'P'harmaceutical
`D'O$ilg:eForms .
`a:ndDrug.
`De,live'rySystems
`
`.-
`
`-
`
`~
`
`Howard C. Ansel
`
`Nicholas G. Popovich
`
`Loyd V. Allen, Jr.
`
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`

`Executive Editor: Donna M. Balado
`Developmental Editor: Frances M. Klass
`Production Coordinator: Peter J. Carley
`Project Editor: Jessica Howie Martin
`
`Copyright © 1995
`Williams & Wilkins
`200 Chester Field Parkway
`Malvern, P A 19355 USA
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form
`or by any means, including photocopying, or utilized by any information storage and retrieval system without
`written permission from the copyright owner.
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book,. but it is pos(cid:173)
`sible they may change. The reader is urged to review the package information data of the manufacturers of the
`medications mentioned.
`Printed in the United States of America
`
`Library of Congress Cataloging in Publication Data
`
`94 95 96 97 98
`1 2 3 4 5 6 7 8 9 10
`
`Ansel, Howard c., 1933-
`Pharmaceutical dosage forms and drug delivery systems I Howard C.
`Ansel, Nicholas G. Popovich, Lloyd V. Allen, Jr.-6th ed.
`p. em.
`Includes bibliographical references and index.
`ISBN 0-683-00193-0
`1. Drugs-Dosage forms. 2. Drug delivery systems.
`I. Popovich, Nicholas G.
`II. Allen, Loyd V.
`Ill. Title.
`[DNI.M: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i
`1995]
`RS200.A57 1995
`615'.1-dc20
`DNLM/DLC
`for Library of Congress
`
`94-22471
`CIP
`The use of portions of the text of USP23/NFI8, copyright 1994, is by permission of the USP Convention, Inc.
`The Convention is not responsible for any inaccuracy of quotation or for any false or misleading implication
`that may arise from separation of excerpts from the original context or by obsolescence resulting from publica(cid:173)
`tion of a supplement.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Print No. 4 3 2 1
`
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`110
`
`Dosage Form Design
`
`Drug Stability
`
`One of the most important activities of pre(cid:173)
`formulation work is the evaluation of the physi(cid:173)
`cal and chemical stability of the pure drug sub(cid:173)
`stance. It is essential that these initial studies be
`conducted using drug samples of known purity.
`The presence of impurities can lead to erroneous
`conclusions in such evaluations. Stability studies
`conducted in the preformulation phase include
`solid state stability of the drug alone, solution
`phase stability, and stability in the presence of
`expected excipients.
`Initial investigation begins through knowl(cid:173)
`edge of the drug's chemical structure which al(cid:173)
`lows the preformulation scientist to anticipate
`the possible degradation reactions.
`Chemical instability of medicinal agents may
`take many forms, because the drugs in use today
`are of such diverse chemical constitution. Chemi(cid:173)
`cally, drug substances are alcohols, phenols, al(cid:173)
`dehydes, ketones, esters, ethers, acids, salts, alka(cid:173)
`loids, glycosides, and others, each with reactive
`chemical groups having different susceptibilities
`toward chemical instability. Chemically, the
`most frequently encountered destructive pro(cid:173)
`cesses are hydrolysis and oxidation.
`HydrolYSiS is a solvolysis process in which
`(drug) molecules interact with water molecules
`to yield breakdown products of different chemi(cid:173)
`cal constitution. For example, aspirin or acetyl(cid:173)
`salicylic acid combines with a water molecule
`and hydrolyzes into one molecule of salicylic
`acid and one molecule of acetic acid:
`
`Aspirin
`
`Salicylic Acid
`
`Acetic Add
`
`The process of hydrolysis is probably the most
`important single cause of drug decomposition
`mainly because a great number of medicinal
`agents are esters or contain such other groupings
`as substituted amides, lactones, and lactams,
`which are susceptible to the hydrolytic process.
`Another destructive process is oxidation. The
`oxidative process is destructive to many drug
`types, including aldehydes, alcohols, phenols,
`sugars, alkaloids, and unsaturated fats and oils.
