logA
`(Eq. 2)
`The slope of a plot of log k against 1/T yields the activation
`energy. This equation provides the underlying basis which
`allows prediction of stability of pharmaceuticals by ex-
`trapolation of rate data obtained at higher tempera-
`tures.
`An understanding of the limitations of the experimen-
`tally obtained heat of activation values is critical in sta-
`bility prediction; the pitfalls of extrapolation of kinetic
`data were described (20-22). For example, the apparent
`heat of activation at a pH value where two or more mech-
`anisms of degradation are involved is not necessarily
`constant with temperature. Also, the ion product of water,
`pKw, is temperature dependent, and -AH, is approxi-
`mately 12 kcal, a frequently overlooked factor that must
`be considered when calculating the hydroxide-ion con-
`centration. Therefore, it is necessary to obtain the heats
`of activation for all bimolecular rate constants involved in
`a rate-pH profile to predict degradation rates at all pH
`values for various temperatures.
`If photolysis is the rate-determining step of the reaction,
`most often no predictive advantage is gained by higher
`temperature studies because the AH,, is small and, hence,
`the effect of temperature is small. Conversely, the heat of
`activation may be high for pyrolytic reactions, but the
`degradation rates obtained at elevated temperatures may
`be of little practical value when extrapolated to room
`temperature.
`Complex reactions, including reversible reactions,
`consecutive reactions, and parallel reactions, are occa-
`sionally encountered in the decomposition of pharma-
`ceuticals. Some of these reactions are discussed under
`Physical Organic Chemistry. A recent review (23) dealt
`with the kinetics of the most frequently encountered
`complex drug degradation reactions.
`Many drugs are derivatives of carboxylic acids or contain
`the functional group based on this moiety, e.g., esters,
`amides, lactones, lactams, imides, and carbamates. The
`members of this class include many important drugs such
`as aspirin, penicillin, ascorbic acid, procaine, meperidine,
`and atropine. This class can illustrate the basic factors
`affecting the rates of all reactions (24).
`The study of hydrolytic reactions as a function of pH
`yields a rate-pH profile. For an ester, the overall hydrolysis
`rate of a drug, D, may be expressed as follows:
`--= dD
`KU t KH+(H+] + KOH-[OH-]
`dt
`+ KN”] t Kcs[CB] + KCA[GA] (Eq. 3)
`where K u is the rate constant for the uncatalyzed or
`water-catalyzed reaction, KH+ is the rate constant for the
`hydrogen-ion-catalyzed hydrolysis, KOH- is the rate con-
`stant for the hydroxide-ion-catalyzed hydrolysis, KN is the
`rate constant for nucleophilic catalysis, KGB is the rate
`constant for general base catalysis, and KGA is the rate
`constant for general acid catalysis.
`The hydrolysis of a compound may be subject to some
`or all of these terms; however, at any given pH, only one
`or two terms are significant. The simplest profile is ob-
`served when a compound is subjected to only hydrogen-ion
`
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`

`

`or hydroxide-ion catalysis. The effects of other nucleo-
`philes or general acids or bases are usually studied by
`varying their concentrations while maintaining the pH
`constant.
`Solvent has a significant effect on the reaction rate. A
`simplified treatment of solvent effects is presented here.
`When both reactants are ions in a solvent medium or a
`continuous dielectric, absolute rate theory gives the fol-
`lowing equation:
`
`(Eq. 4)
`where In k is the rate constant at the dielectric constant
`c, In ko is the rate constant in the medium of infinite di-
`electric constant, N is Avogadro's number, ZA is the charge
`on ion A, Zu is the charge on ion B, e is the electronic
`charge, T is absolute temperature, R is the gas constant,
`t is the dielectric constant, and y is proportional to the
`interatomic distance in the activated complex.
`This equation predicts a linear relationship between In
`k and l / t . No effect of the dielectric constant would be
`noted if one of the molecules were neutral because ZA or
`ZR would be zero. The effect of the dielectric constant on
`the reaction rate between an ion and a neutral molecule is
`expressed as:
`
`(Eq. 5)
`where y is the radius of the reactant ions and the other
`symbols are as defined in Eq. 4.
