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`• PROPERTY OF
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`of Raleigh
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`Exhibit 1028
`ARGENTUM
`IPR2018-00080
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`Entered according roAct of Corigress; in'the year:1885.by4.16-ScPli P Rem.f•
`in the Office of the Librarian of:CongreSS; atWasitingtort DC
`. (cid:9)
`:• (cid:9)
`• (cid:9)
`-
`
`Copyright 1889,1894, 1905, 1907,1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharm arid Scierk0
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by The Philadelphia College of
`Pharmacy and Science
`
`ii
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`The use of structuralformulas from USAN and the USP Dictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia (USP) and/or the National
`Formulary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`representations of them herein, the context and effect of the o fficial compendia shall prevail.
`
`' (cid:9)
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`Printed in the United,State,sr mertc;_ct by the Mack Printing Company, Eastoii, Pennsylnania
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`CHAPTER 92
`
`Oral Solid Dosage Forms
`
`Edward Rudnic, PhD
`Vice President, Pharmaceutical Research and Development
`Pharmavene, Inc.
`Gaithersburg:MD 20878
`
`Joseph D Schwartz. PhD
`.
`lice Professor of Phormoce,utics (cid:9)
`Philadelphia College of Pharmacy end Science
`Philadelp,hio, PA 19104
`
`Drug substances most frequentlyare administered Orally by
`Means of solid dosage forms such as tablets and capsules.
`Large-scale production methods used for their preparation, as
`described later hi the chapter, require the presence of other
`materials in addition to the active ingredients. Additives also
`may be included' in the formulatiOns -to facilitate handling,
`enhance the physical appearance, improve stability and aid in
`the delivery of the drug to the bloodstream after administration.
`These supposedly inert ingredients, as well as the production
`methods employed, have been shown in some cases to influ-
`enee the absorption or bioavailabffity Of the drug Siibstanees.1
`Therefore, care must he taken in the selection and evaluation
`Of additives and preParatipn methods:to ensure, that the drug-
`delivery goals and therapentic efficaey of the active ingredient
`will not be diminished. .
`, (cid:9)
`,
`In a limited number of cases it has been shown that the drug
`substance's solubffity and other physicOchemical characteriST
`tics have. influenced its physiological availability from a solid
`dosage form., These characteristics include its particle size,
`whether it is ,arnorphcius or crystalline, whether it is-solvated
`or nonsolvated and its polymorphic form: After clinically
`effective formulations-.are:obtained, such variations: among
`dosage units' f a given batch, as Well as batch-to-batch differ-
`ences, -should be reduced- to a. mininiumAhrough proper in-
`process controls and good manufacturing practices. The
`recognition of the intortante -of validation both for equip-
`ment and processes greatly 'has enhanced assurance in the
`reproducibility of formulations. It is in these areas that sig-
`nificant progress has been made with the realization that
`large-scale production of a satisfactory tablet or Capsule 416,
`pends not only on the availability of a clinically effective
`
`Fig 1..:crablet pressoperators checking batch -record in conform-
`ance with Current Good ManufaCtu ring Pfabtices (courtesy Lilly)...
`
`formulation but also on the raw materials, facilities, person-
`nel, documentation, validated processes and equipment, pack-
`. aging and the controls used during and after preparation
`(Fig 1).
`
`Tablets may be defined as solid Pharmaceutieal dosage
`forms containing drug substances with or without suitable
`diluents and prepared either by compression. pr 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 used first by.
`JobnWyeth and E5rother. of Philadelphia. DUring this same
`period, molded tablets were introduCed to be used as hpocler-
`mit tablets for the extemporaneous Preparation of soliitions
`for:injection. Tablets remain popular as a.dosage form be-
`cauSeofr.t.h.,advantages.. affoidea bod,.td'Oe.mantifactuter
`(eg, simplicity and economy of preparation,' 'stability and con-
`venience in packaging, shipping and dispensing) and the pa-
`_
`tient (eg, aecuraey of dosage,compactnesS, pOrtability, bland-
`ness
`of taste
`(cid:9) ease of administration).