`Chemically, oxidation involves the loss of elec(cid:173)
`trons from an atom or a molecule. Each electron
`
`lost is accepted by some other atom or molecule,
`thereby accomplishing the reduction of the re(cid:173)
`cipient. In inorganic chemistry, oxidation is ac(cid:173)
`companied by an increase in the positive valence
`of an element-for example, ferrous (+ 2) oxi(cid:173)
`clizing to ferric (+ 3). In organic chemistry, oxi(cid:173)
`dation is frequently considered synonymous
`with the loss of hydrogen (dehydrogenation)
`from a molecule. The oxidative process fre(cid:173)
`quently involves free chemical radicals, which
`are molecules or atoms containing one or more
`unpaired electrons, as molecular (atmospheric)
`oxygen (.0---0) and free hydroxyl (·OH). These
`radicals tend to take electrons from other chemi(cid:173)
`cals, thereby oxidizing the donor. Many of the
`oxidative changes in pharmaceutical prepara(cid:173)
`tions have the character of autoxidations. Autox(cid:173)
`idations occur spontaneously under the initial
`influence of atmospheric oxygen and proceed
`slowly at first and then more rapidly as the pro(cid:173)
`cess continues. The process has been described
`as a type of chain reaction commencing by the
`union of oxygen with the drug molecule and con(cid:173)
`tinuing with a free raclical of this oxidized mole(cid:173)
`cule participating in the destruction of other
`drug molecules and so forth.
`In drug product formulation work, steps are
`taken to reduce or prevent the occurrence of
`drug substance deterioration due to hydrolysis,
`oxidation, and other processes. These techniques
`are discussed in a later section.
`
`Pharmaceutic Ingredients
`In order- to prepare a drug substance into a
`final dosage form, pharmaceutic ingredients are
`required. For example, in the preparation of
`pharmaceutic solutions ... one or more solvents are
`utilized to dissolve the drug substance, preserva(cid:173)
`tives may be added to prevent microbial growth,
`stabilizers may be used to prevent drug decompo(cid:173)
`sition, and colorants and flavorants added to en(cid:173)
`hance product appeal. In the preparation of tab(cid:173)
`lets, diluents or fillers are commonly added to
`increase the bulk of the formulation, binders to
`cause the adhesion of the powdered drug and
`pharmaceutic substances, antiadherents or lubri(cid:173)
`cants to assist the smooth tableting process, disin(cid:173)
`tegrating agents to promote tablet break-up after
`administration, and coatings to improve stabil(cid:173)
`ity, control diSintegration, or to enhance appear(cid:173)
`ance. Ointments, creams, and suppositories
`achieve their characteristic features due to the
`pharmaceutic bases which are utilized. Thus, for
`each dosage form, the pharmaceutic ingredients
`
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`Dosage Fonn Design
`
`111
`
`establish the primary features of the product,
`and contribute to the physical form, texture, sta(cid:173)
`bility, taste and overall appearance.
`Table 4-2 presents the principal categories of
`pharmaceutic ingredients, with examples of
`some of the official and commercial agents cur(cid:173)
`rently used. Additional discussion of many of
`
`the pharmaceutic ingredients may be found in
`the chapters where they are most relevant; for
`example, pharmaceutic materials used in tablet
`and capsule formulation are discussed in Chap(cid:173)
`ter 5, Peroral Solids, Capsules, Tablets, and Con(cid:173)
`trolled-Release Dosage Forms.
`The reader should also be aware of the Hand-
`
`Table 4-2 Examples of Pharmaceutic Ingredients
`
`Ingredient Type
`
`Acidifying Agent
`
`Alkalinizing Agent
`
`Definition
`Used in liquid preparations to
`provide acidic medium for
`product stability.
`
`Used in liquid preparations to
`provide alkaline medium for
`product stability.
`
`Adsorbent
`
`Aerosol Propellant
`
`Air Displacement
`
`Antifungal Preservative
`
`Antimicrobial Preservative
`
`An agent capable of holding other
`molecules onto its surface by
`physical or chemical
`(chemisorption) means.
`An agent responsible for developing
`the pressure within an aerosol
`container and expelling the
`product when the valve is
`opened.
`An agent which is employed to
`displace air in a hermetically
`sealed container to enhance
`product stability.
`Used in liquid and semi-solid
`preparations to prevent the
`growth of fungi. The effectiveness
`of the parabens is usually
`enhanced when they are used in
`combination.
`
`Used in liquid and semi-solid
`preparations to prevent the
`growth of microorganisms.
