modern Pharmaceutics
`
`Third Edition, Revised and Expanded
`
`edited by
`Gilbert S. Banker
`
`University of Iowa
`Iowa City, Iowa
`
`Christopher T. Rhodes
`
`University of Rhode Island
`Kingston, Rhode Island
`
`Marcel Dekker, Inc. (cid:9)
`
`New York• Basel • Hong Kong
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`Library of Congress Cataloging-in-Publication Data
`
`Modern pharmaceutics / edited by Gilbert S. Banker, Christopher T.
`Rhodes.-3rd ed., rev. and expanded.
`p. cm.—(Drugs and the pharmaceutical sciences ; v. 72)
`Includes bibliographical references and index.
`ISBN 0-8247-9371-4 (alk. paper)
`1. Drugs—Dosage forms. 2. Biopharmaceutics.
`3. Pharmacokinetics. 4. Pharmaceutical industry—Quality control.
`I. Banker, Gilbert S. II. Rhodes, Christopher T. III. Series.
`RS200.M63 1995
`615'.1—dc20 (cid:9)
`
`95-33238
`CIP
`
`The publisher offers discounts on this book when ordered in bulk quantities. For more information, write
`to Special Sales/Professional Marketing at the address below.
`
`This book is printed on acid-free paper.
`
`Copyright © 1996 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.
`
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`
`Chemical Kinetics and Drug Stability
`
`J. Keith Guillory and Rolland I. Poust
`College of Pharmacy, University of Iowa, Iowa City, Iowa
`
`6
`
`I. INTRODUCTION
`
`In the rational design and evaluation of dosage forms for drugs, the stability of the active
`components must be a major criterion in determining their suitability. Several forms of insta-
`bility can lead to the rejection of a drug product. First, there may be chemical degradation of
`the active drug, leading to a substantial lowering of the quantity of the therapeutic agent in
`the dosage form. Many drugs (e.g., digoxin and theophylline) have narrow therapeutic indices,
`and they need to be carefully titrated in individual patients so that serum levels are neither so
`high that they are potentially toxic, nor so low that they are ineffective. For these drugs, it is
`of paramount importance that the dosage form reproducibly deliver the same amount of drug.
`Second, although chemical degradation of the active drug may not be extensive, a toxic
`product may be formed in the decomposition process. Dearborn [I] described several examples
`in which the products of degradation are significantly more toxic than the original therapeutic
`agent. Thus, the conversions of tetracycline to epianhydrotetracycline, arsphenamine to oxo-
`phenarsine, and p-aminosalicylic acid to m-aminophenol in dosage forms give rise to potentially
`toxic agents that, when ingested, can cause undesirable effects. Recently, Nord et al. [2] re-
`ported that the antimalarial chloroquine can produce toxic reactions that are attributable to the
`photochemical degradation of the substance. Phototoxicity has also been reported to occur
`following administration of chlordiazepoxide and nitrazepam [3]. Another example of an ad-
`verse reaction caused by a degradation product was provided by Neftel et al. [4], who showed
`that infusion of degraded penicillin G led to sensitization of lymphocytes and formation of
`antipenicilloyl antibodies.
`Third, instability of a drug product can lead to a decrease in its bioavailability, rather than
`to loss of drug or to formation of toxic degradation products. This reduction in bioavailability
`can result in a substantial lowering in the therapeutic efficacy of the dosage form. This phe-
`nomenon can be caused by physical or chemical changes in the excipients in the dosage form,
`
`179
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`Guillory and Poust
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`independent of whatever changes the active drug may have undergone. A more detailed dis-
`cussion of this subject is given in Sec. II.B.
`Fourth, there may be substantial changes in the physical appearance of the dosage form.
`Examples of these physical changes include mottling of tablets, creaming of emulsions, and
`caking of suspensions. Although the therapeutic efficacy of the dosage form may be unaffected
`by these changes, the patient will most likely lose confidence in the drug product, which then
`has to be rejected.
