CFAD EXHIBIT 1005
`
`

`
`Entered acmniing to Act of Congress. in the year 1885 by Joseph P Remington,
`in Lhe(){fice of the Librarian of Congresa at Washington: DC
`
`Copyright 1889, 1894, 1906, 1907, !9l'I, by Joaephf’ Remington
`
`Copyright 1926, 1936. by Joseph P Remington Estate
`
`Copyright 1948, 1951, by’I‘he Philadelphia College of Pharmacy and Science
`
`Copyright © 1956. 1960. 1965, 1970. 1975, 1951), 1986: by The Philadelphia College of Pharmacy and
`Scienu-2
`
`All Rights Reserved
`
`Library of Congress Catalog Catd No 6053334
`ISBN!)-91'II34'(Xi~.')
`
`The use 0/ purlmns 0/ the (ex! 0/ USP XX, NI"XV,nnd USAN and the URI’ !)irlz.'mmr)' Hf Drug
`Names is by p('rm1.»‘s1(2n 0/ the USP Com/en: ion. Tlw (‘mwmmuu as not rexpo uilwle for any
`znnrruracy uf quolulior: or /or any /also ul mslnk-adawt I/Hflficnlwli Um! may unsv from
`s('parah'un of excwpts [mm the uruemal context or by nbsulcscenu» rezvulting from
`publicamm 1.] a supplement
`
`NOTICE This (ext 15‘ not mlended to rep.1»‘sent. nor xhall it be interpreted (u be. thy rtquiualent
`of or a subsutute /ur the 0,/f<ual United States Pharmacopeia (USP) and/or Um Nntionai
`Formulnry (NF)
`In the even! 0/ any di//erence or d£.vcn'pam‘y I--‘In vow (he rurrvnl 0/firial
`USP or NI‘xtan.aaIds of strength, quality. purity, packaging and labelmg for drugs and
`represenlallbrts 0/ them hereimlhe cunlert and effect u/the of/icon! mmpendia aha]!
`prevail.
`
`Primed in the United States of America by 8111! Mack Printmg Company, Easton, Pvnrtsylvaniu
`
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`CHAPTER 90
`
`Oral Solid Dosage Forms
`
`
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`Drug substances are most frequently administered orally
`by meam of solid dosage forms such as tabletsand capsules.
`Large-scale production methods used for their preparation
`asdescribedlater in the chapter require the presence of otha
`materials in addition to the active ingredients. Additives may
`also be included in the formulations to enhance the physical
`appearance, improve stability, and aid in disintegration afier
`administration. These supposedly inert ingredients, as well
`as the production methods employed, have been shown in
`some cases to influence the release of the drug substances.‘
`Therefore care must be taken in the selection and evaluation
`
`‘
`
`of additives and preparation methods to ensure that the
`physiological availability and therapeutic efficacy of the active
`ingredient will not be diminished.
`Ina limited numberofcasesit hm been shownthatthedrug
`substance's solubility and other physical clnracteristics have
`influenced its physiological availability from a solid dosage
`form. These characteristics include its particle size, whether
`it is amorphous or crystalline, whether it is solvated or non-
`solvated, and its polymorphic form. After clinically effective
`formulations are obtained, variations among dosage units of
`a given batch. as well as batch-to-batch differences, are re-
`duced to a minimum through proper in-process controls and
`good manufacturing practices. The recognition of the im-
`portance d‘ validation both for equipment and processes has
`greatly enhanced assurance in the reproducibility of formu-
`lations. It is in these are: that significant progress lm been
`made with the realization that large-scale production of a
`satisfactory tablet orcapsule depends not only on the avail-
`
`
`
`Fig 90-1. Taoist N388 mentors dmockilg batch record it contor-
`mance with Ouronteood Msnmcturhgwsctlces (coutesy. Ully).
`
`ability of a clinically effective formulation but also on the raw
`materials, facilities, personnel, validated processes and
`equipment, packaging, and the controls used during and after
`preparation (Ft 90-1).