`
`Examples
`
`acetic acid
`citric acid
`fumaric acid
`hydrochloric acid
`nitric acid
`ammonia solution
`ammonium carbonate
`diethanolamine
`monoethanolamine
`potassium hydroxide
`sodium borate
`sodium carbonate
`sodium hydroxide
`triethanolamine
`trolamine
`powdered cellulose
`activated charcoal
`
`carbon dioxide
`dichlorodifluoromethane
`dichlorotetrafluoroethane
`trichloromonofluoromethane
`
`nitrogen
`
`benzoic acid
`butylparaben
`ethylparaben
`methylparaben
`propylparaben
`sodium benzoate
`sodium propionate
`benzalkonium chloride
`benzethonium chloride
`benzyl alcohol
`cetylpyridinium chloride
`chlorobutanol
`phenol
`phenylethyl alcohol
`phenylmercuric nitrate
`thimerosal
`
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`I
`I
`I
`
`112
`
`Dosage Form Design
`
`Table 4-2. Continued
`
`Ingredient Type
`
`Antioxidant
`
`Definition
`An agent which inhibits oxidation
`and thus is used to prevent the
`deterioration of preparations by
`the oxidative process.
`
`Buffering Agent
`
`Che/ating Agent
`
`Colorant
`
`Clarifying Agent
`
`Emulsifying Agent
`
`Encapsulating Agent
`
`Flavorant
`
`Used to resist change in pH upon
`dilution or addition of acid or
`alkali.
`
`A substance that forms stable, water
`soluble complexes (chelates) with
`metals. Chelating agents are used
`in some liquid pharmaceuticals as
`stabilizers to complex heavy
`metals which might promote
`instability. In such use they are
`also called sequestering agents.
`Used to impart color to liquid and
`solid (e.g., tablets and capsules)
`pharmaceutical preparations.
`
`Used as a filtering aid because of
`adsorbent qualities.
`Used to promote and maintain the
`dispersion of finely subdivided
`particles of a liquid in a vehicl~ in
`which it is immiscible. The end
`product may be a liquid emulsion
`or semisolid emulsion (e.g., a
`cream).
`
`Used to fonn thin shells for the
`purpose of enclosing a drug
`substance or drug formulation for
`ease of administration.
`Used to impart a pleasant flavor
`and often odor to a
`pharmaceutical preparation. In
`addition to the natural flavorants
`listed, many synthetic flavorants
`are also used.
`
`Examples
`ascorbic acid
`ascorbyl palmitate
`butylated hydroxyanisole
`butylated hydroxy toluene
`hypophophorous acid
`monothioglycerol
`propyl gallate
`sodium ascorbate
`sodium bisulfite
`sodium formaldehyde
`sulfoxylate
`sodium metabisulfite
`potassium metaphosphate
`potassium phosphate, monobasic
`sodium acetate
`sodium citrate anhydrous and
`dihydrate
`edetate disodium
`edetic acid
`
`FD&C Red No.3
`FD&C Red No. 20
`FD&C Yellow No.6
`FD&C Blue No.2
`D&C Green No.5
`D&C Orange No.5
`D&C Red No. 8
`caramel
`ferric oxide, red .
`bentonite
`
`acacia
`cetomacrogol
`cetyl alcohol
`glyceryl monostearate
`sorbitan monooleate
`polyoxyethylene 50 stearate
`
`gelatin
`cellulose acetate phthalate
`
`anise oil
`cinnamon oil
`cocoa
`menthol
`orange oil
`peppermint oil
`vanillin
`
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`-
`Table 4 2 Continued
`
`Ingredient Type
`
`Humectant
`
`Levigating Agent
`
`Ointment Base
`
`Plasticizer
`
`Solvent
`
`Stiffening Agent
`
`Dosage Form Design
`
`113
`
`Definition
`Used to prevent the drying out of
`preparations-particularly
`ointments and creams-due to
`the agent'" s ability to retain
`moisture.
`
`A liquid used as an intervening
`agent to reduce the particle size
`of a drug powder by grinding
`together, usually in a mortar.
`The semisolid vehicle into which
`drug substances may be
`incorporated in preparing
`medicated ointments.
`
`Used as a component of film-
`coating solutions to enhance the
`spread of the coat over tablets,
`beads, and granules.
