1.10
`
`Dosage Form Design
`
`Drug Stability
`
`One of the most important activities of pre-
`formulation work is the evaluation of the physi-
`cal and chemical stability of the pure drug sub—
`stance. It is essential that these initial studies be
`
`conducted! using drug samples of known purity.
`The presence of impurities can lead to erroneous
`conclusionsin 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 exdpients.
`Initial
`investigation begins through lcnowl~
`edge of the drug’s chemical structure which al—
`lows the prefonnulation scientist to anticipate
`flie possible degradation reactions.
`Chemical instability of medicinal agents may
`take many fonns, because the drugs in use today
`are of such diverse chemical constitution. Chemi—
`
`cally, drug substances are alcohols, phenols, al—
`dehydes, ketones, esters, others, acids, salts, alka—
`loids, glycosides and others, each with reactive
`chemical groups having different susceptibilities
`toward chemical
`instability. Chemically,
`the
`most frequently encountered destructive pro—
`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—
`cal constihition. For example, $1st or acetyl-
`salicylic acid combines with a water molecule.
`and hydrolyzes into one molecule of salicylic
`acid and one molecule of acetic acid:
`
`0
`II
`C—OH
`
`'
`
`0
`II
`C~DH
`
`6 um3+H,o-r-v
`
`o—cs“
`D
`
`on
`
`Cl
`H
`
`+CHB—c—oH
`
`Aspirin
`
`Salicylic Acid
`
`Acetic Acid
`
`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 anddes,
`lactones, and lactams,
`
`which are susceptible to the hydrolytic process.
`Another destructive process 15 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-
`trons from an atom or a molecule. Each electron
`
`
`
` ..
`
`
`
`WIQVfir:__-¢.s-;—e=e..:.--...-__._
`
`
`
`lost is accepted by some other atom or molecule,
`thereby accomplishing the reduction of the re-
`cipient. 1n inorganic chemistry, oxidation is ac-
`companied by an inflease in the positive valence
`of an element—for example, ferrous (+2) oxi-
`dizing to ferric (+3). In organic chemistry, oxi-
`dation is frequently considered synonymous
`with the loss of hydrogen (dehydrogenation)
`from a molecule. The oxidative process fre-
`quently involves tree chemical radicals, which
`are molecules or atoms containing one or more
`unpaired electrons, as molecular (atmospheric)
`oxygen (-O—O-JI and free hydroxyl {-OH}. These
`radicals tend to take electrons from other chemi-
`
`cals, thereby oxidizing the donor. Many of the
`oxidative changes in pharmaceutical prepara-
`tions have the character of autoxidatioris. Autox—
`
`idations occur spontaneously under the initial
`influence of atmosphen'c oxygen and proceed
`slowly at first and then more rapidly as the pro-
`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-
`tinuing with a free radical of this oxidized mole-
`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, part-servew
`fives may be added to prevent microbial growth,
`stabilizers may be used to prevent drug decompo—
`sition, and colorants and flavorsnts added to en-
`hance product appeal. In the preparation of tab-
`lets, (literals or fillers are commonly added to
`increase the bulk of the formulation, binders to
`cause the adhesion of the powdered drug and
`pharmaceutic substances, aniiadhererzts or lubri-
`coats to assist the smooth tableting process, disin—
`tegmiing agmits to promote tablet break—up after
`administration, and coatings to improve stabil-
`ity, control disintegration or to enhance appear-
`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
`SHIRE EX. 2010 Part 2
`KVK V. SHIRE
`IPR2018-00290
`
`r/!47
`p. i6
`
`
`
`
`
`Adsorber
`
`Aerosol .
`
`
`
`
`
`l Artffmit
`
`id
`
`SHIRE EX. 2010 Part 2
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`a or molecule,
`ion of the re—
`ridation is ac—
`:sitive valence
`
`synonymous
`ydrogenation)
`process Ire-
`Ldjcals, which
`5 one or more
`
`(atmospheric)
`1 (-OH). These
`.1 other chand—
`
`. Many of the
`tics] prepara-
`ations. Autox—
`
`:ler the initial
`
`and proceed
`ily as the pro-
`een described
`
`.encing by the
`ecule and con-r
`:xidized mole-
`:tion of other
`
`'ork, steps are
`occurrence of
`
`to hydrolysis,
`sse tectmiques
`
`tents
`ostance into a
`
`ngredients are
`separation of
`:re solvents are
`
`ance, preserve—
`robial growth.
`mgdecompo-
`: added to en
`oration of tab-
`
`trLly added to
`ion, binders to
`red drug and
`treats or lubri—
`
`process, disin-
`oreak—up after
`nprove stabil—
`hance appear-
`suppositories
`es due to the
`zed. Thus, for
`
`tie ingredients establish the primary features of the product,
`
`Aerosol Propellerrt
`
`Air Displacement
`
`Antifungal Presemoiioe
`
`
`
`
`Dosage Pom Design
`
`111
`
`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-
`ter 5, Forum! Solids, Capsules, Tablets, and Con-
`trolled—Release Dosage Forms.
`The reader should also be aware of the Hand
`
`and contribute to the physical forts, texture, sta-
`bility, taste and overall appearance.
`Table 4—2 presents the principal categories of
`pharmaceutir:
`ingredients, with examples of
`some of the official and commercial agents cur-
`rently used. Additional dismsion of many of
`
`Table 4—2. Examples of Pharmaceulic Ingredients
`
`Acidifying Agent
`
`Aikafiniziug Agent
`
`Used in liquid preparations to
`provide acidic medium for
`product stability.
`
`acetic acid
`citric acid
`formic acid
`
`hydrochloric acid
`nitric acid
`
`Used in liquid preparations to
`provide alkaline medium for
`product stability.
`
`ammonia solution
`ammonitmr mfoonate
`diethanolamine
`monoethanolarrdne
`
`potassium hydroxide
`sodium borate
`sodium carbonate
`sodium hydroxide
`triethanolamine
`trolarnine
`Adsorbent
`
`powdered cellulose
`activated charcoal
`
`An agent capable of holding other
`molecules onto its surface by
`physical or chemical
`
`(Chemisoqnfion) means.
`carbon dioxide
`An agent responsible for developing
`dictflorodifluommethane
`the pressure within an aerosol
`dichlorotetrafluoroethane
`container and emailing the
`hichloromonofluoromethane
`product when the valve is
`opened.
`
`J
`
`
`r/!48
`p. 37
`
`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.
`
`Antimicrobial Presemotioe
`
`Used in liquid and send—solid
`preparations to prevent the
`growth of microorganisms.
`
`
`
`nitrogen
`
`benzoic acid
`
`butylparaben
`ethylparabon
`methylparabEn
`propylparaben
`sodium benroate
`
`sodium propionate
`bermlkonium chloride
`benzethom'um chloride
`
`benzyl alcohol
`cetylpyridinium chloride
`chlorobutanol
`
`phenol
`phenylethyl alcohol
`phenylmercun'c nitrate
`thimerosal
`
`