`
`Tablets
`
`Tablets may be defined as solid pharmaceutical dosage
`forms containing drug substances with or without suitable
`diluents and prepared either by compression or molding
`methods. They have been in widespread use since the latter
`part of the 19th century and their popularity continues. The
`term compressed tablet is believed to have been first used by
`John Wyeth and Brother of Philadelphia. During the same
`period molded tablets were introduced to he used as “hypo-
`dermic" tablet: for the extemporaneous preparation of solu-
`tions for injection. Tdilets remain popular asa dosage form
`because of the advantages afforded both to the manufacturer
`(es. simplicity and economy of preparation. stability. and
`convenience in packaging, shipping, and dispensing) and the
`Patient (eg, accuracy of dosage, compactness, portability,
`blandness of taste, and ease of administration).
`Although the basic mechanical approach for their manu-
`facture has remained the same, tablet technology has under-
`gone great improvement. Effortrare continually being made
`to understand more clearly the physical characteristics of
`tdilet compression and the factors affecting the availability
`01' the drug substance from the dosage form after oral ad-
`
`ministration. Compression equipment continues to improve
`both as to production speed and the uniformity of tablets
`compressed. Recent advances in tablet technology lave been
`reviewed.’—5
`Although tablets are more frequently discoid in shape, they
`also may be round, oval, oblong, cylindrical, or triangular.
`They may differ greatly in size and weight depending on the
`amount of drug substance present and the intended method
`of administration. Theyare divided into two general classes,
`whether they are made by compression or molding. Com-
`pressed tablets are usually prepared by large-scale production
`methods while molded tablets generally involve small -scale
`operations. The variom tablet types and abbreviations used
`in referring to them are listed below.
`
`Compressed Ts Nets (CT)
`These tablets are formed by compressionand unain no special costing.
`They are made from powdered. crystallire. or granular materiab. alone
`or in combination with binders. dilintegrants. lubricants, diluents, and
`in many cases. colorants.
`Sugar-Coated Tablets (SC'l')—'l"hese are compressed tablets con-
`Iairinga sugar coating. Such matings may be colored and are beneficial
`
`1603
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`

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`1606-
`
`G-IAPTER 90
`
`in covering up drug substances possessirg objectimable tastes or odors,
`and in protecting materials sensitive to oxidation.
`FilIn~Coued Tablets (PCT) These are compressed laliets which
`are ooveredwith a thin layerorfilmda water-sduble material. Anumber
`of polymeric substances with film forming properties may be used Film
`coating imparts the same generd characteristics as agar coating with the
`added advantrge of agreatly reduced time period required for the coating
`oper ation
`Bntalc-Coated Tablets (EC'l‘)—'l‘hese ue crlnpressed tablets coated
`with substances that resist aolutim in gastric lluid but disintegratein the
`intestine. Eateric coatirgs can be used for tablets containirg dng sub-
`aanaea which are inactivated or dedroyed in the stommh. fir those which
`irritate the mucosa, or as a means of delayed release of the medication
`Multiple Compressed ‘l‘ableta(I!Cl‘) Theseus oomprased tablets
`maid: by morre than onecomressirmcycle.
`by
`compressing additimal
`yered oblets—SucII
`lets are prqxared
`tablet granuhtion one previouly oompresed granulatiai.
`"Hue operation
`nary be repeated to produce multilayered tablets of two or three layers
`Special tablet presses are required I) make layered tablets such an the
`Va-as press (Stokes Pennwalr).
`Press-Coated 7'oblets- -Such tablets. also refened to as dry coated. are
`prepared by feedirg previously wmpresed tablets rntoa specialtsblaing
`machine and can
`g another erallulatim hpr armnd the prefomred
`tablets.