`An agent used to dissolve another
`pharmaceutic substance or a drug
`in the preparation of a solution.
`The solvent may be aqueous or
`nonaqueous (e.g., oleaginous).
`Cosolvents, such as water and
`alcohol (hydroalcoholic) and
`water and glycerin, may be used
`when needed. Solvents rendered
`sterile are used in certain
`preparations (e.g., injections).
`
`Used to increase the thickness or
`hardness of a pharmaceutical
`preparation, usually an ointment.
`
`Examples
`
`glycerin
`propylene glycol
`sorbitol
`
`mineral oil
`glycerin
`
`lanolin
`hydrophilic ointment
`polyethylene glycol ointment
`petrolatum
`hydrophilic petrolatum
`white ointment
`yellow ointment
`rose water ointment
`
`diethyl phthalate
`glycerin
`
`alcohol
`corn oil
`cottonseed oil
`glycerin
`isopropyl alcohol
`mineral oil
`oleic acid
`peanut oil
`purified water
`water for injection
`sterile water for injection
`sterile water for irrigation
`cetyl alcohol
`cetyl esters wax
`microcrystalline wax
`paraffin
`stearyl alcohol
`white wax
`yellow wax
`
`Suppository Base
`
`Surfactant (surface active agent)
`
`Used as a vehicle into which drug
`substances are incorporated in the
`preparation of suppositories.
`Substances which absorb to surfaces
`or interfaces to reduce surface or
`interfacial tension. May be used
`as wetting agents, detergents or
`emulsifying agents.
`
`cocoa butter
`polyethylene glycols (mixtures)
`
`benzalkonium chloride
`nonoxynol 10
`oxtoxynol9
`polysorbate 80
`sodium lauryl sulfate
`sorbitan monopalmitate
`
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`T
`
`I
`
`114
`
`Dosage Form Design
`
`Table 4-2 Continued
`
`Ingredient Type
`
`Suspending Agent
`
`Definition
`A viscosity increasing agent used to
`reduce the rate of sedimentation
`of (drug) particles dispersed
`throughout a vehicle in which
`they are not soluble. The resultant
`suspensions may be formulated
`for use orally, parenterally,
`ophthalmically, topically, or by
`other routes.
`
`Sweetening Agent
`
`Used to impart sweetness to a
`preparation.
`
`Tablet Antiadherents
`
`Tablet Binders
`
`Agents which prevent the sticking
`of tablet formulation ingredients
`to punches and dies in a tableting
`machine during production.
`
`Substances used to cause adhesion
`of powder particles in tablet
`granulations.
`
`Tablet and Capsule Diluent
`
`Inert substances used as fillers to
`create the desired bulk, flow
`properties, and compression
`characteristics in the preparation
`of tablets and capsules.
`
`Examples
`
`agar
`bentonite
`carbomer (e.g., Carhopol)
`carboxymethy1cellulose sodium
`hydroxyethyl cellulose
`hydroxypropyl cellulose
`hydroxypropyl methylcellulose
`kaolin
`methylcellulose
`tragacanth
`veegum
`aspartame
`dextrose
`glycerin
`mannitol
`saccharin sodium
`sorbitol
`sucrose
`magnesium stearate
`talc
`
`acacia
`alginic acid
`carboxymethylcellulose sodium
`compressible sugar (e.g., Nu-
`Tab)
`ethylcellulose
`gelatin
`liquid glucose
`methylcellulose
`povidone
`pregelatinized starch
`
`dibasic calcium phosphate
`kaolin
`lactose
`mannitol
`microcrystalline cellulose
`powdered cellulose
`precipitated calcium carbonate
`sorbitol
`starch
`
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`Table 4-2 Continued
`
`Ingredient Type
`
`Tablet Coating Agent
`
`Tablet Direct Compression
`Excipient
`
`Tablet Disintegrant
`
`Definition
`Used to coat a formed tablet for the
`purpose of protecting against
`drug decomposition by
`atmospheric oxygen or humidity,
`to provide a desired release
`pattern for the drug substance
`after administration, to mask the
`taste or odor of the drug
`substance, or for aesthetic
`purposes. The·coating may be of
`various types, including sugar-
`coating, film coating, or enteric
`coating. Sugar coating is water-
`based and results in a thickened
`covering around a formed tablet.