`Although-the basic mechanical.approach for their manufac-
`ture hag remained the same, tablet technbrogy hailindergone
`great improvement. Efforts are being made continually to
`understand more clearlythe physical charaeteristics of pow7
`der compaction and:the factors affecting the:availability, of the
`
`cling SubStance frorrillie doSage forrn after Oral administration.
`Tableting equipment continuegta improve both as to Produc-
`tion speed:and the Unifotrhity of tablets compressed. Recent
`advances in tablettechnology have been revieWed.2-13
`Although tablets frequently are diScoid in shape, they also
`may be round, oval, oblongc cylindrical or triangular. They
`May differ greatly in size and'weight depending on the amoiint
`Of drug "-substance 'present and • the intended method of
`administration. They are, divided'into ttwo general classes;
`whether they are made by compression or molding. Com-
`pressed tablets. usually are prepared by large-scale production
`Methods, while, molded tablets generally involve small-scale
`operations: The various tablet types and abbreviations used
`in referring to them are listed below..
`
`ThesetableiS are formed-Ely eornpressidh and contain no Special coating.
`They:afe madel from powdered, 'crystalline or granular materials, alone or
`in Combination with binders; disiritegxants;'controlled‘release polymera,
`lubricants, dibientSancl, inraanY cases, colorants, .
`
`1615
`
`000003
`
`

`

`1 61 6 (cid:9)
`
`CHAPTER 92
`
`Sugar-Coated Tablets (SCT)—These are compressed tablets contain-
`ing a sugar coating. Such coatings may be colored and are beneficial in
`covering up drug substances possessing objectionable tastes or odors, and
`in protecting materials sensitive to oxidation.
`Film-Coated Tablets (FCT)—These are compressed tablets which
`are covered with a thin layer or film of a water-soluble material. A number
`of polymeric substances with film-forming properties may be used. Film
`coating imparts the same general characteristics as sugar coating with the
`added advantage of a greatly reduced time period required for the coating
`operation.
`Enteric-Coated Tablets (ECT)—These are compressed tablets coated
`with substances that resist solution in gastric fluid but disintegrate in the
`intestine. Enteric coatings can be used for tablets containing drug sub-
`stances which are inactivated or destroyed in the stomach; for those which
`irritate the mucosa or as a means of delayed release of the medication.
`Multiple Compressed Tablets (MCT)—These are compressed tab-
`lets made by more than one compression cycle.
`Layered Tgblets—Such tablets are prepared by compressing addi-
`tional tablet granulation on a previously compressed granulation. The
`operateOMMay be repeated to produce multilayered tablets of two or three
`SPecial tablet presses are required to make layeredtabletS' such
`•
`as the yetsa presS(Slokes/PenfrzwalL). (cid:9)
`Tablets-7-SuchOblas, alSoi'eferred to as dry-coated, are
`prepared by feeding previously compressed tablets-into a special tableting
`(cid:9)the preformed
`machine and compressing another granulation layer
`tablets. They have all the advantages of compresSeritablets, ie, slotting,
`monogramming, speed of disintegration, etc, while retaining the attributes
`of .sugar.:cbated tablets in masking the taste of the.diug substance iMthe
`core` tablets. An eXample of a hress-Poated tablet press is the ManOty
`Hrycota. Press-coated tablets alsO can be used to separate incompatible
`(Ong Substances; in addition; they can provide a means to give an enteric
`coating to the"core tableta. iDtth types of multiple-compressed tablets
`haVe been used widely in thedealgrrof prolOngerbaction dosage forms.