`Equation 5 predicts that the logarithm of the rate con-
`stant will vary linearly with the reciprocal of the dielectric
`constant. However, many drugs are quite complex and
`often do not appear to follow theory; e.g., the solvolysis rate
`of the aspirin anion increases with an increasing ethanol
`content, but the rates are relatively constant with an in-
`creasing dioxane content. Both of these solvents should
`have produced a decrease in the overall rate. However,
`based on this type of information, it was concluded that
`a possible rate-determining step was the attack of water
`or ethanol on an uncharged cyclic intermediate (25,26).
`For reactions involving two ionic species, the rate con-
`stant is dependent on the ionic strength, p. For aqueous
`solutions at 25", Eq. 6 expresses the variation of the rate
`constant with ionic strength:
`log k = log ko + 1.bZZAZB ./;
`(Eq. 6)
`A straight line with a slope equal to 1.022,42s is ob-
`tained when one plots log k versus 4. Equation 6 would
`predict no effect on a reaction when one reactant is neutral;
`but the activity coefficient of a neutral molecule is affected
`by ionic strength, and one can observe a linear relationship
`between the logarithm of the rate constant and ionic
`strength:
`
`(Eq. 7 )
`
`I n k = In ko + bk
`where b is an empirical constant.
`These two ionic effects are commonly called the primary
`salt effect. In addition, one observes what is called the
`secondary salt effect, which is the effect of ionic strength
`on the dissociation constant of a buffer species.
`Many pharmaceuticals are subject to general acid,
`general base, or nucleophilic catalysis in addition to hy-
`drogen-ion or hydroxide-ion catalysis. Several linear free
`
`energy relationships quantitate the catalytic rate constant
`with a property of the species and relate the rate constant
`for a series of reactions. For acid-base catalysis, this free
`energy relationship is the Bronsted catalysis law and can
`be expressed as:
`
`and:
`
`kcA = C A K A ~
`
`(Eq. 8)
`
`k G B = C B K B ~
`(Eq. 9)
`where KA and KH are acid and base dissociation constants,
`respectively; and GA, Gg, a, and P are constants charac-
`teristic of the solvent, temperature, and reaction.
`Many drugs have ionizable groups, and the reactions
`may proceed differently for the ionized and unionized
`forms. However, analytically one usually measures the
`total drug concentration, DT. For a weak base, the con-
`tribution of the ionized, DH+, and unionized, D , drug are
`related through the pKa of the drug and the pH of the
`medium; thus:
`DT = D + DH+
`(Eq. 10)
`The overall reaction rate observed is the sum of both re-
`actions. Two examples, aspirin and barbiturates, that
`demonstrate the effect of ionization on the rate constant
`and the mode of degradation are provided in the next
`section.
`The basic kinetic effects are important to an under-
`standing of the reaction and of possible adverse, practical
`effects. For example, addition of an inert salt such as so-
`dium chloride to adjust isotonicity can affect the reaction
`rate as a primary salt effect. Buffers used to control pH are
`also ionic species and can exert a primary salt effect. In
`addition, they exert a secondary salt effect and also act as
`catalysts. Sulfite salts are frequently added as antioxi-
`dants, but they can form addition products with the active
`ingredient or act as catalysts.
`Organic solvents such as alcohol are generally used for
`solubilization; the concentration of the organic solvent can
`affect the dielectric constant of the solvent and thus in-
`fluence the degradation rate of the active ingredients. The
`preservatives used to inhibit bacterial growth or other
`pharmaceutical aids may decompose and their decompo-
`sition products may, in turn, influence the decomposition
`rate of the active ingredients by one or more of the means
`discussed previously.
`basic kinetic
`Physical Organic Chemistry-The
`principles outlined are applicable to all chemical systems.
`However, relatively simple molecules have been used to
`elucidate a principle or to establish fundamental rela-
`tionships. A generation ago, physical chemistry and organic
`chemistry were considered to be two separate nonrelated
`disciplines. But a number of standard textbooks in the
`field, ranging from Hammett's (27), through classic works
`by Bell (28) and Ingold (29), to more recent treatises, relate
`reaction mechanisms and catalysis to biochemical systems.