`Sugar-coated tablets generally
`start to break up in the stomach.
`A film coat is a thin cover around
`a formed tablet or bead. Unless it
`is an enteric coat, the film coat
`will dissolve in the stomach. An
`enteric-coated tablet or bead will
`pass through the stomach and
`break up in the intestines. Some
`coatings that are water-insoluble
`(e.g., ethylcellulose) may be used
`to coat tablets and beads to slow
`the release of drug as they pass
`through the gastrointestinal tract.
`
`Used in direct compression tablet
`formulations.
`Used in solid dosage forms to
`promote the disruption of the
`solid mass into smaller particles
`which are more readily dispersed
`or dissolved.
`
`Dosage Form Design
`
`115
`
`Examples
`
`sugar coating:
`liquid glucose
`sucrose
`film coating:
`hydroxyethyl cellulose
`hydroxypropyl ~ellulose
`hydroxypropyl methylcellulose
`methylcellulose (e.g., Methoce!)
`ethylcellulose (e.g., Ethoce!)
`enteric coating:
`cellulose acetate phthalate
`shellac (35% in alcohol,
`"pharmaceutical glaze")
`
`dibasic calcium phosphate (e.g.,
`Ditab)
`
`alginic acid
`carboxymethylcellulose calcium
`microcrystalline cellulose {e.g.,
`Avice!)
`polacrilin potassium (e.g.,
`Amberlite)
`sodium alginate
`sodium starch glycollate
`starch
`
`Tablet Glidant
`
`Tablet Lubricant
`
`Tablet/Capsule Opaquant
`
`Agents used in tablet and capsule
`formulations to improve the flow
`properties of the powder mixture.
`Substances used in tablet
`formulations to reduce friction
`during tablet compression.
`
`Used to render a capsule or a tablet
`coating opaque. May be used
`alone or in combination with a
`colorant.
`
`colloidal silica
`cornstarch
`talc
`calcium stearate
`magnesium stearate
`mineral oil
`stearic acid
`zinc stearate
`titanium dioxide
`
`Tablet Polishing Agent
`
`Used to impart an attractive sheen
`to coated tablets.
`
`carnauba wax
`white wax
`
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`116
`
`Dosage Form Design
`
`Table 4-2. Continued
`Ingredient Type
`
`Tonicity Agent
`
`Vehicle
`
`Definition
`Used to render a solution similar in
`osmotic characteristics to
`physiologic fluids. Ophthahnic,
`parenteral, and irrigation fluids
`are examples of preparations in
`which tonicity is a consideration.
`A carrying agent for a drug
`substance. They are used in
`formulating a variety of liquid
`dosage for oral and parenteral
`administration. Generally, oral
`liquids are aqueous preparations
`(as syrups) or hydroa1coholic (as
`elixirs). Parenteral solutions for
`intravenous use are aqueous,
`whereas intramuscular injections
`may be aqueous or oleaginous.
`
`Viscosity Increasing Agent
`
`Used to change the consistency of a
`preparation to render it more
`resistant to flow. Used in
`suspensions to deter
`sedimentation, in ophthalmic
`solutions to enhance contact time
`<e.g., methylcellulose), to thicken
`topical creams, etc.
`
`Examples
`
`dextrose
`sodium chloride
`
`Flavored/Sweetened
`Acacia Syrup
`Aromatic Syrup
`Aromatic Elixir
`Cherry Syrup
`Cocoa Syrup
`Orange Syrup
`Syrup
`Oleaginous
`Corn Oil
`Mineral Oil
`Peanut Oil
`Sesame Oil
`Sterile
`Bacteriostatic Sodium
`Chloride Injection
`Bacteriostatic Water
`for Injection
`alginic acid
`bentonite
`carbomer
`carboxymethylcellulose sodium
`methylcellulose
`povidone
`sodium alginate
`tragacanth
`
`book of Phnrmaceutical Excipients: which presents
`monographs on about 150 excipients used in
`pharmaceutical dosage form preparation. In(cid:173)
`cluded in each monograph is such information
`as: nonproprietary, chemical, and commercial
`names; empirical and chemical formulas and
`molecular weight; pharmaceutic specifications
`and chemical and physical properties; incompat(cid:173)
`ibilities and interactions with other excipients
`and drug substances; regulatory status; and ap(cid:173)
`plications in pharmaceutic formulation or tech(cid:173)
`nology.