`A drug product, therefore, must satisfy stability criteria chemically, toxicologically, thera-
`peutically, and physically. Basic principles in pharmaceutical kinetics can often be applied to
`anticipate and quantify the undesirable changes so that they can be circumvented by stabili-
`zation techniques. Some chemical compounds, called prodrugs [5,6], are designed to undergo
`chemical or enzymatic conversion in vivo to pharmacologically active drugs. Prodrugs are
`employed to solve one or several problems presented by active drugs (e.g., short biological
`half-life, poor dissolution, bitter taste, inability to penetrate through the blood—brain barrier,
`and others). They are pharmacologically inactive as such, but are converted back in vivo to
`their parent (active) compounds. Naturally, the rate and extent of this conversion (which are
`governed by the same laws of kinetics that will be described in this chapter) are the primary
`determinants of the therapeutic efficacy of these agents.
`In the present chapter, stability problems and chemical kinetics are introduced and surveyed.
`The sequence employed is as follows: 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; a delineation of the factors that can affect degradation rates, with an emphasis on
`stabilization techniques; and, finally, a description of stability-testing protocols employed in
`the pharmaceutical industry. It is not the intent of this chapter to document stability data of
`various individual drugs. Readers are referred to the compilations of stability data [7] and to
`literature on specific drugs [e.g., Ref. 8 and earlier volumes] for this kind of information.
`
`II. ROUTES BY WHICH PHARMACEUTICALS DEGRADE
`Since most drugs are organic molecules, it is important to recognize that many pharmaceutical
`degradation pathways are, in principle, similar to reactions described for organic compounds
`in standard organic chemistry textbooks. On the other hand, it is also important to realize that
`different emphases are placed on the types of reactions that are commonly encountered in the
`drug product stability area, as opposed to those seen in classic organic chemistry. In the latter,
`reactions are generally described as tools for use by the synthetic chemist; thus, the conditions
`under which they are carried out are likely to be somewhat drastic. Reactive agents (e.g., thionyl
`chloride or lithium aluminum hydride) are employed in relatively high concentrations (often >
`10%) and are treated using exaggerated conditions, such as refluxing or heating in a pressure
`bomb. Reactions are effected in relatively short time periods (hours or days). In contrast,
`reactions occurring in pharmaceuticals often involve the active drug components in relatively
`low concentrations. For example, dexamethasone sodium phosphate, a synthetic adrenocorti-
`coid steroid salt, is present only to the extent of about 0.4% in its injection, 0.1% in its topical
`cream or ophthalmic solution, and 0.05% in its ophthalmic ointment. The decomposition of a
`drug is likely to be mediated not by reaction with another active ingredient, but by reaction
`with water, oxygen, or light. Reaction conditions of interest are usually ambient or subambient.
`Reactions in pharmaceuticals ordinarily occur over months or years, as opposed to the hours
`or days required for completion of reactions in synthetic organic chemistry.
`Reactions such as the Diels-Alder reaction and aldol condensations, which are important in
`synthetic and mechanistic organic chemistry, are of only minor importance when drug degra-
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`Chemical Kinetics and Drug Stability (cid:9)
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`181
`
`dation is being considered. Students need to refocus their attention on reactions such as hy-
`drolysis, oxidation, photolysis, racemization, and decarboxylation, the routes by which most
`pharmaceuticals degrade.
`A cognizance of reactions of particular functional groups is important if one is to gain a
`broad view of drug degradation. It is a difficult task to recall degradative pathways of all
`commonly used drugs. Yet, through the application of functional group chemistry, it is possible
`to anticipate the potential mode(s) of degradation that drug molecules will likely undergo. In
`the following discussion, therefore, degradative routes are demonstrated by calling attention to
`the reactive functional groups present in drug molecules. The degradative routes are described,
`through the use of selected examples, as chemical when new chemical entities are formed as
`a result of drug decomposition, and as physical when drug, loss does not produce distinctly
`different chemical products.
`
`A. Chemical Degradative Routes
`
`Solvolysis
`In this type of reaction, the active drug undergoes decomposition following reaction with the
`solvent present. Usually, the solvent is water; but sometimes the reaction may involve phar-
`maceutical cosolvents, such as ethyl alcohol or polyethylene glycol. These solvents can act as
`nucleophiles, attacking the electropositive centers in drug molecules. The most common sol-
`volysis reactions encountered in pharmaceuticals are those involving "labile" carbonyl com-
`pounds, such as esters, lactones, and lactams (Table 1).