`Most modern textbooks in organic chemistry now integrate
`physicochemical principles (16-19,30-36).
`Since most modern pharmaceuticals are complex or-
`ganic molecules, a firm understanding of mechanistic or-
`ganic chemistry is vital to any detailed study of drug deg-
`radation; conversely, degradation studies of many classic
`drugs have added to an understanding of the mechanism
`
`Vol. 67, No. 4, April 19781 445
`
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`Page 3
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`

`

`of many organic reactions. Most widely used drugs have
`been studied and provide good models for future studies.
`It is not within the scope of this article to review the myriad
`studies that have been conducted, but we shall illustrate
`the complexity and depth through review of two classic
`examples-aspirin and barbiturates-and
`highlight the
`types of reactions that drugs can undergo by a review pri-
`marily of the literature of the last few years.
`Aspirin is an excellent example of a pharmaceutical
`compound on which in-depth kinetic studies have been
`performed and for which reaction mechanisms have been
`proposed (37-39). The first detailed studies on aspirin
`hydrolysis were published in 1950 by Edwards (40,41), 42
`years after the first study was reported (42). His work
`clearly demonstrated specific acid-base catalysis and
`pH-independent solvolysis of aspirin to salicylic acid. The
`rate constants for hydrogen-ion and hydroxide-ion cata-
`lyses were found to differ with the charge of the molecule.
`Edwards explained the relationship between the observed
`rate constant and pH on the assumption that aspirin hy-
`drolysis occurs according to the six simultaneous reactions
`shown in Scheme I.
`
`The observed overall first-order rate constant, h , can
`be expressed as a function of the six second-order rate
`constants and the acid dissociation constant, K , of aspi-
`rin:
`kl[CH+] t ~ ~ [ C H , O ] + k3[COH-l
`k =
`1 + K/[CH+]
`
`Garrett (25, 26) also investigated the pH-rate profile
`for aspirin hydrolysis, particularly in the pH 4-8 range.
`Garrett's work pointed to intramolecular nucleophilic
`catalysis by the ionized carboxyl group. When the car-
`boxylate ion is intramolecular, it catalyzes a number of
`ester reactions, although it is not a particularly strong
`nucleophile. As mentioned, the addition of alcohol in-
`creases the solvolysis rate, thus strongly suggesting the
`involvement of a solvent molecule in the transition state.
`On the basis of the kinetic and isotopic studies, aspirin
`hydrolysis was shown to be an intramolecular nucleophilic
`catalyzed hydrolysis involving an anhydride intermediate.
`It was assumed that the transition state of the reaction
`involved addition of the carboxylate ion to the carbonyl
`group of the ester, forming a tetrahedral addition inter-
`mediate.
`
`446 I Journal of Pharmaceutical Sciences
`
`Fersht and Kirby (43,44) studied the reactivity of a se-
`ries of substituted aspirins toward hydrolysis. The results
`show that the most likely mechanism for aspirin hydrolysis
`was one in which the carboxylate group acted not as a nu-
`cleophile but as a general base. The pH-rate profile for
`aspirin hydrolysis, as determined by Edwards (40, 41),
`showed that the transition state for hydrolysis in the
`pH-independent region involved the aspirin anion, either
`alone in a unimolecular reaction or together with one or
`more molecules of solvent.
`Three mechanisms have been proposed on the basis of
`the kinetic results for the intramolecular catalytic hy-
`drolysis of aspirin by the carboxyl group: ( a ) a unimolec-
`ular process in which the carboxylate group acts as a nu-
`cleophile, ( b ) a general acid catalysis in which the undis-
`sociated carboxylic acid group reacts with hydroxide ion,
`and (c) a general base catalysis in which the carboxylate
`anion reacts with a water molecule.