`There is great interest nowadays in the inter(cid:173)
`national "harmonization" of standards applica(cid:173)
`ble to pharmaceutical excipients. This is due to
`the fact that the pharmaceutical industry is mul(cid:173)
`tinational, with major companies having facili(cid:173)
`ties in more than a single country, with products
`sold in markets worldwide, and with regulatory
`
`approval for these products generally r~quired
`in each individual country. Standards for each
`drug substance and excipient used in pharma(cid:173)
`ceuticals are contained in pharmacopeias-or,
`for new agents, in an application for regulatory
`approval by the FDA or another nation's govern(cid:173)
`ing authority. The four pharmacopeias with the
`largest international use are the United States
`Phnrmacopeia/National Formulary (USP /NF), Brit(cid:173)
`ish Pharmacopeia (BP), European Pharmacopeia
`(EP), and the Japanese Phnrmacopeia (JP). Uniform
`standards for excipients in these and other phar(cid:173)
`macopeias would facilitate production effi(cid:173)
`ciency, enable the marketing of a single formula(cid:173)
`tion of a product internationally, and enhance
`regulatory approval of pharmaceutical products
`worldwide. The goal of harmonization is an on(cid:173)
`going effort undertaken by corporate representa(cid:173)
`tives and international regulatory authorities.
`
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`

`Drug Product Stability
`As indicated previously, many pharmaceutic
`ingredients may be utilized in preparing the de(cid:173)
`sired dosage form of a drug substance. Some of
`these agents may be used to achieve the desired
`phYSical and chemical characteristics of the
`product or to enhance its appearance, odor, and
`taste. Other substances may be used to increase
`the stability of the drug substance, particularly
`against the hydrolytic and oxidative processes.
`In each instance, the added pharmaceutic ingre(cid:173)
`dient must be compatible with and must not de(cid:173)
`tract from the stability of the drug substance in
`the particular dosage form prepared.
`There are several approaches to the stabiliza(cid:173)
`tion of pharmaceutical preparations containing
`drugs subject to deterioration by hydrolysis. Per(cid:173)
`haps the most obvious is the reduction, or better
`yet, the elimination of water from the pharma(cid:173)
`ceutical system. Even solid dosage forms con(cid:173)
`taining water-labile drugs must be protected
`from the humidity of the atmosphere. This may
`be accomplished by applying a waterproof pro(cid:173)
`tective coating over tablets or by enclosing and
`maintaining the drug in tightly closed contain(cid:173)
`ers. It is not unusual to detect hydrolyzed aspirin
`by noticing an odor of acetic acid upon opening
`a bottle of aspirin tablets. In liquid preparations,
`water can frequently be replaced or reduced in
`the formulation through the use of substitute liq(cid:173)
`uids such as glycerin, propylene glycol, and alco(cid:173)
`hoL In certain injectable products, anhydrous
`vegetable oils may be used as the drug's solvent
`to reduce the chance of hydrolytic decomposi(cid:173)
`tion.
`Decomposition by hydrolysis may be pre(cid:173)
`vented for other drugs to be administered in liq(cid:173)
`uid form by suspending them in a non-aqueous
`vehicle rather than by dissolving them in an
`aqueous solvent. In still other instances, particu(cid:173)
`larly for certain unstable antibiotic drugs, when
`an aqueous preparation is desired, the drug may
`be supplied to the pharmacist in a dry form for
`reconstitution by adding a specified volume of
`purified water just before dispensing. The dry
`powder supplied commercially is actually a
`mixture of the antibiotic, suspending agents,
`flavorants, and colorants, which, when reconsti(cid:173)
`tuted by the pharmaCist, remains a stable sus(cid:173)
`pension or solution of the drug for the time
`period in which the preparation is normally con(cid:173)
`sumed. Storage under refrigeration is advisable
`for most preparations considered unstable due
`
`Dosage Form Design
`
`117
`
`to hydrolytic causes. Together with temperature,
`pH is a major determinant in the stability of a
`drug prone to hydrolytic decomposition. The hy(cid:173)
`drolysis of most drugs is dependent upon the
`relative concentrations of the hydroxyl and hy(cid:173)
`dronium ions, and a pH at which each drug is
`optimally stable can be easily determined. For
`most hydrolyzable drugs the pH of optimum sta(cid:173)
`bility is on the acid side, somewhere between
`pH 5 and 6. Therefore, through judicious use of
`buffering agents, the stability of otherwise un(cid:173)
`stable compounds can be increased.