`'l1Iey have all the advantages of eompreued tablets. ie, slottirj,
`mootgralnrning, greed of diintegratlm. etc while retaining tln attributes
`cl sugar-mated tablets in nnskirg the taste of the drug substance in the
`core tablets. An aample of a press-coated tablet press is the Honesty
`Dryoots. Plea.-coated tablets eanaho be usodto scporoteinoosnpotiblc
`dug aubstancafin addition, they can provide ameam togise an enteric
`coating to the core tablets. Both types of multiple-compused taliets
`have been widely uad in the denial of prolonpd-action dosage forms.
`Ccrtrolled-Release Tablets—Compreseed tablets can be fornulated
`to rdease the dny substame inamannerto provide medication our :1
`period of time.
`'l‘here are a number of types which include deh
`tablets hwhiehthe releasedthe dng aubstaneeis prevuated branin
`terval of time afteradministratlon or until certain physiologiml conditions
`exist: repeat action tdilets which periodically release a complete doseof
`thedrug substance to the adrointestiral fluids: and theextended rdease
`or sustained refit: tablets which continuously release incremeria d’ the
`contained drug ulntanoe to the gastrointestinal fluids These tablets
`are discussed in C-hapter99.
`Tablets for Solution—Compressed tablets to be used for pl!‘-Daring
`solutions or imparting given charaderistlcs toaolutions must be labeled
`
`to indicate thatthey are not to beswallowed. Examples of these umlets
`are ‘Halasone Tablda for Solution and Potassium Permanganate Tablets
`for Solution.
`In addition so the drug substance. these con»
`Effervescent Tablets
`tab sodium bicarbmate and an orgmicacid suchas tartaric or citric.
`in
`the prsenoe of water, these additives react liberating mrbon dioxide which
`acts as a distintegrator and produces effervcscence. Except for small
`quantities of lubricants pruent. etlervescent tablets are soluble.
`Compressed Suppositories or Inserts-Occasionally vaginal sup-
`positories. such as Metronidarole Tablets, are prepared by compression.
`Tablets for this use usually contain lactose as the diluent.
`In this case.
`as well as for any tablet intended for administrationother than by swaI~
`lowing. the label must indicate 1 manner in which it is to beueed.
`Buccal and Sulilntual ‘Pallets These are small. flat, oval tablets:
`Tablets intended for buccal administration by inserting into the buccd
`pouch dissolve or erode slowly. therefore they are formulated and com-
`pressed with sufficient pressure to give a hard tablet. Propderoae
`Tablets rnaybeadministeredh thisway. Sublirgud tdrlebmuch as those
`cmtainirg nitrqlyoerin.
`isoproterenol hydrochloride. or erythrityl
`tetranitrate. are placed under the tongue. Sublirgual tablets dissolve
`rapidly and the dug substancesare readily absorbed by th form ofad
`ministration.
`
`Molded Tablets or Tablet Trlturatcs t'l"I')
`Tablet triturates are usually made from moist materialusing a triturate
`mold which gives them the shapeof cut sedionsofa cylinder. Such tablets
`must be eomplotobr and rapidly oolublo. The problem arising from
`compressiai of these tablets is the failure to find a lubricant that is com-
`pletely water-soluble.
`Dispensing Tablets (Ul)—'l.'hese tablets provide a convenient
`quantity of poterl dng that can be incorporated readily into powders and
`l's]uide thuscircumventingthenecessity to weigh small quantities. Thee
`tablets are supplied primarily as a convenience for extemporaneous
`compounding and should never be dispensed u a dosage form.
`Hypodermlc Tablets (lfI‘l—Hypodermic tablets are soft, readily
`soluble tablets and were originally used for the preparation of solutions
`to be injected. Since stable parenterd solutions arenow available for most
`drug substances. there is nojustification for theuse of hypodermic tablets
`for injection. Tlnir use in thi manner slnuld be discouraged since the
`resulting solution: are not sterile. Large quantities of these tablets con-
`tinue to he made but for oral administration. No hypodermic tablets have
`ever been recognised by the oflicial compendia.