`The barbiturates provide another excellent example of
`the complex mechanisms by which drugs degrade (Scheme
`11). Early workers (45,46) assumed that the hydrolysis of
`barbiturates Ia and Ib to the corresponding malonuric
`acids was irreversible, and various degradation schemes
`were predicted on that assumption. Garrett et al. (47), in
`the process of further elucidating the hydrolysis kinetics
`of several important barbiturates, discovered that dieth-
`ylmalonuric acid (IIa) in basic solution may cyclize to form
`barbital (Ia). Gardner and Goyan (48) confirmed the re-
`versibility of hydrolysis of the barbituric acid nucleus and
`noted that it may have interesting biological ramifications.
`Furthermore, they rationalized previous findings (46) in
`the light of a similar reaction involved in the cyclization
`of 2-ureidobenzoic acid (49). Thus, the unionized barbi-
`turate (111) could be cleaved at the 1,2-position, leading to
`production of the bisamide (IV), or at the 1,6- (3,4-) posi-
`tion, leading to the ureide (V); the ionized barbiturate
`would cleave only at the 1,6- (3,4-) position, leading to the
`ureide (or malonic acid) exclusively.
`
`Iu: R1 = R2 = C,H,
`Ib: R, = CYHS, R, =C,H,
`
`H
`
`IIQ and IIb
`
`V
`
`-
`I11
`
`IV
`
`Scheme I I
`Recently, Khan and Khan (50) observed that earlier
`workers did not kinetically detect the existence of di- and
`trianionic tetrahedral addition intermediates in the
`base-catalyzed hydrolysis of barbituric acid because their
`alkali concentration range was low. A t pH values higher
`than the pKaz of barbituric acid, the equilibrium concen-
`tration of undissociated barbituric acid was negligible
`compared to the concentration of mono- and dianionic
`
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`

`barbituric acids. The equations were developed for kl,obs
`and kZ,,,b, for the following consecutive irreversible first-
`order reaction path: barbituric acid kl,obsmalonuric acid
`-ammonia.
`The rate constants showed three regions
`of hydroxide-ion dependence:
`1. The reciprocals of the rate constants were linearly
`related to the reciprocal of the hydroxide concentration
`at low concentration.
`2. The rate constants were independent of the hy-
`droxide-ion concentration at higher concentrations of
`hydroxide ion.
`3. The rate constants observed the following relation-
`ships at even higher concentrations of hydroxide ion:
`hob6 = a + h[OH-] 4- c[OH-]'
`(Eq. 12)
`The empirical parameters a, b, and c were evaluated
`using the method of least squares. A trianionic tetrahedral
`intermediate was proposed to account for the second power
`of the hydroxide ion in Eq. 12.
`Hydrolysis-One
`common pathway by which drugs
`degrade is hydrolysis; the two reactions already discussed
`exemplify this route. Several other examples of drug hy-
`drolysis are included in Table I. Also included in this table
`are drugs containing other functional groups that can
`undergo various elimination or addition reactions in an
`aqueous medium frequently classified as hydrolysis, al-
`though the elements of water are not necessarily involved.
`This list was drawn primarily from the literature of the
`1970's; the references listed earlier (1-19) give numerous
`other examples.
`Oxidation-After hydrolysis, the next most common
`pathway for drug breakdown is oxidation. Many major
`drugs, such as narcotics, vitamins, antibiotics, and steroids,
`are prone to undergo this reaction, but there is a dearth of
`detailed studies on oxidation reactions.
`The most common form of oxidative decomposition
`occurring in pharmaceuticals is autoxidation through a free
`radical chain process. The free radicals are produced by
`
`The radicals readily remove electrons from other mole-
`cules, and this process is oxidation. The autoxidation of
`the free radical chain process can be described by the re-
`actions in Scheme 111.
`
`homolytic bond fission of a covalent bond: A:B - A* + B..
`-
`- RO;
`heat. light
`RH
`R + 0 2
`ROOH - RO. + .OH
`ROOH + R
`RO, t RH
`R02 + X - products
`RO, + RO; - products
`
`R + H
`
`catalysis
`
`+
`
`Scheme III
`The heavy metals (copper, iron, cobalt, and nickel)
`catalyze oxidation by shortening the induction period and
`also affect the oxidation rate by promoting free radical
`formation.