`

`
`
`112
`
`Dosage Pam: Design
`
`Table 4-2. Continued
`
`
`
`Antioxidant
`
`Ingredient Type
`
`I
`
`
`
`
`
`ascorbic acid
`
`
`An agent wldch inhibits oxidation
`and thus is used to prevent the
`ascorbyl palmitate
`
`
`deteriomdon of preparations by
`butylated hydxoagmu'sole
`
`
`
`the oncidative process.
`butylated hydroxytoluene
`'
`
`
`
`hypophophorous acid
`monotlfioglycerol
`
`propyl gallate
`sodium ascorbate
`sodium bisulfite
`
`sodium formaldehyde
`
`sflfoxylate
`
`
`sodium metabisulfite
`
`
`Used to ma’st change in pll upon
`potassium metaphosphate
`alkali.
`dilution or addition of acid or
`potassium phosphate, monobasic
`
`sodium acetate
`
`sodium citrate anhydrous and
`
`dillydrate
`
`edetnle disodium
`
`
`A substance that forms stable, water
`Deleting Agent
`
`edelic acid
`soluble mplexes (chelatesl 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.
`
`
` FD&C Red No. 3
`Used to impart color to liquid and
`
`
`
`MC Red No. 20
`solid (e.g., tablets and capsules)
`
`
`
`FD&C Yellow No. 6
`pharmaceutical preparations.
`
`
`
`
`
`MC Blue No. 2
`
`D&C Green No. 5
`
`DkC Orange No. 5
`
`D&C Red No. a
`
`caramel
`
`
`ferric oxide, red
`
`
`
`
`Clarifying Agent
`Used as a filtering aid because of
`bentonite
`
`
`
`adsorbent qualifies.
`
` acacia
`
`Used to promote and maintain the
`Emulsffliug Agent
`
`
`
`dispersion of finely subdivided
`cetomacrogol
`
`
`
`cot-y! alcohol
`particles of a liquid in a vehicle in
`
`
`
`which it is inurfiscible. The and
`glyceryl monastearate
`
`
`
`sorbitan monooleate
`product may be a liquid emulsion
`
`
`
`
`
`polyoxyethylene 5|] stearale
`or semisolid emulsion (e.g., :4
`
`
`
`
`am).
`
`
`Used to £01m thin shells for the
`
`
`
` gelatin
`Enmpsulntfng Agent
`
`
`purpose of enclosing a drug
`cellulose acetate phthalate
`
`
`substance or drug foundation for
`
`
`ease of admiidstrafion.
`
` Flanagan!
`
`Used to impart a pleasant flavor
`and often odor to a
`
`pharmeoeutical preparation. In
`
`addition to the natural flavorants
`
`listed, many synthetic flavorants
`
`are also used.
`
`
`Lenigating
`
`Horned-am
`
` Table 4-2.
`
`r/!49
`
`
`
`