`
`carpressed Tablets (or)
`
`and is subsequently ejected from the die. The weight of the
`tablet is determined by the volume of the material which fills
`the die cavity. Therefore. the ability of the granulation to
`flow freely into the die is important in inst:-ing anuni form fill,
`as well as the continuous movement of the granulation from
`the source of supply or feed hopper.
`If the tablet granulation
`does not possess cohesive properties, the tablet after com-
`pression will crumble and fall apart on handling. As the
`punches must move freely within the die and the tablet must
`be readily ejected from the punch faces. the meter ial must
`have a degree of lubrication tominimize friction and to allow
`for the removal of the compressed tablets.
`(1)
`There are three general methods of tablet preparation:
`the wet.-granulation method; (2) the dry-granulation method;
`and (3) direct compression. The method of preparation and
`the added ingredients are selected in order to give the tablet
`formulation the desirable physical characteristics allowing
`the rapid compression of tablets. After compression the
`tablets must have a number of additional attributes such as
`appearance, hardness, disintegration ability, appropriate
`dissolution characteristics, and uniformity which are also
`influenced both by the method of preparation and by the
`added materials present in the fonnulation.
`In the prepa-
`ration of compressed tablets the formulator must also be
`cognizant of the effect which the ingredients and methods of
`preparation may have on the availability of the active ingre-
`dients and hence the therapeutic efficacy of the dosage form.
`In response to a request by physicians to change a dicumarol
`tablet in order that it might be more easily broken. a Canadian
`company reformulated to make a large tablet with a score.
`Subsequent use of the tablet containing the same amount of
`
`In order for medicinal substances, with or without diluents,
`to be made into solid dosage forms with pressure, using
`available equipment. it is necessary that the material, either
`in crystalline or powdered form. possess a number of physical
`characteristics. These characteristics include the ability to
`flow freely, cohesiveness and lubrication. Since most ma-
`terials have none or only some of these properties, methods
`of tablet formulation and preparation have been developed
`to impart these desirable characteristics tothe materialwhich
`is to be compressed into tablets.
`tablet-compression
`in all
`The basic mechanical unit
`equipment includes a lower punch which fits into a die from
`the bottom and an upper punch, having a head of the same
`shape and dimensions, which enters the die cavity from the
`top after the tableting material fills the die cavity. See Fig
`90-2. Thetabletisformedby essureappliedonthe punches
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`H990-2. Basic meehacicsuri tortablstoorrnression:
`me. and upper pinch (courtesy. Vectorlcoltcn).
`
`tower ranch.
`
`

`
`drug substance as the previous tablet, resulted in complaints
`that larger-than usual doses were needed to produce thesame
`therapeutic response. On the other hand. literature reports
`indicate that the reformulation of a conunercial digoxin tablet
`resulted in a tablet, although containing the same quantity
`of drug substance, that gave the desired clinical response at
`half its original dose. Methods and principles that can be
`used toassess the effects ofexcipients and additives on drug
`absorption have been reviewed .57 See Chapters 38. 76. and
`77.
`
`Tablet Ingredients
`
`In addition to the active or therapeutic ingredient. tablets
`contain a number of inert materials. The latter are known
`as adritives or excipients. They may be classified according
`to the part they playin the finished tablet. The first group
`contains those which help to impart satisfactory processing
`and compression characteristics to the formulation. These
`include (1) filuents. (El binders. and (-3) glidantc and Miri-
`mnts. The second group or added substances helps to give
`additional desirable physical characteristics to the finished
`tablet.
`Included in this group are (1) disintegrants. (2) colors,
`and in the case of chewable tablets, (3) flavors, and (4)
`sweetening agents.
`Although the term inert has been applied to these added
`materials, it is becoming increasingly apparent that there is
`an important relationship between the properties of the ex-
`cipientsand the dosage forms containing them.
`l’reformu-
`lation studies demonstrate their influence on stability. bio-
`availabiity. and the processes lg which the tissue forms are
`preparatl.