`Oxidations in solution are also subject to specific acid-
`base catalysis and generally follow first- or second-order
`kinetics. For example, the oxidative degradation of pred-
`nisolone is base catalyzed and exhibits first-order depen-
`dency (82). Other solvents may have a catalytic effect on
`reactions when used alone or in combination with water.
`
`Table I-Hydrolytic Reactions
`
`Reaction
`Compound
`Amide hydrolysis
`Salicylamide
`Substituted amide hydrolysis
`N-Haloacetylphthalimides
`l-Acyl-3,5-dimethylpyrazoles Substituted amide hydrolysis
`N - Acylphthalimides
`Imide hydrolysis
`MeDeridine
`Ester hydrolysis
`Ester hvdrolvsis
`Pyiidoxine monooctanoate
`Ester hydrolysis
`Trantelinium bromide
`Salicylanilide N -
`Carbamate hydrolysis
`methylcar hamate
`Carbamate hydrolysis
`4-Biphenyl-N-methylcar ha-
`mate
`17a-Acetoxy-6a-methyl-4-
`Hydrolysis of oximino ester
`pregnen-3,20-dione 3-
`oximino ester
`Hydrolysis of P-lactam
`Penicillins
`Hydrolysis of p-lactam
`Cephalosporins
`Intramolecular aminolysis
`Dethiomethylation
`Clindamycin
`Deamination
`5-Aminodihenzo[a ,d]cyclo-
`heptane derivatives
`Deamination
`Cytarabine
`(arabinosylcytosine)
`Deamination
`Cytosine
`Deamination
`Cytidine
`Deamination
`5-Azacytidine
`Scission of N-C bond
`Deamination
`Chlordiazepoxide
`Scission of C=N linkage
`Dechlorination
`N-Chlorosuccinimide
`Dechlorination
`N-Chloroquinuclidinium ion
`Dechlorination
`N-Chloro-N-methylbenzene-
`sulfonamide
`Dechlorination
`N-Chlorinated piperidines
`Deiodination
`Iodocytosine
`Deamination
`Hydration and ether sdvolysis
`Ag-Tetrahydrocannabinol
`Hydrolytic ring cleavage
`Antimycin A1
`Loss of CHO group
`Hydrolysis of ketal group
`Dexoxadrol
`Ring opening through
`Hydrochlorothiazide
`hydration of free or cationic
`imine
`Scission of C=N linkage
`Ring cleavage
`Lactonization
`Scission of C-S bond
`Lactonization
`
`Mazindol
`Methaqualone
`Coumarinic acid
`Canrenone
`
`Refer-
`ence
`51
`52
`53
`52
`24
`54,55
`56
`57
`57
`58
`
`59-61
`62,63
`64
`65
`66
`67
`67
`68
`69
`70
`70
`70
`71
`72
`
`73
`74
`75
`76,77
`
`78
`79
`80
`81
`
`Ketones, aldehydes, and ethers may also influence free
`radical reactions, either directly or through trace impuri-
`ties such as peroxides.
`Many drugs are complex molecules and contain multiple
`functional groups subject to both hydrolysis and oxidation, .
`e.g., ascorbic acid, penicillins, and phenylbutazone. The
`studies conducted on the latter are summarized here.
`The rates and degradation mechanisms of phenylbu-
`tazone were studied extensively (83-89). Phenylbutazone
`can undergo both hydrolysis and oxidation; the initial
`hydrolytic or oxidative products can be decarboxylated
`and/or further hydrolyzed or oxidized. On the basis of a
`detailed study, it was concluded that the equilibrium be-
`tween phenylbutazone and the carboxylic acid resulting
`from hydrolysis of the pyrazolidine ring was dependent on
`solvent but practically independent of pH (86). Slingsby
`and Zuck (87) noted that oxidation at the C-4 position to
`produce 4-hydroxyphenylbutazone was the major de-
`composition route in the solvents they investigated. Awang
`et al. (89) proposed the hydroperoxide at C-4 as an inter-
`mediate en route to its formation. They also proposed a
`mechanism for formation of several other compounds on
`hydrolysis, decarboxylation, and oxidation of 4-hydroxy-
`phen ylbutazone.