`

`1e
`
`nonobasa'e
`
`“sand
`
`ante
`
`late
`
`
`
`
`
`Table 4-2. Continued
`
`Momma
`Hwnectcm
`
`Lem'gafing Agent
`
`Dino-nan! Base
`
`90mm Dmign
`
`113
`
`Used to prevent the drying out o!
`preparations—particularly
`ointmmts and creams—due to
`
`
`
`
`glymfin
`
`
`propylene glycol
`
`
`sorbitol
`
`the agent’s ability to retain
`
`
`
`
`moi-Store.
`
`A liquid used as an 1.1mm;
`agent to reduce the particle size
`of a, drug powder by glinding
`
`together, usually in a mortar.
`lanolin
`The semisolid vehicle into which
`
`
`
`drug subs-hows may be
`hydmpl'dlic Ointment
`
`
`irmrp‘omtEd in pulsating
`polyethylene glycol ointment
`
`
`
`
`medicated oimments.
`petroleum!
`hydrophilic petroleum
`
`while ointment
`
`
`yellow atom
`
`rose water ointment
`
`
`
`Used as a componmt of film—
`diethyl phkhalete
`coating solutions to alliance the
`glycerin
`Spread of the coat over tablets,
`
`beast, and granules.
`
`
`
`An agent used to dissolve another
`‘ alcohol
`phaxmaceotlc substance or a drug
`corn oil
`
`
`cottonseed oil
`in the pmpsrefion of a solution.
`
`
`The solvent may be aqueous or
`glycerin
`
`
`nonaqueous leg. oleaginousl.
`iaopropyl alcohol
`
`
`Cosolvents. such as water and
`mineral oil
`
`
`alcohol .(hydxoalcoholic) and
`olelc add
`
`
`
`water and glycerin. may be used
`peenul oil
`
`
`
`when needed. Solvents rendered
`purified water
`
`
`
`sterile are used in certain
`water Tor fixjoc‘tion
`
`
`
`prepemtions leg, injections).
`sterile water for injection
`
`
`
`
`sterile water for tn'igation
`
`
`Used to innease the thickness or
`cetyl alcohol
`
`hardness of a phammceutical
`cetyl esters wax
`
`preparetiom usually an ointment.
`microcystalline wax
`
`
`
`paraffin
`
`shanty] alcohol
`
`
`white wax
`
` yellow wax
`
`Dome butter
`Used as a vehicle into which drug
`
`mostams are incorporated in the
`polyethylene glymls (nannies)
`preparation of suppooilm'ies.
`
`Substances which absorb to smfeoes
`Surfimlanl {511me active ogmt)
`benzaIl-torrtum chloride
`
`or interlaces to mdoce surface or
`moxynol 10
`
`interfacial tension. May be used
`oxloxynol 9
`as wetting agents, detergents or
`polyourbete BO
`emulsifying agents.
`sodium leuryl sulfate
`
`aorlzltan mono-palmitste
`
`Plasfldzar
`
`-
`
`
`
`
`
`
`
`Siiffenfng Agent
`
`Suppository Base
`
`
`
`r/!4;
`
`