`'l'he need for acquiring more information and use
`slundnrdl for excipienta has heenreengnized in a jointventure
`of the Academy of Pharmaceutical Sciences and the Council
`of the Pharmaceutical Sodety of Great Britain. The program
`is called the Codex of Pharmaceutical Excipient Project and
`the Academy's industrial Pharmaceutical Technology Section
`has undertaker its organization and implementation.
`
`Diluents
`
`Frequently the single dose of the active ingredient is small
`and an inert substance is added to increase the bulk in order
`to make the tablet a practical size for compression. Com-
`pressed tablets of dexamethasone contain 0.75 mg steroid per
`tablet, hence it is obvious that another mrnerial must be added
`to malte tableting possible. Diluents used for this purpose
`include dicalcium phosphate, calcium sulfate. lactose. cellu-
`lose, lraolin, mannitol, sodium chloride. dry starch.and pow-
`dered sugar. Certain diluents, such as mannitol, lactose,
`sorbitoL sucrose. and inositol. when present in sufficient
`quantity. can impart properties to some comprsed tablets
`that permit disintegration in the mouth by chewing. Such
`tablets are commonly called chewable tablets. Upon chewing.
`properly prepared tableb will disintegrate smoothly at a
`satisfactory rate, lave a pleasant taste and feel.and leave no
`unpleasant aftertaste in the mouth. Diluents used as excip-
`ients for direct compression formulas have been subjected to
`prior processing to give them flowability and compressibiity.
`These are disctnsed under Direct Compression. p 1613.
`Most tablet formulators tend to use consistently only one
`or two diluents selected from the above group in their tablet
`formulations. Usually these have been selected on the basis
`of experience and cost factors. However, in the formulation
`of new therapeutic agents the compatibility ofthe diluent with
`the drug must be considered. Forexamplecalciumsalts used
`as diluents for the broad spectrum antibiotic tetracycline have
`been shown tointerfere with the drug's absorption from the
`gastrointestinal tract. When dmg substances have low water
`
`ORAL SOUD DOSAE FORMS
`
`1805
`
`solubility. it ‘I recommended that water-soluble diluents be
`used to avoid pofible bioavailebility problems. Highly ad-
`sorbent substanccs. cu. bentonite and kaolin. are to be uvtided
`in making tablets of drugs used clinically in small dosage.such
`as the cardiac glycosides, alkaloids, and the synthetic tro-
`gens. These drug substances may be adsorbed to the point
`where they are not completely avai lable aftcr ad ministration.
`The combination of amine bases with lactose. or amine salts
`with lactose in the presence of an alkaline lubricant, results
`in tablets which discolor on aging.
`Microcrystalline cellulose (Avicel) is usually used as an
`excipient in direct compression formulm. However.
`its
`presencein 5-15% concentratiom in wet granulations has been
`shown to be beneficial in the granulation and drying processes
`in minimizing case-hardening of the tablets and in reducing
`tablet mottling.
`
`Binders
`
`Agents used to impart cohesive qualities to the powdered
`material are referred to as binders or granulators.
`'l‘h'eyim-
`part a cohesiveness to the tablet formulation which insures
`the tablet remaining intact afier compression, as well as im
`proving the free-flowing qualities hy the formulation of
`granules of desired hnnlnfi and size. Materials commonly
`used as binders include starch. gelatin, and sugars as sucrose.
`glucose, dextrose. molasses, and lactose Natural and syn
`thetic gums which have been used include acacia. sodium al-
`ginate, extract of Irish moss, panwar gum, ghatti gum, muci-
`lage of isapol husks. carboirymethylcelluloee, methylcellulose,
`polyvinylpyrrolidone. Veegum. and larch arabogalactan.
`Other agents which may beconsidered binders under certain
`circumatanaa are polyethylene glycol. ethylcelluloee. waxes,
`water, and alcohol.