`'1C.Ontrolled4teteaseffablets;t---Corripressed tablets can be formulated
`tOrelealesthe drug sloWlY over prolonged period of time: ;Hence, these
`dosage ftirrnS have beetireferred'to as Protong6:4-/elease or Stisiciiried-
`Relgos0460..0, forms asivell. These tablets (as well as, capSuleyerliOris)
`Canlie'dategorizedntothree types; (1) those .1.Vhich respond to some
`physiological condition to Mease the' drug, such -,ai.enteric coatings (2)
`thoSe that releasethe drug in relatively steady; 'controlled manner and;(0)
`thOse that ciiiribine cOmbinations of mecbaniSrn.s to release;"pulsein of
`drug, such as Tepeat-action tablets: 'The erferinance. of these systems
`
`• (cid:9)
`• • (cid:9)
`•
`are described in more detail in Chapikk. 94; • (cid:9)
`•
`. (cid:9)
`, (cid:9)
`• (cid:9)
`Tablets-fbr sSolution—COmpressed. tablets" to be used- for preparing
`solutions or imparting given characteristics to solutions must beIabeled to
`indicate that theyare not to be swallowed. Examples of these tablets are
`Halazone Tablets for Solution and Potassium Permanganate Tablets for
`Solution.
`
`Effervescent Tablets—In addition to the drug substance, these con-
`tain sodium bicarbonate and an organic acid such as tartaric or citric. In
`the presence of water, these additives react liberating carbon dioxide
`which acts as a distintegrator and produces effervescence. Except for
`small quantities of lubricants present, effervescent tablets are soluble...
`Compressed Suppositories or- Inserts—Occasionally, vaginal sup-
`positories, such as Metronidazole 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 administration other than by swallowing,
`the label must indicate the manner in which it is to be used.
`Buccal and Sublingual Tablets—These are small, flat, oval tablets.
`Tablets intended for buccal administration by inserting into the buccal
`pouch may dissolve or erode slowly; therefore, they are formulated and
`compressed with sufficient pressure to give a hard tablet. Progesterone
`Tablets may be administered in this way.
`Some newer approaches use tablets that melt at body temperatures.
`The matrix of the tablet is solidified while the drug is in solution. After
`melting, the drug is automatically in solution and available for absorption,
`thus eliminating dissolution, as, a: rate-limiting step in the absorption of
`poorly soluble compounds. Sublingual tablets,.such as those containing
`nitroglycerin; isoproterenol hydrochloride Or erythrityi tetrartitrate, are
`placed under the tongue. Sublingual tablets dissolve rapidly and the drug
`substances are absorbed readily by this form of administration.
`
`MCdded Tablets or Tablet Triturates- (TT)
`Tablet; triturates usually are made from moist material using a triturate
`mold which gives them the shape of cut sections of a cylinder. SUCh
`tablets Must be completely and rapidly soluble. The problem arising
`frOm compression of these tablets, is the failure to find a lubricant that is
`completely water soluble.
`Dispensing Tablets (DT)—These tablets provide a convenient quart-
`illy of potent drug that can be incerporated readily into powders' and,
`liqUids,''thtiS circumventing the necessity to weigh small 'qtraniltieS '
`These tablets are supplied primarily as a convenience for extemporattemli
`compounding and should never be dispensed as adOSage form.
`Hypodermic" Tablets (UT)=Hypodermic tablets are soft; readily
`soluble tablets and originally were used for the preparation of solutionsto
`be injected: Since stable parenteral solutions are now available forunist
`drug substances, there is nojustification for, the use of hypodermic tablets
`for injection. r. Their use in this manner should be discouraged since ,,the
`resulting solutions are not sterile. Large quantities of these tablets con-
`timie to be made, but for oratadministration.,. No hypodermic tablets ever
`have been recognized by the official compendia.
`
`Compressed Tablets (CT)
`
`In order for medicinal substances, with or without diluents,
`to be made into solid dosage forms with pressure, using avail-
`able 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. The ingredients
`such as disintegrants designed to break the tablet up in gastro-
`intestinal fluids, and. controlled-release polymers designed to
`slow down drug release, ideally should possess these charac-
`teristics, or not interfere with the desirable performance traits
`of the other excipients. Since most materials, have none or
`only some of these properties, methods of tablet formulation
`and preparation have been developed to impart these desir-
`able characteristics to the material which is to be compressed
`into tablets.
