DRUGS AND THE PHARMACEUTICAL SCIENCES
`
`VOLUME 72
`
`POTN oh
`
`oo LAYER
`
`DRUG
`
`PARTICLE
`
`SUTeg
`
`ne
`
`dauTc
`
`© MOLECULES
`|!
`tee eee
`
`GUATUETaT
`
`SNM MAES MYLAN EXHIBIT 1042
`
`en:
`CONTENTS
`Se
`
`“3
`
`ace
`
`'
`
`BLOOD
`CIRCULATION
`
`meeeaac
`MOLECULES
`PRP icc
`
`GI
`ara
`
`cra iCoen
`Ci oYslg Om bye](o1
`
`MYLAN EXHIBIT 1042
`
`

`

`

`

`

`

`Modern Pharmaceulics
`
`Third Edilion, Revised and Exoanded
`
`edited by
`Gilbert S. Banker
`
`University of Iowa
`Iowa City, Iowa
`
`Christopher T. Rhodes
`
`University of Rhode Island
`Kingston, Rhode lslond
`
`Marcel Dekker, Inc.
`
`New York• Basel• Hong Kong
`
`This m-ate:ria l was co.pied
`attheNLMandmay!J.e,
`Subject US Copyright Laws
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`

`Library of Congress Catalnging-in-Puhlication Data
`
`Mod ern pharmaceutics/ edited by Gilbert S. Uanker, Christopher T.
`Rhodes.-3rd ed., rev. and expanded.
`p.
`cm.-(Drugs and the pharmaceutical sciences ; v. 72)
`Includes bibliographical references and index.
`!SUN 0-8247-9371-4 (alk. paper)
`I. Drugs-Dosage forms. 2. Biopharmaceutics.
`3. Pharmacokinetics. 4. Pharmaceutical industry-Ouality control.
`l. Banker, Gilbert S.
`II. Rhodes. Christopher T.
`Ill. Series.
`RS200.M63 1995
`6 J 5'. J -de20
`
`95-33238
`Cll'
`
`The publisher offers discounts on this book when ordered in hulk quant itics. For morc information, write
`to. Special Saks/l'rofcssional Markcting at the addrcss hclow.
`
`This book is printcd on acid-frcc paper.
`
`Copyright ({'.) J 996 by Marcel Dekker, Inc. All Rights Rcscrved.
`
`Neither this book nor any part may be reproduecd or transmitted in any form or hy any means, electronic
`or mrchanical, including photocopying, microlilming, and rccording, or by any information storage and
`n:trieval systcm, without permission in writing from the publisher.
`
`Marcel Dckker, Inc.
`270 Madison Avcnuc, Ncw York, New York 1()())6
`
`Cum:nt printing (last digit)
`·I 3 2
`IO
`<J 8 7 6 5
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`PRINTED IN TIIE UNITED STATES OF AMERICA
`
`Th is mat e.-ia I w as c0<p.ie,:f
`at t he r.lLM, and may 00
`S:Ubiact USCoavril!ht Laws
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`

`

`Contents
`
`I >reface
`Co11trih111<1rs
`
`I. Drug Products: Their Role in the Treatment of Disease, Their Quality,
`and Their Status as Drug Delivery Systems
`Gi/l)('r/ S. Uanka
`
`2. Principles of Drug Absorption
`Micluwl M11yasoh11
`
`3. Pharmarnkinctics
`Dm·id iv. A. /Jmir111• and /,1•wis \Y. Diuert
`
`4. Factors Influencing Drug Absorption and Drug Availability
`/li'Uy-111111 I /ocncr mu/ /,cs/it• l . /Jen('(
`
`5. The Effect of Route of Administration and Distribution on Drug Action
`S1·ei11 0ic 1111d /,1•.\lic l. lknct
`
`<,. Chemical Kinetics and Drug Stability
`.I. Keith Guillory 11111/ Uollwul I. />oust
`
`7.
`
`!'reformulation
`.frm ·1: Carstrn.w11
`
`8. Cutaneous and Transdermal Dd ivcry: Processes and Systems of Delivery
`(;on/011 I.. Fl.r1111
`
`Th.i s materi:aJ w as. copied
`at the fRMand .ma yb,e
`!M!ject IJSCopyright Laws
`
`Ill
`vii
`
`l
`
`21
`
`75
`
`121
`
`155
`
`179
`
`21~
`
`V
`
`