`The quantity of binder used has considerable influence on
`the characteristics of the compressed tablets. The use of too
`much hinder or too strong a binder will make a hard tablet
`which will notdisintegr-ate easily and which will causeexces—
`sive wear of punches and dies. Differences in binders used
`for CT Tolbutamide resulted in differences in hypoglycemic
`effects observed clinically. Materials which have nncohesive
`qualities of their own will require a stronger hinder than those
`with these qmlities. Alcohol and water are not hinders in the
`true sense of the word; but because of their solvent action on
`some ingredients such as lactose, starch, and celluloses. they
`change the powdered material to granules and the residual
`moiture retained enables the materials to adhere together
`when compressed.
`Binders are used both as a solution and in a dry form de
`pending on the other ingredients in the formulation and the
`method of preparation. The same amount of binder in so-
`lution will be more effective than if it were dispersed in a dry
`form and moistened with the solvent. By the latter procedure
`the binding agent is not as effective in reaching and wetting
`each of the particlcswithin the man of powtlers. Rnchnl‘ the
`particles iu a powder blend has a coating of adsorbed air out
`its surface. and it is this tilm which rnustbe penetrated before
`the powders can be wettcd by the binder solution. Sim:
`powders differ with respect to the one with which they can
`bewetted. it is preferable to incorporate the binding agent. in
`solution. By this technique it is often possible to gain effec-
`tive binding with a lower concentration cs‘ binder.
`It shodd
`be noted that there are several “pregelatinined" starches
`available which are intended to be added in the dry form so
`that water alone can be used as the granulating solution.
`The direct compression method for preparing tablets (see
`page 1613) reqiirm a mataial that not only is free-flowing but
`also sufficiently cohesive to act as a binder. This use has been
`described for a number of materials including microcrystalline
`cellulose, microcrystalline dextrose. amylase, and polyvinyl
`
`
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`__g
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`1606
`
`CHAPTER 90
`
`It ha been postulated that microcrystalline
`pyrrolidone.
`telluloseis aspecial form of celluloaefihril in which the indi-
`vidual crystallita are held trxether largely by hydrmen
`bonding.
`'I‘he disintegration of tablets containing the cello -
`lose occurs by breaking the intercrystallite bonds by the dis-
`integrating medium.
`Starch Paste-—Corn starch '3 widely used as a binder. The
`concentration may vary from 10 to 20% It is usudly prepared
`as it is to be used by dispersing corn starch in sufficient cold
`purified water to make a 10% w/w solution and warming in a
`water bath with continuous stirring until a translucent paste
`forms.
`Gelatin Solution Gelatin '3 generally used as a 10 flflb
`solution; gelatin solutions should be freshly prepared as
`needed and used while warm tl‘ they will solidify. The gelatin
`is added to cold purified water and allowed to stand until it
`'3 hydrated. It is then warmed in water bath to dhsolve the
`gelatin and the solution '3 made up to the final volume on a
`weight basis to give the concentration desired.
`Glucose Sol ution—Generally a 25 50% solution '3 used
`Glucose does not dry out well and is therefore not suitable
`where the tablets are subject to humid conditions. These
`solutions are not true 25 and 50% solutions since the corn
`syrup contains only approximately 80% solids. To prepare
`the binder solution. the corn syrup '3 weighed and dissolved
`in purified water. Sufficient purified water is added to give
`the concentration desired on a weight basis.
`If clarifiution
`is desirable. it can he strained through cloth.
`It is used ef-
`Ethylcellulose—'l‘his is insolublein water.
`fectively as a binder when dissolved in alcohol. or as a dry
`binder in agranulation which is then wetted withalcohol. As
`a binder in solution it is usually used as a 5% solution.
`It is
`widely used as a binder for moistureserisitive materials. To
`make the solution. ethylcellulose is dissolved in anhydrous
`denatured alcohol and made up to tie final volumeon a we'ght
`basis.
`PVP Polyvinylpyrrolidone can be used asan aqueous or
`an alcoholic solution and this versatility has increased its
`popularity. Concentrations range from 2% and vary consid-
`erably.