`. The basic mechanical unit in all tablet-compression equip-
`ment includes a lower punch which fits into a die from the
`bottom and anupper 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 2). The
`tablet is formed by pressure applied on the punches and
`subsequently is 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 insuring a uniform 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 compression will
`crumble and fall apart on handling. As the punches must
`move freely within the die and the tablet must be ejected
`readily from the punch faces, the material must have a degree
`of lubrication to minimize friction and allow for the removal of
`the compressed tablets.
`There are three general methods of tablet preparation
`wet-granulation method, the dry-granulation method and
`-4 or
`
`Fig 2. Basic mechanical unit for tabet coMpression: lower puhch
`196
`die and upper punch (courtesy, Vector/Colton): (cid:9)
`
`000004
`
`

`

`rect compression. The method of preparation and the added
`ingredients are selected m order to give the tablet formulation
`the desirable physical characteristics allowing the rapid com-
`pression of tablets. After compression, the tablets must have
`a number of additional attributes such as appearance, hard-
`ness, disintegration ability, appropriate dissolution character-
`istics and uniformity which also are influenced both by the
`method ,of preparation and by, the.added materials present in
`the formulation. In the preparation of compressed tablets,
`the formulator also must:be cognizant of the, effect which the
`ingredients and methods of preparation may have on the
`availability, of the active ingredientsand, hence, the therapeu-
`tic efficacy of the dosage form. In response to a request by
`physicians to change a dicumarol tablet in order that it might
`be broken more easily, a Canadian company reformUlated to
`make a large tablet with a score. SubseqUent use of the
`tablet, containing the same amount., of drug substance as the
`previous tablet, resulted in complaints that larger-than-usual
`doses were needed to prOduee the same therapentic response.
`On the other hand, literature reports indicate that the reforinu-
`lation of a commercial digoxin tablet resulted in a, tablet,
`although containing the same quantity of drugsubstance, that
`gave the desired clinical response at half its original dose.
`Methods and principles that can be Used to assess the effects
`of, excipients and additives on drug absorption have been
`-
`reViewed. ,14;15 See Chapter* 35, 42:and 83. (cid:9)
`
`Tablet Ingredients .
`
`In addition to the active or therapeutic ingredient, tablets
`containanuniber of inert materials,. The latter are known as.
`additives or excipie-nts. They may be classified according to
`the part they play in the finished tablet. The first group
`contains those which help to. impart satisfactory processing
`and compression characteristics to the formulation... These
`include diluents,.binders, glidants and lubricants. The sec-
`ond group of added substances lielps.to give additional desir-
`able physical characteristics to the :finished tablet. Included
`in this group are dishategrants, colors; and in ,the case of
`chewable tablets, flavors and sweetening agents, and in the
`case of controlled-releasetablets, polymers or waxes or other
`solubility-retarding materials.
`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 eXcipi-
`ents and the, desage forms containing them. Preformulation
`studies demonstrate theininfluence ,on stability, bioavailabil-
`ity and the processes by which the dosage forms are prepared.
`The need 'for acquiring more information and use standards
`for excipients has been recognized in a joint venture of the
`Academy of Pharmaceutical Sciences and the Council of the
`Pharmaceutical Society of Great Britain. The result is called
`the Handbook of Pharmaceutical Excipients. This refer-
`ence now is distributed widely throughout the world.'6
`
`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: f dexamethasone contain 0.75 mg steroidper
`tablet; hence, it is obvious that -another -material must. be
`added to make tableting ,possible. Diluents used for this
`purpose. include dicalcium phosphate,al ccium sulfate, lac-
`tose, cellulose, kaolin, mannitol, sodium chloride, dry starch
`and powdered sugar. Certain diluents, such as mannitol,
`lactose, sorbitol, sucrose and inositol; when. present insuffi-
`cient quantity, can impart properties to some compressed
`tablets :that permit disintegration in the mouth by chewing.