`

`vi
`
`Contents
`
`9. Disperse Systems
`S. Esmail Tabibi and Christopher T. Rhodes
`
`10. Tablet Dosage Forms
`Edward M. Rudnic and Mary Kathryn Kottke
`
`11. Hard and Soft Shell Capsules
`Larry L. Augsburger
`
`12. Parenteral Products
`James C. Boylan, Alan L. Files, and Stei•en L. Nail
`
`13. Design and Evaluation of Ophthalmic Pharmaceutical Products
`Gerald Hecht, Robert E. Roehrs, John C. Lang,
`Denise /~ Rodchcal'cr, and Ma.mod A. Chowhan
`
`14. Pharmaceutical Aerosols
`John J. Sciarra
`
`15. Sustained- and Controlled-Release Drug Delivery Systems
`Gwen M. Jantzen and Joseph R. Robinson
`
`16. Target-Oriented Drug Delivery Systems
`Vijay Kumar and Gilbert S. Hanker
`
`17. Packaging of Pharmaceutical Dosage Forms
`Donald C. Liebe
`
`18. Optimization Techniques in Pharmaceutical Formulation and Processing
`Joseph B. Schwartz and Roln:rt E. 0 'Connor
`
`19. Food and Drug L1ws that Affect Drug Product Design,
`Manufacture, and Distribution
`Gamet E. Peck
`
`20. European Aspects of the Regulation of Drug Products
`Brian R. Matthews
`
`21. Pediatric and Geriatric Aspects of Pharmaceutics
`Michele Danish and Mary Kathryn Kottke
`
`22. Biotechnology-Based Pharmaceuticals
`S. Kathy Edmond Roll{m
`
`23. Veterinary Pharmaceutical Dosage Forms: An Overview
`J. Patrick McDonnell
`
`24. A View to the Future
`Gilbert S. /Janker and Christopher 7: Rlwdes
`
`lnd<'x
`
`This m .ate.ri.a l w a s copied
`at the NL M .an<fm,iy be
`Subject US Copyright Law s
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`299
`
`333
`
`395
`
`441
`
`489
`
`547
`
`575
`
`611
`
`681
`
`727
`
`753
`
`773
`
`809
`
`843
`
`875
`
`887
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`1)()7
`
`