`Although all the functional groups cited are, in principle, subject to solvolysis, the rates at
`which they undergo this reaction may be vastly different. For example, the rate of hydrolysis
`of a 13-lactam ring (a cyclized amide) is much greater than that of its linear analog. The half-
`life (the time needed for half the drug to decompose) of the 13-lactam in potassium phenethi-
`cillin at 35°C and pH 1.5 is about 1 hr. The corresponding half-life for penicillin G is about
`4 min [9]. In contrast, the half-life for hydrolysis of the simple amide propionamide in 0.18
`molal 11,SO, at 25°C is about 58 hr [10]. It has been suggested that the antibacterial activity
`of p-lactam antibiotics arises from a combination of their chemical reactivity and their molec-
`ular recognition by target enzymes. One aspect of their chemical reactivity is their acylating
`power and, although penicillins are not very good acylating agents, they are more reactive than
`simple, unsubstituted amides [11]. Unactivated or "normal" amides undergo nonenzymatic
`hydrolysis slowly, except under the most extreme conditions of pH and temperature, because
`the N—C(0) linkage is inherently stable, yet when the amine function is a good leaving group
`(and particularly if it has a pK, greater than 4.5), amides can be susceptible to hydrolysis at
`ordinary temperatures. [For a recent review on this subject see Ref. 12.] Acyl-transfer reactions
`in peptides, including the transfer to water (hydrolysis), are of fundamental importance in
`biological systems in which the reactions proceed at normal temperatures, and enzymes serve
`as catalysts.
`The most frequently encountered hydrolysis reaction in drug instability is that of the ester,
`but certain esters can be stable for many years when properly formulated. Substituents can
`have a dramatic effect on reaction rates. For example, the tent-butyl ester of acetic acid is
`about 120 times more stable than the methyl ester, which, in turn, is approximately 60 times
`more stable than the vinyl analog [13]. Structure–reactivity relationships are dealt with in the
`discipline of physical organic chemistry. Substituent groups may exert electronic (inductive
`and resonance), steric, or hydrogen-bonding effects that can drastically affect the stability of
`compounds. Interested students are referred to a recent review by Hansch and Taft [14], and
`to the classic reference text written by Hammett [15].
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`GulDory and Poust
`
`Table 1 Some Functional Groups Subject to Hydrolysis
`
`Drug type (cid:9)
`
`Esters
`
`RCOOR'
`
`RO PO
`3
`
`M
`
`x
`
`Examples
`
`Aspirin, alkaloids
`Dexamethasone sodium phosphate
`Estrone sulfate
`Nitroglycerin
`
`Lactones
`
`R
`
`Amides
`
`Lactams
`
`Oximes
`
`Imides
`
`Malonic ureas
`
`R
`
`ROS0
`
`3
`RO NO
`
`M
`
`x
`
`2
`
`0
`
`RCONR'
`
`C = NOR
`
`R
`
`2
`
`C=0
`NH
`C=0
`0
`II
`C—NH
`C=0
`C—NH
`II
`0
`
`Pilocarpine
`Spironolactone
`
`Thiacinamide
`Chloramphenicol
`
`Penicillins
`Cephalosporins
`
`Steroid oximes
`
`Glutethimide
`Ethosuximide
`
`Barbiturates
`
`Nitrogen mustards
`
`/
`R-N
`
`
`
`CH2CH2C1
`
`CH2CH2C1
`
`Melphalan
`
`A dramatic decrease in ester stability can be brought about by intramolecular catalysis. This
`type of facilitation is affected mostly by neighboring groups capable of exhibiting acid—base
`properties (e.g., —NH2, —OH, —COOH, and COO—). If neighboring-group participation leads
`to an enhanced reaction rate, the group is said to provide anchimeric assistance [16]. For
`example, the ethyl salicylate anion undergoes hydrolysis in alkaline solution at a rate that is
`106 times larger than the experimental value for the uncatalyzed cleavage of ethyl p-hydroxy-
`benzoate. The rate advantage is attributed to intramolecular general base catalysis by the phen-
`olate anion [17].