`Such tablets commonly are called chavOle tablets. Upon
`chewing, properly prepared tablets will disintegrate smoothly at a
`satisfactory rate, have a pleasant taste and feel ;and leave -no
`unpleasant aftertaste in the mouth. Diluents used, asrexcipients
`for direct compression formulas have been subjected to prior
`
`ORAL SOLID DOSAGE FORMS (cid:9)
`
`1617
`
`processing to give them flowability and compressibility. These
`are discussed tuiderpirect Compression, page 1626.
`Most formulators of immediate-release tablets 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 of the diluents with the drug must be consid-
`ered, eg, calcium salts used-as diluents for the broad-spectrnm
`antibiotic tetracycline have been shown to interfere with the
`drug's absorption from the gastrointestinal tract. When drug
`substances have low water solubility„ it is recommended that
`water-soluble diluents. be Usecito avoid possible bioavailabil-
`ity, problems. Highly adsorbent substances, eg, bentonite
`and. kaolin, are to be avoided making tablets of drugS used
`clinically in., small dosage, such as the, cardiac glycosides,
`alkaloids: and the synthetic estrogens. These drug sub-
`stances may be adsorbed after administration. The combina,
`tion of amine bases withiactose, or amine salts with lactose in
`the presence of an alkaline lubricant, results in tablets whiCh
`discoloron aging. ,
`MicroCrYstalline celhilose (Avicel) usually is used as, an
`excipient indirect-cOMpression formulas. However; Its press
`eneein 5 to 15% concentrations in wet granulations has been
`shown to be beneficial lir the gramilation and; rying prOcesseS
`in minimizing Case-hardening of the tablets and ,in reducing
`tablet mottling.
`Many ingredients are used for several different purpoSes,
`even within the same formulation; eg, corn starch can be used
`in paste form, as a binder. When added in drugOr suspension
`form, it is a good disintegrant. Even though theSe two uses
`are to achieve opposite goals, some tablet formulas use corn
`starch in both ways. In, some ccintrolledrelease formulas,
`the pdlynier hydroxyprOpylinethylcellulose (HPMC): is used
`both as an aid to prolong the release from the tablet, as wellas
`a film-former in the tablet coating. Therefore, most exeitii= .
`ents used in for-rat:dating tablets arid capsule* have many:uses,
`and a. thorough understanding of their propertieS and lirnita-
`tioris is necessary in order to use them rationally.
`
`Binders
`
`Agents used to impart cohesive qualities to the powdered
`material are referred to- as binders or granidators.. They im-
`part a cohesiveness to the -tablet formulation which insures
`the tablet remaining intact after .compression; as well as im-
`proving the free-flowing qualities bythe formulation of gran-
`ules of desired hardness and size. Materials commonly used
`asbinders include starch, gelatin, and.sugars as sucrose, glu-
`cose; dextrose, molasses and lactose. Natural and synthetic
`gums which have heen used include acacia, sodium alginate,
`extract of Irish .moss,„ panwar gum; ghatti guni, mucilage of
`isapol husks, carboxymethylcellulose, methylcellulose, poly-
`virtylpyrrolidone, ..Veegiun and larch arabogalactan. Other
`agents which may be considered binders under-certain `Circum,
`stances are polyethylene:glycol, ,ethylcellulose, waxes, water
`and alcohol.
`The quantity of binder used has considerable influence on
`the characteristics of the compressed tablets, The use of too
`much binder or too strong a -binder will make a hard tablet
`which,will not disintegrate easily and which will cause exces-
`sive wear of punches and dies. Differences in binders used
`for CT Tolbutarnide,resulted in differences in hypoglycemic
`effects observed clinically. Materials which have no cohe-
`sive qualities of their own will rewire a stronger binderthan
`those with these qualities. Alcohol and water are not binders
`in: the true sense of the word, ;but because of their solvent
`action On some ingredientS such as lactose, starch and cellu-
`loses, they change the powdered material to granules and the
`residual moisture retained enables- the • materials. to .adhere
`together when compressed.
`-.Binders are used both. as. a solution and in a dry form
`.