`Pharmaceutically, the oxidation of a suscepti(cid:173)
`ble drug substance is most likely to occur when
`it is maintained in other than the dry state in the
`presence of oxygen, exposed to light, or com(cid:173)
`bined in formulation with other chemical agents
`without proper regard to their influence on the
`oxidation process. The oxidation of a chemical
`in a pharmaceutical preparation is usually atten(cid:173)
`dant with an alteration in the color of that prepa(cid:173)
`ration. It may also result in precipitation or a
`change in the usual odor of a preparation.
`The oxidative process is diverted, and the sta(cid:173)
`bility of the drug is preserved by agents called
`antioxidants, which react with one or more com(cid:173)
`pounds in the drug to prevent progress of the
`chain reaction. In general, antioxidants act by
`providing electrons and easily available hydro(cid:173)
`gen atoms that are accepted more readily by the
`free radicals than are those of the drug being
`protected. Various antioxidants are employed in
`pharmacy. Among those more frequently used
`in aqueous preparations are sodium sulfite
`(NaZS03), sodium bisulfite (NaHS03), hypo(cid:173)
`phosphorous acid (H3POz), and ascorbic acid. In
`oleaginous (oily or unctuous) preparations, al(cid:173)
`phatocopherol, butyIhydroxyanisole, and ascor(cid:173)
`byl palmitate find application.
`In June 1987, FDA labeling regulations went
`into effect requiring a warning about possible
`allergic-type reactions, including anaphylaxis in
`the package insert for prescription drugs to
`which sulfites have been added to the final dos(cid:173)
`age form. Sulfites are used as preservatives in
`many injectable drugs, such as antibiotics and
`local anesthetics. Some inhalants and ophthalmiC
`preparations also contain sulfites, but relatively
`few oral drugs contain these chemicals. The pur(cid:173)
`pose of the regulation is to protect the estimated
`0.2% of the population who suffer allergiC reac(cid:173)
`tions from the chemicals. Many of the sulfite(cid:173)
`sensitive persons suffer from asthma or other al(cid:173)
`lergic conditions. Previous to the regulations
`
`: ;
`i
`
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`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
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`

`

`118
`
`Dosage Fonn Design
`
`dealing with prescription medication, the FDA
`issued regulations for the use of sulfites in food.
`Asthmatics and other patients who may be sul(cid:173)
`fite-sensitive should be reminded to read the la(cid:173)
`bels of packaged foods and medications to check
`for the presence of these agents.
`The most frequent symptom of a sulfite reac(cid:173)
`tion is difficulty breathing. Other symptoms in(cid:173)
`clude diarrhea, nausea and vomiting, abdominal
`pain and cramps, dizziness, wheezing, hives,
`itching, local swelling, rash, difficulty swallow(cid:173)
`ing, headache, fainting, change in body tempera(cid:173)
`ture, chest pain, change in heart rate, uncon(cid:173)
`sciousness and coma. Symptoms usually occur
`within minutes of ingesting or taking sulfited
`foods or drug products.
`Sulfiting agents covered by the regulations are
`potassium bisulfite, potassium metabisulfite, so(cid:173)
`dium bisulfite, sodium metabisulfite, sodium
`sulfite and sulfur dioxide.
`The labeling of drugs to which sulfites have
`been added to the final dosage form must con(cid:173)
`tain the following statement in the "Warnings"
`section of the labeling:
`"Contains (name of the sulfite), a sulfite that may cause
`allergic-type reactions including anaphylactic symptoms
`and life-threatening or less severe asthmatic episodes in cer(cid:173)
`tain susceptible people. The overall prevalence of sulfite sen(cid:173)
`sitivity in the general population is unknown and probably
`low. Sulfite sensitivity is seen more frequently in asthmatic
`than nonasthmatic people."