`

`Table 4—
`
`| Tablet C
`
`1—
`
`i T
`
`hbk
`Ex
`
`Table
`
`
`
`Tab]
`
`
`
`Tab
`
` Tai
`
`I Tell
`
`
`
`
`
`r/!51
`
`
`to
`A viscosity increasing agent used
`reduce the rate of sedirnentafion
`
`Definition
`
`agar
`bentonite
`
`Examples
`
`114
`
`Dosage Form Design
`
`E S
`
`mgredient Type
`
`uspeoding Agent
`
`Table 4-2. Continued
`
`
`
`
`Used to impart sweetness to a
`preparation.
`
`Tablet Aniiadhermts
`
`carbomer (e.g._. Carbopol}
`of {drug} particles dispersed
`carboxymethylcellrflose sodium
`throughout a vehicle in which
`hydroxyelhyl cellulose
`they are not soluble. The resultant
`
`hydroxy'propyl cellulose
`suspensions may be fomiulated
`
`hydroxypropyl methylcellulose
`for use orally, parenterally,
`
`kaolin
`ophthalmically, topically, or by
`
`other routes.
`methylcellulose
`tragaoanth
`
`
`
`
`veegum
`
`
`
`Smetmr‘ng Agmt
`aspartame
`
`dextrose
`
`glycerin
`
`marmitol
`saccharin sodium
`
`sorbito]
`
`sucrose
`
`
`magnesium stearate
`
`Agents which prevent the sticking
`talc
`of tablet formulation ingredients
`
`to punches and dies in a tabletirig
`
` machine during production.
`
`Substances used to cause adhesion
`acacia
`Tablet Binders
`
`
`alginic acid
`carboxymethylccllulose sodium
`compressible sugar leg, Nu-
`Tab)
`ethylcellulose
`gelatin
`liquid glucose
`methylcellulose
`povidone
`
`pregelatinized starch
`
`of powder particles in tablet
`granulations,
`
`lrlert substances used as fillers to
`create the desired bulk, flow
`Properties, and compression
`charactei-istica in the preparation
`of tablets and capsules.
`
`
`
`
`
`djbasic calcium phosphate
`kaolin
`lactose
`marmitol
`
`
`
`l
`
`Tablet and Capsule Effluent
`
`
`
`microcrystalfine cellulose
`powdered cellulose
`precipitated calcium carbonate
`sorbitol
`
`starch
`
`
`
`

`

`
`Ingredient Type
`Doinitisn
`Used to coat a fanned tablet for the
`
`Tablet Casting Agent
`
`
`
`Dosage Form Design
`
`
`Examples
`
`sugar coating:
`liquid glucose
`sucrose
`
`film coating:
`hydroxyethyl cellulose
`hydroiqrproPyl cellulose
`hydroocypropyl methylcellulose
`methylcelluloae (e.g., Methocel}
`ethylcelhdose (efg.I Ethocel}
`mtm‘r coating:
`cellulose acetate phthalate
`shellac (35% in alcohol,
`“pharmaceutical glaze“)
`
`Purpose of protecting against
`drug decomposition by
`amm3pheric oxygen or humidity,
`to profide a desired release
`pattern for the drug substance
`after adnfinistration, to mask the
`taste or odor of the drug
`substance, or for aesthetic
`purposes. The coating may be of
`various types, including sugar-
`coafing, 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
`emetic—coated tablet or head will
`pass through the stomach and
`break up in the intestines. Same
`coming-s that are water-firmloble
`leg” ethylceilulose) may he used
`to coat tablets and beads to slow
`
`
`
`the release of drug as they yam
`
`through the gastrointestinal tract.
`
`dibasic calcium phosphate tag,
`Used in direct compression tablet
`Tablet Direct Compression
`Ditab)
`formulations.
`Excipienl
`
`Tablet Disintegrant
`
`Used in solid dosage forms to
`promote the dismption of the
`solid mass into smaller particles
`which are more readily dispersed
`or dissolved.
`
`alginic acid
`ca'rboxymethyIcellulose calcium
`micromystalline cellulose (e.g.,
`Avicel)
`
`polacrilin potassium (e.g.,
`Amberlite)
`sodium algi'na'te
`sodium starch glycollate
`starch
`
` Table 4—2. Continued
`
`
`
`Tablet Glfdaut
`
`Tablet Lubricant
`
`Agents used in tablet arid capsule
`formulations to improve the flow
`properties of the powder odxmrc.
`Substances used in tablet
`formulations to reduce friction
`
`during tablet compression.
`
`colloidal silica
`cornstarch
`talc
`
`calcium stearate
`
`magnesium stearate
`mineral oil
`stearic acid
`zinc stearate
`
`
`
`Tablethcpsule Dpaquant
`
`Used to render a capsule or a tablet
`coating opaque. May be used
`alone or in combination with a
`colorant.
`
`titanium dioxide
`
`Tablet Pollshmg Agent
`Used to impart an attractive sheen
`to coated tablets.
`
`carnauba wax
`white Wax
`
`
`
`r/!52
`p. 41
`
`