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`Chemical Kinetics and Drug Stability (cid:9)
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`183
`
`Oxidation
`Oxidation reactions are important pathways of drug decomposition. In pharmaceutical dosage
`forms, oxidation is usually mediated through reaction with atmospheric oxygen under ambient
`conditions, a process commonly referred to as autoxidation. Oxygen is, itself, a diradical, and
`most autoxidations are free-radical reactions. A free radical is a molecule or atom with one or
`more unpaired electrons. Of considerable importance to pharmaceutical scientists is a reliable
`method for determining and controlling oxygen concentration in aqueous solutions [18]. A
`thorough review of autoxidation and of antioxidants has been published [19].
`The mechanisms of oxidation reactions are usually complex, involving multiple pathways
`for the initiation, propagation, branching, and termination steps. Many autoxidation reactions
`are initiated by trace amounts of impurities, such as metal ions or hydroperoxides. Thus, ferric
`ion catalyzes the degradation reaction and decreases the induction period for the oxidation of
`the compound procaterol [20]. As little as 0.0002 M copper ion will increase the rate of vitamin
`C oxidation by a factor of 105 [21]. Hydroperoxides contained in polyethylene glycol suppos-
`itory bases have been implicated in the oxidation of codeine to codeine-N-oxide [22]. Peroxides
`apparently are responsible for the accelerated degradation of benzocaine hydrochloride in aque-
`ous cetomacrogol solution [23] and of a corticosteroid in polyethylene glycol 300 [24,25].
`Many oxidation reactions are catalyzed by acids and bases [26].
`A list of some functional groups that are subject to autoxidation is shown in Table 2. The
`products of oxidation are usually electronically more conjugated; thus, the appearance of, or a
`change in, color in a dosage form is suggestive of the occurrence of oxidative degradation.
`
`Photolysis
`Normal sunlight or room light may cause substantial degradation of drug molecules. The energy
`from light radiation must be absorbed by the molecules to cause a photolytic reaction. If that
`
`Table 2 Some Functional Groups Subject to Autoxidation
`
`Functional group (cid:9)
`
`Phenols
`
`Catechols
`
`Ethers
`
`Thiols
`
`Thioethers
`
`Carboxylic acids
`
`Nitrites
`
`Aldehydes
`
`HO
`
`HO
`
`HO
`
`R —O —R'
`
`RCH
`
`SH
`
`2
`
`R —S — R'
`
`RCOOH
`
`R NO 2
`
`RCHO
`
`Examples
`
`Phenols in steroids
`
`Catecholamines (dopamine,
`isoproterenol)
`
`Diethylether
`
`Dimercaprol (BAL)
`
`Phenothiazines (chlorpromazine)
`
`Fatty acids
`
`Amyl nitrite
`
`Paraldehyde
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`Guillory and Poust
`
`energy is sufficient to achieve activation, degradation of the molecule is possible. Saturated
`molecules do not interact with visible or near-ultraviolet light, but molecules that contain ar-
`electrons usually do absorb light throughout this wavelength range. Consequently, compounds
`such as aromatic hydrocarbons, their heterocyclic analogues, aldehydes, and ketones, are most
`susceptible to photolysis. In general, drugs that absorb light at wavelengths below 280 nm
`have the potential to undergo decomposition in sunlight, and drugs with absorption maxima
`greater than 400 nm have the potential for degradation both in sunlight and room light.
`A dramatic example of photolysis is the photodegradation of sodium nitroprusside in aque-
`ous solution. Sodium nitroprusside, Na2Fe(CN)5N0.21-120, is administered by intravenous
`infusion for the management of acute hypertension. If the solution is protected from light, it
`is stable for at least 1 year; if exposed to normal room light, it has a shelf life of only 4 hr
`[27].
`Photolysis reactions are often associated with oxidation because the latter category of re-
`actions can frequently be initiated by light. But, photolysis reactions are not restricted to oxi-
`dation. For sodium nitroprusside, it is believed that degradation results from loss of the nitro-
`ligand from the molecule, followed by electronic rearrangement and hydration. Photo-induced
`reactions are common in steroids [28]; an example is the formation of 2-benzoylcholestan-3-
`one following irradiation of cholest-2-en-3-ol benzoate. Photoadditions of water and of alcohols
`to the electronically excited state of steroids have also been observed [29].