`
`Vol. 67, No. 4. April 19781 447
`
`Opiant Exhibit 2304
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 5
`
`

`

`Table IV-Miscellaneous Reactions
`Type of
`Reaction
`Addition
`Addition
`
`Reactant
`Sodium bisulfite
`Sodium bisulfite
`
`Compound
`Morphine
`Dexamethasone phos-
`phate
`Fluorouracil
`Benzylideneanilines
`Homatropine
`Morphine
`Aspirin
`Thiamine
`Epitetracycline
`Tetracycline
`Penicillin
`Lincomycin monoesters
`Tetracyclines
`
`Pilocarpine
`
`Prostaglandin El and
`dinoprostone (E2)
`Ampicillin sodium
`Amuicillin-hetacillin
`Acetaminophen
`Heterocyclic
`compounds
`
`Table 11-Oxidation
`Compound
`Vitamin A esters
`Amitriptyline
`hydrochloride
`Hydrocortisone
`Dipyrone
`Dopa
`Methyldopa
`Ascorbic acid
`Methylprednisolone
`Phenothiazine
`Chloramphenicol
`
`Site of Oxidation
`Aliphatic chain
`Dimethylamino side chain
`
`Reference
`90
`91
`
`Dihydroxyacetone side chain
`Methanesulfonate
`Phenolic groups
`Phenolic groups
`Hydroxyl groups
`Hydroxyl at C-21
`5-S in the ring
`Combination of hydrolysis and
`oxidation
`
`92
`93
`94
`95
`96,97
`98
`99
`100
`
`Recent references on oxidation of several drugs are in-
`cluded in Table 11.
`Miscellaneous Reactions-In addition to hydrolysis
`and oxidation, many other degradative reactions of drugs
`have been studied, including addition, elimination, isom-
`erization and epimerization, polymerization, acylation,
`transesterification, and photolysis. (Most often, light ca-
`talysis provides energy to initiate an oxidation reaction.)
`Some examples of catalysis are included in Table 111. Ex-
`amples of miscellaneous reactions are summarized in Table
`IV.
`
`DOSAGE FORMS
`Preformulation-The
`excipients employed in phar-
`maceutical formulations are quite complex and are
`sometimes even heterogeneous mixtures. To determine the
`effect of these substances on the drug, it is necessary to
`conduct semiempirical studies with these excipients as an
`interface between basic physicochemical evaluation of the
`substance and final formulation. Preformulation studies
`are conducted to ascertain the compatibilities of the drug
`substance with excipients, including biological and
`chemical preservatives that may be necessary for a given
`formulation.
`Since the selection of a type of dosage form is deter-
`mined primarily by the preferred route(s) of drug admin-
`istration, the development pharmacist must provide a
`relatively stable formulation within these constraints.
`Consideration also must be given at this time to potential
`packages for the drug product and their possible effects
`on stability.
`
`Table 111-Catalysis
`
`Penicillin G potassium
`
`Compound
`Epinephrine
`
`Penicillins
`
`Catalyst
`Sodium metabisulfite
`Sodium bisulfite
`Acetone bisulfite
`Copper(II)-glycine
`chelate
`Copper(I1)
`Monohydrogen and
`dihydrogen citrate
`ions
`Perchloric acid
`Cyclic anhydrides
`Nalidixate sodium
`Light
`Light
`9-Aminomethylacridan
`Phenothiazine
`Light
`Light
`Dihydroergotamine mesylate
`Light
`Antipyrine (phenazone)
`Light
`Aminopyrine (aminophenazone)
`Light
`Dipyrone (noramidopyrine
`methanesulfonate)
`a-((Dibutylamino)methyl]-6,8-di- Light
`chloro-2- (3’,4’-dichlorophenyI) -4-
`quinolinemethanol
`
`Refer-
`ence
`101
`
`102,
`103
`104
`
`105
`106
`107
`108
`109
`110
`110
`110
`
`111
`
`448 I Journal of Pharmaceutical Sciences
`
`Refer-
`ence
`112
`113
`
`114
`115
`
`116
`117
`118,119
`120
`121
`122
`123,124
`125,126
`121
`
`128
`129
`
`130
`131.132
`133
`134
`
`Addition
`Addi