`

`
`
`116
`
`Doug: Fm Design
`
`
`
`l
`
`.
`Vehicle
`
`
`
`
`
`
`
`Table 4-1. Continued
`
`
`Ingredient Type
`
`
`
`Tonicity Agmt
`Used to render a solution similar in
`
`osmotic characteristics to
`
`physiologic fluids. Ophthalmic.
`parenteral, and irrigation fluids
`
`are examples of preparations in
`which tortidty is a consideration.
`
`
`_
`
`
`FleunrertISweetmed
`A carrying agent for a drug
`Acacia Symp .1”
`substance. They are used in
`
`
`
`Aromatic Syrup
`formulating a variety of liquid
`
`
`dusage for oral and parenteral
`Aromatic Bird:
`
`administration Generally, oral
`Cherry Syrup
`
`
`
`liquids are aqueous preparations
`Cocoa Syrup
`
`
`
`{as syrups) or hydmalcohollc (as
`Orange Syrup
`Elixirs). Parenteral solutions for
`Syrup
`
`
`intravenous use are aqueous.
`Olrogincms
`
`
`_
`whereas intramuscular infections
`Com Oil
`
`
`
`may be aqueous or oleagmoun.
`Mineral 01]
`
`
`
`
`Sesame on
`Sterile
`Bacterioslatic Sodium
`
`Chloride spam
`
`Bactmiostatic Water
`
`__
`for Injection
`
`Viscosity Increasing Agent
`Used to change the consistency of a
`alginic acid
`
`
`bentonite
`preparation to render it more
`
`
`resistant to flow. Used in
`carbomer
`
`suspensions to deter
`carboxymethylcellulose sodium
`
`
`sedimentation. in ophthalmic
`methylcellulose
`solutions to enhance contact lime
`povidone
`
`
`03.3., methylcelltdoael, to tlfickon
`sodium alginate
`
`
`
`”Esau-nth
`topical HEELS, Eh;
`
`
`
`
`
`
`
`
`book of Phomaceulical Excipients} which presents
`monographs on about 150 excipieots used in
`pharmaceutical dosage form preparation In-
`cluded in each monograph is such information
`as: nonpropfietary, chemical, and commercial
`names; empirical and chemical formulas and
`molecular weight; pharmaceutic specifications
`and chemical and physical properties; inoompat—
`ibilifies and interactions with other excipieMs
`and drug substances; regulatory status; and ap—
`plications in pharmaceutic formulation or tech—
`nology.
`There is great interest nowadays in the inter—
`national ’mamonization” of standards applica-
`ble to pharmaceutical excipients. This is due to
`the fact that the pharmaceutical industry is mul-
`tinational, with major companies having facili—
`ties in more than a single country, with products
`sold in markets worldwide, and with regulatory
`
`approval for these products generally required
`in each individual country. Standards for each
`drug substance and excipient used in pharma—
`ceuficals are contained in pharmacopeias—or,
`for new agents, in an application for regulatory
`approval by the FDA or another nation’s govern-
`ing authority. The four pharrnacopeias with the
`largest international use are the United States
`PharmacopeiflfNatfonfll Fonnulary (USP/NF], Brit-
`is}: Pharmacopcio (31"), European Phnnnacopein
`(HP), and the Japanese Phannncopeth UP). Uniform
`standards for excipients in these and other phar—
`macopeias would facilitate production effi—
`Clancy, enable the marketing of a single .Eorrnula—
`tion of a product internationally, and enhance
`regulatory approval of pharmaceutical products
`worldwide. The goal of harmonization is an on—
`going effort undertaken by corporate ropresenta-
`lives and international regulatory authorities.
`
`r/!53
`p. 42
`
`D
`As indic:
`mgrEdlents
`sired dosag
`these agent
`.
`phyelcal a
`product or
`taste. Othe
`the stabilit
`_
`against lhe
`In each ms
`client “1115‘
`U35: from
`the patriot
`There or
`{ion of p11
`drugs sub}
`hops the n
`Ye“.
`.9
`“33mm 53
`Ms W
`from 3‘81
`be accent;
`tective co;
`maintalm
`ers. ltrs m
`by noticir
`a bottle 0!
`water car
`the fonr'u.‘
`uids such
`1101. In C
`vegetable
`to reduc:
`
`lion.
`DECO!“
`“'11th ft
`"id form
`“Eh-id? '
`aqueous
`1313’ for
`an aqua
`be supp!
`reconstfll
`purified
`pOWdEI
`mixture
`flavoran
`tuted b)
`pension
`period i
`somed.
`for mos
`
`