`
`Dehydration
`The preferred route of degradation for prostaglandin E2 and tetracycline is the elimination of
`a water molecule from their structures. The driving force for this type of covalent dehydration
`is the formation of a double bond that can then participate in electronic resonance with neigh-
`boring functional groups. In physical dehydration processes, such as those occurring in the-
`ophylline hydrate and ampicillin trihydrate [30], water removal does not create new bonds, but
`often changes the crystalline structure of the drug. Since it is possible that anhydrous com-
`pounds may have different dissolution rates compared with their hydrates [31,32], dehydration
`reactions involving water of crystallization may potentially affect the absorption rates of the
`dosage form.
`
`Racemization
`The racemization of pharmacologically active agents is of interest because enantiomers often
`have significantly different absorption, distribution, metabolism, and excretion, in addition to
`differing pharmacological actions [33]. The best-known racemization reactions of drugs are
`those that involve epinephrine, pilocarpine, ergotamine, and tetracycline. In these drugs, the
`reaction mechanism appears to involve an intermediate carbonium ion or carbanion that is
`stabilized electronically by the neighboring substituent group. For example, in the racemization
`of pilocarpine [34], a carbanion is produced and stabilized by delocalization to the enolate. In
`addition to the racemization reaction, pilocarpine is also degraded through hydrolysis of the
`lactone ring.
`Most racemization reactions are catalyzed by an acid or by a base. A notable exception is
`the "spontaneous" racemization of the diuretic and antihypertensive agent, chlorthalidone,
`which undergoes facile SN1 solvolysis of its tertiary hydroxyl group to form a planar carbonium
`ion. Chiral configuration is then restored by nucleophilic attack (S,2) of a molecule of water
`on the carbonium ion, with subsequent elimination of a proton [35].
`
`Incompatibilities
`Chemical interactions between two or more drug components in the same dosage form, or
`between active ingredient and a pharmaceutical adjuvant, frequently occur. An example of
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`
`drug—drug incompatibility is the inactivation of cationic aminoglycoside antibiotics, such as
`kanamycin and gentamicin, by anionic penicillins in IV admixtures. The formation of an in-
`active complex between these two classes of antibiotics occurs not only in vitro, but apparently
`also in vivo in patients with severe renal failure [36]. Thus, when gentamicin sulfate was given
`alone to patients on long-term hemodialysis, the biological half-life of gentamicin was greater
`than 60 hr. But, when carbenicillin disodium (CD) was given with gentamicin sulfate (GS) in
`the dose ratio CD/GS = 80:1, the gentamicin half-life was reduced to about 24 hr.
`Many pharmaceutical incompatibilities are the result of reactions involving the amine func-
`tional group. A summary of the potential interactions that can occur between various functional
`groups is given in Table 3.
`
`Other Chemical Degradation Reactions
`Other chemical reactions, such as hydration, decarboxylation, or pyrolysis, also are potential
`routes for drug degradation. Thus, cyanocobalamin may absorb about 12% of water when
`exposed to air, and p-aminosalicylic acid decomposes with evolution of carbon dioxide to form
`m-aminophenol when subjected to temperatures above 40°C. The temperature at which pyro-
`lytic decomposition of terfenadine occurs has been used as a criterion for determining which
`of several tablet excipients will be perferable for long-term stability of the drug substance [37].
`
`B. Physical Degradative Routes
`
`Polymorphs are different crystal forms of the same compound [38]. They are usually prepared
`by crystallization of the drug from different solvents under diverse conditions. Steroids, sul-
`fonamides, and barbiturates are notorious for their propensity to form polymorphs [39]. Yang
`and Guillory [40] attempted to correlate the occurrence frequency of polymorphism in sulfon-
`amides with certain aspects of chemical structure. They found that sulfonamides that did not
`exhibit polymorphism have somewhat higher melting points and heats of fusion than those that
`were polymorphic. The absence 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 several
`polymorphs and solvates (substances that incorporate solvent in a stoichiometric fashion into
`the crystal lattice) are present, the conditions under which they may interconvert can become
`quite complex, as is true of fluprednisolone [41].