`Sulfite-containing epinephrine for injection for
`use in allergic emergencies must contain the fol(cid:173)
`lowing statement:
`"Epinephrine is the preferred treatment for serious allergic
`or emergency situations even tlwugh this product contains
`(name of sulfite), a sulfite that may in other products cause
`allergic-type reactions including anaphylactic symptoms or
`life-threatening or less severe asthmatic episodes in certain
`susceptible persons. The alternatives to using epinephrine
`in a life-threatening situation may not be satisfactory. The
`presence of a sulfite(s) in this product should not deter the
`administration of the drug for treatment of serious allergic
`or other emergency situations."
`The FDA permits the use of sulfites in pre(cid:173)
`scription products, with the proper labeling, be(cid:173)
`cause there are no generally suitable substitutes
`for sulfites to maintain potency in certain medi(cid:173)
`cations.
`The proper use of antioxidants involves their
`specific application only after appropriate
`biomedical and pharmaceutical studies. In cer(cid:173)
`tain instances other pharmaceutical additives
`have been found to inactivate a given antioxi(cid:173)
`dant when used in the same formulation. In
`other cases certain antioxidants have been found
`
`I,
`I
`ii
`i,
`:i
`II
`ii
`
`"
`iii
`
`to react chemically with the drugs they were in(cid:173)
`tended to stabilize, without a noticeable change
`in the appearance of the preparation.
`Because the stability of oxidizable drugs may
`be adversely affected by oxygen, certain pharma(cid:173)
`ceuticals may require an oxygen-free atmo(cid:173)
`sphere during their preparation and storage. Ox(cid:173)
`ygen may be present in pharmaceutical liquids
`in the airspace within the container or may be
`dissolved in the liquid vehicle. To avoid these
`exposures, oxygen-sensitive drugs may be pre(cid:173)
`pared in the dry state and they, as well as liquid
`preparations, may be packaged in sealed con(cid:173)
`tainers with the air replaced by an inert gas such
`as nitrogen. This is common practice in the com(cid:173)
`mercial production of vials and ampuls of easily
`oxidizable preparations intended for parenteral
`use.
`Trace metals originating in the drug, solvent,
`container, or stopper are a constant source of-dif(cid:173)
`ficulty in preparing stable solutions of oxidizable
`drugs. The rate of formation of color in epineph(cid:173)
`rine solutions, for instance, is greatly increased
`by the presence of ferric, ferrous, cupric, and
`chromic ions. Great care must be taken to elimi(cid:173)
`nate these" trace metals from labile preparations
`by thorough purification of the source of the con(cid:173)
`taminant or by chemically complexing or bind(cid:173)
`ing the metal through the use of specialized
`agents that make it chemically unavailable for
`participation in the oxidative process. These
`agents are referred to as chelating agents and are
`exemplified by calcium disodium edetate and
`ethylenediamine tetra-acetic acid (EDTA).
`
`CH,-COOH
`HOOC-CH,
`N-CH -CH -N
`/
`+Ca++-----*
`\
`'
`2
`
`"
`
`/
`HOOC-CH,
`
`CHz-COOH
`
`EDTA
`
`,/'"
`'0
`ya
`0
`/
`C~O
`
`OOC-CH,
`
`CH,
`
`N
`I
`CH,
`I
`CHz
`I
`N
`I '" /
`OOC-CH,
`CH,
`
`C~O
`
`1
`
`Proposed calcium complex
`of EDT A
`
`Light can also act as a catalyst to oxidation
`reactions. As a photocatalyst, light waves trans-
`
`NOVARTIS EXHIBIT 2020
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 11 of 13
`
`

`

`Table 4-3. Examples of Some Official Drugs and Preparations Especially Subject to Chemical or Physical
`Deterioration
`
`Dosage Form Design
`
`119
`
`Epinephrine Bitartrate Ophthalmic Solution, USP 1
`
`Preparation
`
`Epinephrine Inhalation Solution, USP
`Epinephrine Injection, USP
`Epinephrine Nasal Solution, USP
`Epinephrine Ophthalmic Solution, USP
`Isoproterenol Sulfate
`Inhalation, Solution, USP
`Isoproterenol Inhalation Solution, USP
`
`Category
`
`Adrenergic
`
`Adrenergic
`(bronchodilator)
`
`Nitroglycerin Tablets, USP
`
`Antianginal
`
`Paraldehyde,