`

`Drug Product Stability
`
`As indicated previously, many pharmaceutic
`ingredients may be utilized in preparing the de—
`sired dosage form of a drug substance. Some of
`these agents maybe 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 oxidatiye processes.
`In each instance, the added pharmaceutic ingre-
`dient must be compatible with and must not de-
`tract from the stability of the drug substance in
`the particular dosage form prepared.
`'Ihere are several approaches to the stabiliza—
`tion of pharmaceutical proparations containing
`drugs subject to deterioration by hydrolysis. Per—
`haps the most obvious is the reduction, or better
`yet, the elimination of water from the pharma-
`ceutical system. Even solid dosage forms con-
`taining water-labile drugs must be protected
`from the humidity of the atmosphere. This may
`be accomplished by applying a waterproof pro—
`tective coating over tablets or by enclosing and
`maintaining the drug in tightly closed contain
`era. 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—
`uids such as glycerin, propylene glycol, and alco
`ha].
`in certain injectable‘ products, anhydrous
`vegetable oils may be used as the drug's solvent
`to reduce the chance of hydrolytic decomposi-
`lion.
`
`Decomposition by hydrolysis my be pre
`vented for other drugs to be administered in liq—
`uid form by suspending them in a nonaqueous
`Vehicle rather than by dissolving them in an
`aqueous solvent. In still other instances, particu—
`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
`nuance of the antibiotic, suspending agents,
`flavor-ants, and colorants, which, when reconsti-
`tuted by the pharmacist, remains a stable ans:
`pension or solution of the drug for the time
`period in which the preparation is normally con-
`sinned. Storage under refrigeration is advisable
`for most preparations considered unstable due
`
`DosageFomDen’gn
`
`1.1?
`
`to hydrolytic causes. Together with temperature,
`pH is a major determinant in the stability of a
`drug prone to hydrolytlc decomposition The hy-
`drolysis of most drugs is dependent upon the
`relative concentrations of the hydroxyl and hy-
`dronium ions, and a pH at which each drug is
`optimally stable can be easily deters-timed. For
`most hydrolyzable drugs the pH of optimum sta-
`bility is on the acid side, somewhere between
`pH 5 and 6. Therefore, through judicious use of
`buffering agents, the stability of otherwise un-
`stable compounds can be increased.
`Phannaceutically, the oxidation of a suscepti-
`ble drug substance is most likely to occur when
`itis mahitainedinotherthanthedrystateinthe
`presence of oxygen, exposed to light, or com-
`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-
`dant with an alteration in the color of that prepa-
`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-
`bility of the drug is preserved by agents called
`antioxidants, which react with one or more com—
`
`pounds in the drug to prevent progress of the
`chain reaction. In general, antioxidants act by
`providing electrons and easily available hydro—
`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
`(NazSOal. sodium bisulfite (Nail-1503), hypo-
`phosphorous acid (HaPOI), and ascorbic acid In
`oleaginous (oily or unctuous) preparations, at"
`phatocoPherol, butylhydroxyarfisole, and ascor~
`by} 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 entities have been added to the final dos-
`
`age form. Sulfites are used as presuvatiVes in
`many injectahle 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—
`pose of the regulation is to protect the estimated
`0.2% of the population who suite: allergic reac-
`tions from the chemicals. Many of the sulfite—
`sensitive persons suffer from asthma or other a1-
`lergic conditions. Previous to the regulations
`
`sodium
`
`y reouired
`‘s for each
`
`n pharma-
`peias—or,
`
`i's govern—
`s with the
`int States
`
`INF}, Brit»
`armowpeia
`l. Uniform
`
`+ther phar-
`ttion effi-
`e formula-
`:l enhance
`
`lproducts
`1 is an on-
`
`apresenta-
`horities.
`
`r/!54
`
`