`It will be noted that binder solutions are mually made up
`to weight rather than volume. This is to enable the formu-
`lator to determine the weight of the solids which have been
`added to the tablet granulation in the binding solution. This
`becomes part of the total weightof the granulation and must
`be taken into consideration in determining the weightof the
`compressed tablet wlu'ch will contain the stated amountof the
`therapeutic agent.
`
`Lubricants
`
`Lubricants have a number at’ functions in tablet manufao
`tore. They prevent adhesion of the tablet material to the
`surface of the dies and puncha. reduce interparticle friction.
`facilitate the ejecthn of tie tableu from the die caviy, and
`may improve the rate of flow of the tablet granulatioo.
`Commonly used lubricants include talc. magnesium staarate,
`calcium stearate.stearicacid.and hydrrgenated vegetnbleoils.
`Most lubricants with the exception of talc are used in con-
`centrations less than l%. Mien med alone. talc may require
`concentrations as high as 5%. Lula-icants are ‘I: most cmea
`hyd aiphobic materials. Poor selection or excenive amounts
`can result ii "waterproofing" the tablets. resulting in poor
`tablet disintegral ion and dissolution of the drug substance.
`The addition of the proper lubricant is highly dedmble if
`the material to he talileted tends tosticlr to the puncha and
`dies.
`Immediately after compression niust tablets have the
`tendency to expand and will hind and stick to the sideof the
`die. The choice of tie proper lubricant wiil effectively over
`some this.
`
`The method of adding a lubricant to a granulation is im-
`portant if the material is to perform its function satiafactaily,
`The lubricant should be finely divided by passing it through
`a 60 to 1(X)—mesh nylon cloth onto the granulation.
`in pro-
`duction this is called “bolting" tin lubricant. Alter adding
`the lubricant the granulation is tumbled or mixed lently to
`distribute the lubricant without coating the particles too well
`or breaking them down to finer particles.
`Prolonged blending of lubricant with a granulation can
`materially afl'ect. the hardneai. disintegration time and dis-
`solution performance for the raultant tablets.
`'I‘he quantity
`of lubricant vnria. being a low as 0.1%. and in some cases as
`high as 5%. Lubricants have been added to the granulating
`gents in the form of suspensions or emulsions.
`'Hiis tech-
`nique serves to reduce theaumluer of operational procedures
`and thus reduce the proceuing time.
`ln selectinga lubricant. proper attention must hexiven to
`its compatibility with the drug agent. Perhaps the most
`widely investigated drug in acetylsalicylic acid. Dil't'erent tales
`varied significantly the stability of aspirin. Talc with a high
`mlcium cmtentanda high larson
`wasamociesed with
`increased aspirin decomposition. Frarn astabilitystandpoint.
`the relative acceptability of tablet lubricants for combination
`with aspirin WI3 found to decrease in the following order;
`hydrogenated wgetabla oil. stearic acid. talc. and aluminum
`stearate.
`
`The primary problem in the preparation (I a water soluble
`tablet '3 the selection of a satisfactory lubricant. Soluble
`lubricants reported to be effective include sodium benzoate,
`a mixture of sodium benzoate and sodium acetate, sodium
`chloride. leucine. and Carbovraa 4000. Howeverjthas been
`suggested that formulations need to prepare water-soluble
`tablets may represent a nlnnber of cornprcrniaea between
`compression efficiency and water solubility. While magno-
`aium stearate is one of the most widely ined lubricants. is
`hydnrphobic properties can retard disintegration and disso-
`lution. To overcome these waterproofing charactu-istics
`sodium lau ryl sulfate '3 sometimes included. One compound
`found to have the lubricating properties of magnesium stea-
`rate without its disadvantages is magnesium lauryl sulfate.
`Its safety for use in pharmaceuticals has not yet been estab-
`lished.