`depending on the other ingredients in the formulation and the
`method of preparation. - However, several pregelatinized
`
`000005
`
`

`

`1618 (cid:9)
`
`CHAPTER 92
`
`starches available are intended to be added in the dry form so
`that water alone can be used as the granulating soltition The
`same amount of binder in solution 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 particles within
`the mass of powders. Each of the particles in a powder blend
`has a coating of adsorbed air on its surface, and it is this film
`which must be penetrated before the powders can be wetted
`by the binder solution: After wetting, a certain period.of time
`is necessary to dissolve the binder completely and make it
`completely available for use. Since powders differ with re-
`spect to the ease with which they can be wetted, and their rate
`of solubilization, it is preferable to incorporate the .binding
`agent in sOlutiOn. By this techniqUe it often is possible to
`gain effective binding with a lower concentration of binder.
`The directcompression method for preparing tablets (see
`page 1630) requires a material 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 inicrocrys-
`tailine cellulose, micro crystalline dextrose, amylose and
`poly-vinylpyrrolidone. It hasbeen poStulated that microcrys-
`talline cellulose is a special form& cellulose fibril in which the
`individual cryStallites are held together largely by hydrogen
`bonding. The disintegration of tablets containing the cellu-
`lOse occurs by breaking the intercrystallite bonds by the disin-
`tegrating medium.
`Starch PasteL--:Corn starch is used widely as a binder.
`The concentration may vary from 10 to 20%. It usually is
`prepared as it 'is to be used by, dispersing corn starch in
`sufficient cold purified water to make a 5 to 10% w/w suspen-
`sion and Watining in a Water bath with continuous stirring until
`a trafislneent paste' Minis. It has been observed that .during
`paste formation; not all of the starch is hydrdlyzed Starch
`paste then, is not.only useful as a binder; but also as a method
`to ineorporate some disintegrantinside the granules.
`GOatiik SointionGelatin generally is used as a 10 to
`20% SolutiOn; gelatin solutions should be prepared freshly as
`needed and used while warm or they will solidify. The gelatin
`is added to cold purified water and. allowed to stand until it is
`hydrated. It then is warmed in a' ater bath to dissolve the
`gelatin, and the solution is made up to the final volume on a
`weight basis to give the concentration desired.
`CellitlosicSolutions—Various cellulosieS have been used
`as binders in 'solution. form. Hydroxypropylmethylcellulose
`(HPMC) hag be&I used widely in this regard. Typical of a
`number of celhilosics, HPMC is more soluble in cold water
`than hot. It also is more dispersable in hot water than cold.
`Hence, M orderto obtain a good, smooth gel that is free from
`lumps' "ffSheyes," it is necessary to add the HPMC in hot,
`almost' boiling' water and, under agitation, cool the mixture
`doWn as quickly as possible; as low as possible. Other water-
`sOluble- cellulosics such as hydrokyethylcellulose (HEC) and
`hydro?pyiiropylcelitilose (HPC) have been used successfully in
`solution* binders.
`Not all celinlOSicS are soluble hi water. Ethylcellulose can
`be used effectively when dissolved in alcohol, or as a dry
`binder Which 'then is Wetted with 'alcohol. It is. used as a
`binder for materials that are moisture-sensitive.
`-PidyvinylpyriolidonePVP can be used as an aqueous or
`alcoholic solution •and • this versatility has increased its
`poPularity. Concentrations range from 2% and vary consid-
`erably:
`It wiLlbenoted that binder soluticins usually are made up to
`Weight rather than volume: This is to enable the formulator
`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 weight of the granulation and must be taken
`into' Consideration in determining the weight of the com-
`presSed 'tablet, 'Which will contain the stated amount of the
`therapeutic agent.
`As can be seen by the list of :binders in this chapter, most
`modern binders used in solution'are polyinerie in form:
`cause of. this, the flow or • SpreadabilitY of these solutions
`
`becomes important when selecting the appropriate granulat-
`ing equipment. • The rheology of polymeric solutions is a
`fascinating subject in and of itself, and should be considered
`for these materials.