`

`
`
`
`
`LE
`
`ry
`
`n the phar-
`adensively
`one as well
`tion sched~
`
`[uality con-
`ition, there
`
`working of
`lity control
`rate labors:
`
`operations
`sms. These
`lance with
`
`Itions, pro-
`rt, and cost
`example of
`ndustry for
`
`devices in-
`ace manual
`
`ytical sam-
`
`idle-y, Adviser
`1troller (PLCJ.
`tortoperfcrmt
`
`'Dosags Form Design
`
`153
`
`
`
`Fig. 4—12. Robotics in laboratory use. Perkin-Elmer Robotic Am and Perkin-Elmer lambda 1a WW1? Spectrophotometer.
`(Courtesy of Elan Corporation, pic.)
`
`pling, and packaging. Figure 4—12 presents an
`example of the use of robotics in laboratory use.
`Laboratoryrobotics provides automationm such
`areas as sample preparation and handling, wet
`chemistry procedures, laboratory process con-
`trol, and instrumental analysis.31 Pharmaceutical
`applications include automated product han~
`dljng in production lines and in procedures as
`sampling and analysis, tablet content uniformity,
`and dissolution testing.
`Among the advantages cited for computer use
`and automation Within the pharmaceutical in-
`dustry areal“!
`'
`
`- increased productivity reducing labor
`- improved process and product quality
`- reduction in operator error and levels of prod-
`uct rejections
`- increased process yields {as from chemical syn-
`thesis of drug compounds)
`- enhanced repeatability of processes
`- improved operator protection due to less
`”hands on" activity
`- automated diagnostic and alarm actions alert—
`ing of possible mechanical malfunction, pro-
`cess decontrol or product defect
`- assist in process and product validation efforts
`- aesist in bookkeeping efforts
`° assist in scheduling efficacy
`- reduced cost per product unit
`
`Movement toward Paperless Electronic
`Records
`
`There is an effort underway by the FDA and
`the pharmaceutical industry to replace the tradi-
`
`tional use of paper with electronic systems to
`record, transmit, and maintain needed docu—
`mentation. This includes records developed by
`industry to support applications for drug prod-
`uct approvals—e.g., computer assisted new
`drug applications (CANDAS)-—and FDA inspec-
`tions for CGMP compliance.
`Among the regulatory and legal issues in-
`volved in the effort toward a paperless system
`are the authenticity, integrity, and security of
`electronic records, and the electronic means of
`replacing conventional handwritten signatures
`and initials, as required on reports and decu-
`ments to identify individuals having functional
`responsibility and operational authority.
`
`References
`
`H
`
`. Poole,J.W.: Prefomulation. FMC Corporation, 1982.
`2. Handbook of Pkarmceutical Excipienls. American
`Pharmaceutical Association, Wasldngton, DC,
`1986.
`3. Brange, ]'., Langkjaer, L., Havelund, 8., and Volund,
`A; Chemical Stability of Insulin. Hydrolytic Deg-
`radation During Storage of Pharmaceutical Prepa-
`rations. Pharm. Res, 9:715—726, 1992.
`4. Parrott, E.L.: Stability of Pharmaceuticals. I. Am.
`Pharm. Assoc, NSS:73‘76, 1966.
`5. Guidelinefor Submitting Documntatianfor the Stabil—
`ity inf-Human Drugs and Biologics, Food and Drug
`Administration, Rockville, MD, 1987.
`6. Lewis, R.: When Smell and Taste Go Awry. FDA.
`Canswner 25:29—33, 1991.
`7. Homstein, 1., and Teranishi, R.: The Chemistry of
`Flavor. Chem. Eng. News, 45:92—103, 1967.
`8. Murphy, D.H.: APracficalCompa'ldium on Sweet-
`em'ng Agents. Amer. Pharm, N523:32-37, 1983.
`
`
`
`r/!55
`p. 44
`
`