`Polymorphs may exhibit significant differences in important physicochemical parameters,
`such as solubility, dissolution rate, and melting point [42]. Thus, the conversion from one
`polymorph to another in a pharmaceutical dosage form may lead to a drastic change in the
`physical characteristics of the drug. A well-known example of this phenomenon is the con-
`version of a more soluble crystal form (form II) of cortisone acetate to a less soluble form
`(form V) when the drug is formulated into an aqueous suspension [43]. This phase change
`leads to caking of the cortisone acetate suspension.
`Another physical property that can affect the appearance, bioavailability, and chemical sta-
`bility of pharmaceuticals is the degree of crystallinity. It has been reported that crystalline
`insulin [44] and crystalline cyclophosphamide [45] are much more stable than their amorphous
`counterparts.
`
`Vaporization
`Some drugs and pharmaceutical adjuvants possess sufficiently high vapor pressures at room
`temperature that their volatilization through the container constitutes a major route of drug
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`
`Table 3 Some Potential Drug Incompatibilities
`
`Schiff's base formation
`
`(e g , aminophylline + glucose
`penicillamine + acetaldehyde)
`
`Racemization
`
`(e.g., epinephrine + HSO3)
`
`Amine (cid:9)
`
`Precipitation
`
`(e.g., epinephrine sulfate + steroid
`phosphate sodium)
`
`1. Amide formation
`(e.g., benzocaine + citric acid)
`2. Salt/complex formation
`(e.g., gentamicin + carbenicillin)
`
`Aminolysis
`
`(e.g., aspirin + phenylephrine)
`
`Aldehyde
`
`Bisulfite adduct
`
`Bisulfite
`
`Large anions
`
`Carboxylic acid
`
`Ester
`
`Alcoholysis
`(e.g., aspirin + PEG)
`
`L Alcohol
`
`loss. Flavors, whose constituents are mainly ketones, aldehydes and esters, and cosolvents (low
`molecular weight alcohols) may be lost from the formulation in this manner. The most fre-
`quently cited example of a pharmaceutical that "degrades" by this route is nitroglycerin, which
`has a vapor pressure of 0.00026 mm at 20°C and 0.31 mm at 93°C [46]. Significant drug loss
`to the environment can occur during patient storage and use. In 1972, the Food and Drug
`Administration (FDA) issued special regulations governing the types of containers that may
`be used for dispensing sublingual nitroglycerin tablets [47].
`Reduction of vapor pressure, and thereby of volatility, of drugs such as nitroglycerin can
`be achieved through dispersion of the volatile drug in macromolecules that can provide phys-
`icochemical interactions. The addition of macromolecules, such as polyethylene glycol, poly-
`vinylpyrrolidone, and microcrystalline cellulose, allows preparation of "stabilized" nitroglyc-
`
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`
`erin sublingual tablets [48,49]. A 13-cyclodextrin—nitroglycerin tablet is currently being
`marketed in Japan to achieve the same purpose.
`Another aspect of nitroglycerin instability has been observed by Fusari [49]. When conven-
`tional (unstabilized) nitroglycerin sublingual tablets are stored in enclosed glass containers, the
`high volatility of the drug gives rise to redistribution 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 dete-
`rioration in the uniformity of the tablets on storage.
`
`Aging
`The most interesting, and perhaps the least-reported, area of concern about the physical insta-
`bility of pharmaceutical dosage forms is generally termed aging. This is a process through
`which changes in the disintegration or dissolution characteristics of the dosage form are caused
`by subtle, and sometimes unexplained, alterations in the physicochemical properties of the inert
`ingredients or the active drug in the dosage form [50]. Since the disintegration and dissolution
`steps may be the rate-determining steps in the absorption of a 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.