`
`Glidants
`
`A glidant is a substance which improves the llow charac
`leristics of a powder mixture. These materials are always
`added in thedry state justprior to compression (ie. during the
`lubrication step). Colloidalsilison dioxide [Cab-o-sil (Cabot):
`Quso (Phila Quarlz)l is the most commonly med gliclant and
`is generally used in low concentrations of l% or less. Talc
`(asbestos-free) is also used and may serve the dual purpose
`as lubricant/glidant.
`
`Diainleflton ts
`
`A disintegranl. is a substance. or a mixture of substances.
`added to a tablet to facilitate its breakup or disintegratbn
`after administration The active ingredient must be released
`from the tablet matrix as efficiently as possible to allow for
`its rapid dissolution. Materials serving as disintegrants have
`been chemicallyclamified asstarches. clays, celluloaca. algirls.
`gums. and cmsslinlted polymers.
`Tle oldest and still the most pqiular dkinlegrnnts are com
`and potato starch wh.ich have been well—rlrierl and powdered.
`Starch has a great affinity for water and swells when mois-
`tened. thus facilitating the rupture of the tablet. matrix.
`However. others have suggested that its didntemating action
`in tablets '3 due to capillary action rather than swelling; the
`spherical shape of the starch grains increases the porosity of
`the tablet. thus promoting capillary action. Starch. 5% is
`
`

`
`suggested. but if more rapid disintegration is desired. this
`amount may be increased to 10 or l5‘la. Although it might be
`expected that disintegration time would decrease as the per-
`centge of starch in the tablet increased, thiedoes not appear
`to be the cue for talbutaruide tablets.
`In this instance. there
`appears to be a critical starch concentration for different
`granulations of the chemical. When their disintegration ef-
`fect is desired, starchesare added to the powder blends in the
`thy state.
`A newgroup of materials known as "super disintegrants"
`have recently gained in popularity as disintegrating agents.
`Tia name comesfrom the low levels (24%) at which they are
`completely effective. Croscarmelose. Croapovidone. and
`sodium starch glycolate rqrreaent examples of a crosslinked
`celluiose, a crosslinked polymer. and a modified starch mol-
`ecule, respectively.
`In addition to the starches a large variety of materials have
`been used and are reported to be effective as disintegrants.
`This group includes Veegum l-IV. methylcellulose. agar.
`bentonite. cellulose and wood products. natural sponge. cat-
`ion-exchange resins. alginic acid.goar gum. citrus pulp. and
`carboxymetluylcellulose. Sodium lauryl sulfate in combina-
`tion withstarch also has been demonshated to be an effective
`disintegrsnt.
`In some cases the apparent effectiveness of
`surfactants in improving tablet disintegration is postulated
`as being due loan increase in the rate of wetting
`The disintegratirg agent is usually mixed with the active
`ingredients and diluents prior togranulation.
`in some cases
`i may be advantageous todivide thestarch into two portions;
`one part is added to the powdered formula prior to granula-
`liar. and the remainder is mixed with the lubricantand added
`prior to compression.
`Incorporated in this manner the starch
`serves a double P119030: the portion added to the lubricant
`rapidly hredts the tablet down to granules. and the starch
`mixed with the active ingredients disintegrate: the granules
`into smaller particles. Veegum has been shown to be more
`effective as a disintegrator io suilfathhisole tdilets when most.
`of the quantity is added after granulation and only asrnall
`amount before granulation. Likewise. the montmorillonite
`clays werefound to begood tabletdisintegranta when added
`to prepared granulations as powder.
`'l'hey are much less ef-
`fective rn cisintegrants when incorporated within the gran-
`ules.
`Fmtors other than the presence of disintegrants can affect
`significantly the disintegration time of compressed tablets.
`The binder, tablet hardness. and the lubricant have been
`shown to influence the disintegration time. Thus. when the
`fonnulator is faced with a problem concerning the disinte-
`gration of acompressed tablet, the answer may not lie in the
`selection and the quantity of the disintegrating agent
`alone.
`The evolution of carbon dioxide is also an effective way to
`cause the disintegration tl