`
`Lubricants
`
`Lubricants have a number of functions in tablet manufacture.
`They prevent adhesion of the tablet material to the surface of
`the dies and punches, reduce interparticle friction, facilitate
`the ejection of the tablets from the die cavity and may improve
`the rate of flow of the tablet granulation. Commonly used
`lithricants include talc; magnesium stearate, calcium stearate,
`stearic acid, hydrogenated vegetable oils and polyethylene
`glycol (PEG). Most lubricants, with the exception of talc, are
`used in concentrations less than 1%. When used alone, talc
`may require concentrations as high as 5%. Lubricants are in
`most cases hydrophobic materials. Poor selection or exces-
`sive amounts can result in "waterproofing" the tablets, result
`ing in poor tablet disintegration and/or delayed dissolution of
`the drug substance.
`The addition of the proper lubricant is highly desirable if the
`Material to be tableted tends to stick to the punches and dies.
`Inimediately after conapression, most tablets have the ten-
`dency *to eXpand and will bind and Stielc to the side of the die.
`The choice of the proper lubricant effectively will overcome
`this.
`The method of adding a lubricant to a granulation is impor-
`tant if the material is to perform its function satisfactorily.
`The'litbricant should be divided finely by pasSing it through a
`60- to 100-mesh nyldn cloth onto the granulation. In produc-
`tion this is called boltiUg the lubricant. After adding the
`lubriCant, the granulation is tumbled Or mixed gently to distrib-
`ute thelubricant without coating the particles too well or
`breaking them doWn to finer particles. Some research has
`coneluded that the order of mixing of lubricants and other
`excipients can have a profound effect on the performance of
`the final dosage form. Thus, attention to the mixing process
`itself is just as important as the selection of lularicant materi-
`als.
`These process variables can be seen in the prolonged blend-
`ing of a lubricant in a granulation. Overblending materially
`Can affect the hardness, disintegration time and dissolution
`performance for the resultant tablets.
`The quantity of lubricant varies, being as low as 0.1%, and in
`some cases as high as 5%. Lubricants have been added to the
`granulating agents in the form of suspensions or emulsions.
`ThiS technique serves to reduce-.the inuriber of operational
`prdeechires and thus reduce the processing time.
`In selecting a lubricant, proper attention must be given to its
`compatibility with the drug agent. PerhapS the most widely
`investigated drUg is acetylsalicylic acid. Different talcS var-
`ied significantly the stability of aspirin. Talc with a high
`calcium content and a high losS•on ignition was associated
`with increased aspirin decomposition. From a stability stand-
`point, the relative acceptability of tablet lubricants for combi-
`nation with aspirin was found to decrease in the following
`order: hydrogenated vegetable oil, stearic acid, talc and alu-
`minum stearate.
`•.:The primary problem in the preparation of a water-soluble
`tablet is the selection of a satisfactory lubricant. Soluble
`lubricants reported to be effective include sodium benzoate, a
`mixture of sodium benzoate and sodium acetate, sodium, chlo-
`ride, leucine and. Carbowax' 4000. However, it has been
`suggested that formidations used to prepare water-soluble
`tablets may represent a number of compromises between
`compression effidiency and water solubility. While magne-
`shim stearate is one of the most widely used lubricants, its
`hydrophobic properties can retard disintegration and
`diSsolution. To overcbtrie-these'waterprocifing characteris=
`ties, soclininlauryl.sulfate sometimes is included. One com-
`pound found to have the lubricating properties of magnesium'
`stearate withOut IS disadvantages is magnesium lauryl sulfate:
`ItS safety for use in pharmaceuticals has not been established:
`
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`Gliclants
`
`A glidant is a substance which improves the flow character-
`istics of a powder mixture. These materials always are added
`in the dry state just prior to compression (ie, during the
`lubrication step). Colloidal silicon dioxide [Cab-o-sil
`(Cabot)] is the most commonly used glidant and generally is
`used in low concentr