`

`24.
`
`26.
`
`2?.
`
`Compfiance Policy Guide. Food and Drug Adminis-
`tration, 1992.
`Resolution: Pharmacy Compounding and the
`Mamiachzring of Drugs. National Association of
`Boards of Pharmacy. 1992..
`38min en's Phomeceufical‘ Sciences, 19th ed., Eas-
`ton, P Mack 1’11ng (20., 1995.
`Allen, L.V., In: Extemporaneous Compounding in
`the 1998's. LLS. thnadaf, 14:58—64 1989.
`Allen. 1..V.. Jr.: Vehicles for Li d Oral Dosage
`Forms. LLS. Pharmacist 15:724-? 1991.
`Crawford 5.Y. and Demnlzlarmhole.I SR: Extempo
`raneous Compounding Activities and the Associ-
`ated Informational Needs of Pharmacists. Am. J.
`Hosp. Pharm, 43:1295—1218, 1991.
`Wiest D...B 831113.55.WPagncz,L.R and Zeigiee
`V.: Stability of I-‘lecairdde Acetate in an Extempote-
`neously Componnded Oral Suspension. Am. J.
`Hosp. Phone. 49:1467—1470 1992.
`Guidelines on Conng of Nmsterik' Products in
`Pharmacies. Amer. Society Hospital 91132111., Be-
`Lhesdehlfl) 1993.
`laboratory Robotics Handbook Zymark Corp. Hop—
`kinlon. MA. 1938.
`Praede. 13].: An Overview and Case Hieiofies of
`Computer Applimtions in a thtacentical [mine
`try. Proceedings. Eighfl: laminae! Good Mflnkfnc-
`luring Predicts Cookware, The Drivel-oily of Gear-
`gia. Athens, 1934.
`. Cornstock T..:A Computer Utilization in GM?
`ted Manufachn-ing.Procoedings, Seventeenth
`Intonalfomzf Good Men edurfizg Practice Confir—
`ence. The University of
`eorgia,gAthens, 1993
`
`29.
`
`31.
`
`32.
`
`154
`
`Dosage Form Dfiig'n
`
`9. Ineknowilz, AJJ Artificial 5mm How Safe
`Are They? ILLS. Phanmcfsf, 13:23—31, 1988.
`11}. Kmeger. 11.1., Topoieweld, M... and Havican, 5.: In
`Search of the Ideal Sweetener. Pharmacy Times.
`72—77,]111}! 1991.
`11. Locos, C.W.: Sweetness Minus Calories = Contro-
`versy. FDA Consumer, 19:18—23, 1935.
`12. Code of Failure! Regulations. Title 21, Parts 70-82.
`13. Colorants for Drug Tablets and Capsules. Drug and
`Cosmetic Industry, 13.3 (2)914, 1953.
`14. Code of Federal Regulations, Title 21, Part3 210—211.
`15. The Unite! States PM
`‘ 23,89on.13! Emu-—
`fury 13, The United States Pharmmpeial Conven-
`tion, Rockvflle, MD, 1995.
`16. Guideline for Submitting Dom mmfiefianfor Packaging
`of Human Drugs and Biologis. Food and Drug Ad-
`ministration. Rockvifle, MD 1987.
`1'7. The [Jailed States Phamecopefiz XXHINefiomI Fer—
`mulmy XVII, The United States Pharmacopeial
`Convention Rockville, 8183,1990 16364637.
`18. Smifii,D.L:Comp1iemePackaging:APafieotEdu~
`cation Tool. Amer. Pine-mu 1952931243, 1989.
`19. The United Slates Phermnmpeie ZifNefioml' Fame-
`lwy 18. The United States Pharmaoopeial Conven-
`tion. Rockvifle, MD,1995. 11.
`20. Code of Federal Regulations, TR]! 21, Parts 603—630.
`21. Code of Federal Regulations, Title 21, Part 328.
`22. Code of Feda'af Regulations, Title 21, Part 226.
`23. Manufacture, Distribufiml. and Promotion ofAdeHer—
`and. Mfubmnded, or 1.1me New Drugs for
`Human Use by SIate—Liemed Pharmacies—FDA
`
`
`
`WW ME:
`
`in dry for
`quently 1.1:
`13311th
`tion. and
`
`standpoin
`more stat
`and thus.
`
`Dry powd
`ing in we
`capsules 2
`patients if
`dosage fo
`ders are t
`skin. Whil
`tics is limi
`
`preparatic
`substance
`
`powdered
`dered mel
`
`prlor tofa'
`dared dn’
`
`ments. pa
`forms do:
`ules, whit:
`n'als Pm?
`are utilm
`
`andm drj
`tuted to 11
`
`of the am
`
`As a f
`(Latin. PHI
`and I or cl
`differenti:
`
`”130de
`used to c
`chemical
`
`A pow!
`ration, a
`
`product (
`prepared
`
`
`
`r/!56
`p. 45
`
`

`

`5
`
`Peroral Solids, Capsules, Tablets, and
`
`Controlled-Release Dosage Forms
`
`
`WHEN NIEDICA'l‘IONS are to be administered orally
`in dry form, capsules and tablets are most fre—
`quently used. They are effective and provide the
`patient with convenience of handling, identifica-
`tion, and administration. From a pharmaceulic
`standpoint, solid dosage forms are generally
`more stable than are their liquid counterparts
`and thus are preferred for poorly stable drugs.
`Dry powders are taken orally [usually after mix-
`ing in water} to a much lesser extent than are
`capsules and tablets, but are preferred by some
`patients who are unable to swallow the solid
`dosage forms. However, most medicated pow-
`ders are utilized as external applications to the
`skin. While the use of powders parse in therapeu—
`tics is limited, the use of powders in dosage form
`preparation is extensive. Most of the