`An example of this phenomenon was provided by deBlaey and Rutten-Kingma [51], who
`showed that the melting time of aminophylline suppositories, prepared from various bases,
`increased from about 20 min to over an hour after 24 weeks of storage at 22°C. Like the
`dissolution time for solid dosage forms, the melting time for suppositories can be viewed as
`an in vitro index of drug release. Thus, an increase in melting time can perceivably lead to a
`decrease in bioavailability. The mechanism responsible for this change appeared to involve an
`interaction between the ethylenediamine in aminophylline and the free fatty acids present in
`the suppository bases. Interestingly, no increase in melting time was detected when the sup-
`positories were stored at 4°C, even up to 15 months.
`Aging of solid dosage forms can cause a decrease in their in vitro rate of dissolution [52],
`but a corresponding decrease in in vivo absorption cannot be assumed automatically. For ex-
`ample, Chemburkar et al. [53] showed that, when a methaqualone tablet was stored at 80%
`relative humidity for 7-8 months, the dissolution rate, as measured by in vivo absorption, was
`not affected. This lack of in vitro dissolution—in vivo absorption correlation for the aged
`product was observed even through the particular dissolution method (that of the resin flask)
`was shown by the same workers to be capable of discriminating the absorption of several trial
`dosage forms of the same drug.
`
`Adsorption
`Drug—plastic interaction is increasingly being recognized as a major potential problem when
`intravenous solutions are stored in bags, or when they are infused through administration sets
`that are made from polyvinyl chloride (PVC). For example, up to 50% drug loss can occur
`after nitroglycerin is stored in PVC infusion bags for 7 days at room temperature [54]. This
`loss can be attributed to adsorption, rather than to chemical degradation, because the drug can
`be recovered from the inner surface of the container by rinsing with a less polar solvent
`(methanol here). A diverse array of drugs, including diazepam [55], insulin [56], isosorbide
`dinitrate [57], and others [58], have shown substantial adsorption to PVC. The propensity for
`significant adsorption is related to the oil/water partition coefficient of the drug, since this
`process depends on the relative affinity of the drug for the hydrophobic PVC (dielectric constant
`of about 3) and the hydrophilic aqueous infusion medium.
`
`NOVARTIS EXHIBIT 2014
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 11 of 35
`
`

`
`188 (cid:9)
`
`Guillory and Poust
`
`Physical Instability in Heterogeneous Systems
`The stability of suspensions, emulsions, creams, and ointments is dealt with in other chapters.
`The unique characteristics of solid-state decomposition processes have been described in re-
`views by Monkhouse [59,60] and in the more recently published monograph on drug stability
`by Carstensen [61].
`
`III. QUANTITATION OF RATE OF DEGRADATION
`
`Before undertaking a discussion of the mathematics involved in the determination of reaction
`rates is undertaken, it is necessary to point out the importance of proper data acquisition in
`stability testing. Applications of rate equations and predictions are meaningful only if the data
`used in such processes are collected using valid statistical and analytical procedures. It is
`beyond the scope of this chapter to discuss the proper statistical treatments and analytical
`techniques that should be used in a stability study. But, some perspectives in these areas can
`be obtained by reading the comprehensive review by Meites [62] and from the section on
`statistical considerations in the stability guidelines published by the FDA in 1987 [63].
`
`A. Kinetic Equations
`
`Consider the reaction
`
`aA + bB --> mM + nN
`
`(1)
`
`where A and B are the reactants; M and N, the products; and a, b, m, and n, the stoichiometric
`coefficients describing the reaction. The rate of change of the concentration C of any of the
`species can be expressed by the differential notations —dCA/dt, —dCB/dt, dCwildt, and dCadt.
`Note that the rates of change for the reactants are preceded by a negative sign, denoting a
`decrease in concentration relative to time (rate of disappearance). In contrast, the differential
`terms for the products are positive in sign, indicating an increase in concentration of these
`species as time increases (rate of appearance). The rates of disappearance of A and B and the
`rates of appearance of M and N are interrelated by equations that take into account the stoi-
`chiometry of the reaction:
`
`1 dCA (cid:9)
`1 dCN
`1 dCB 1 (cid:9)
`a dt - b dt - m dt - n dt
`
`(2)
`
`The Rate Expression
`The rate expression is a mathematical description of the rate of the reaction at any time t in
`terms of the concentrat