`

`This material may be protected by Copyright law (Tit!e 17 U.S. Code)
`
`Tablet Dosage Forms
`
`Edward M. Rudnlc
`l'lwrmarrnr·, Inc., Uochi/11·, ,\foryl1111rl
`Mary Kathryn Kottke
`t\1110/111111r111,·, /11c., /,,·.rill!!,fmr. ,\fussaclrrm·t1.1·
`
`10
`
`I.
`
`INTRODUCTION
`
`D'.ir!ng the past three and a half decades, the pharmaceutical industry has invested vast amounts
`01 tum: and money in the study of tablet compaction. This expenditure is quite reasonable
`whcn one considers how valuable tablets, as a dosage form, arc to the industry. As oral dosage
`forms can he self-administered by thc patient. they arc obviously more profitable 10 manufac(cid:173)
`'.1'.r~ t~ian parcntcral dosagc forms, which usually must be administered by trained personnel.
`I l11s is rcflcctcd by the fact that well over 80% of the drugs in the United States that ;'.re
`formulated to produce systemic effects arc marketed as oral dosage forms. Compared wit_h
`othe~ oral dosage forms, t;1hlcts arc the mairnfacturers' dosage form of choice .b~cause of_the1r
`relatively l'.iw cost of manufacturing, packaging, and shipping: increased st,~b.thly, and virtual
`tamper res1stann: (i .e., most tampercd tablets either bccomc discolored or d1s111tegrate).
`
`II. DESIGN AND FORMULATION OF COMPRESSED TABLETS
`A. General Considerations
`Th: most comnwn :,..olid dosage forms in contclllporary practice arc tal,/cts, _whi~h m,_iy be
`defined as unit forllls of solid medicaments prepan:d hy compaction. Most consist of a llltXturc
`of powders that arc compaded in a dic to produce a single, rigid body. The most common
`typcs of tablets arc tho-.e intcndcd to be swallowed whole and then disintegrate and release
`their medkamcnts in the gastrointestinal tract (CilT). /\ less comnHlll type of tablet is fori~111latcd
`to allow dissol11tion or dispnsion in water bdme administration. Ideally. for this type ol tablet,
`all ingredients should be solulllc, but frcqul'ntly. a tine s11spe11sion has to be al'L:cpted. Mat~y
`tablets of this type arc formulated to be l'lll·n·escent, and their main advantages 111cludc rapid
`rclea-;e of medicament and 111i11i111i1atio11 of gastric irritation.
`Some t;1hkts ;1rr 1ksignnl lo lw masticaled (chewed). This typl' of tablet is often used when
`;,ti ... orption 110111 thr b11rral cavity is iksitl'd, Ill lo rnhanl'L' dispersion bt"forc swallowing.
`333
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`Subject US Cnpyright Laws.
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`

`

`334
`
`Rudnlc and Kottke
`
`Alternatively, a tablet may be intended to dissolve slowly in the mouth (e.g., lozenges) to
`provide local activity of the drug. A few tablets arc designed to be placed under the tongue
`(sublingual) or between the teeth and gum (buccal) and rapidly release their medicament into
`the bloodstream. Buccal or sublingual absorption is often desirable for drugs subject to exten(cid:173)
`sive hepatic metabolism by the first-pass effect (e.g., nitroglycerin, testosterone) . Recently, a
`lozenge on a stick, or "lollipop," dosage form of fcntanyl was developed for pediatric use .
`There arc now many types of tablet formulations that provide for the release of the medi(cid:173)
`cament to be delayed or to control the rate of the drug's availability. Some of these preparations
`arc highly sophisticated and arc rightly referred to as complete "drug-delivery syskms."
`"Sustained-release" tablets can encompass a broad range of technologies. Since the con(cid:173)
`cepts of prolonged drug delivery arc the subjects of Chapter 15, the strategics of these systems
`will not be discussed here. However, solid dosage formulators must l>c aware of the various
`options available to them .
`For example, some water-soluble drugs may need to be formulated so that their release and
`dissolution is controlled over a long period. For 1111.:se, certain water-insoluble materials will
`have to be coformulated with the drug. If the dose of this drug is high, the drug will dictate
`the tableting properties of the formula. If the drug exhibits poor compactibility, hydrophobic
`agents, such as waxes, will surdy make matters worse . To solve such a p~'.>hlem, the formu (cid:173)
`lators would have to turn to other types of water-insoluble materials, such as polymers, to
`achieve drug n.:lcase and tableting goals.
`Some tablets combine sustained-release characteristics with a rapidly disintegrating tablet .
`Such products as K-Dur (Key Pharmaceuticals) combinc coated potassium chloridc (KCI) crys(cid:173)
`tals in a rap idly releasing tablet. In this partirnlar inslance, lhc <.:ryslals arc coaled wilh clhyl (cid:173)
`ccllulose, a water-insoluble polymer and arc then incorporated in a rapidly disinlcgrating mi(cid:173)
`crocrystalline cellulose matrix. Thc purpose of this tablet is to minimizc GI 11lcera1io11,
`commonly seen with KCI therapy. This simple, but clcgant, formulation is a mas!crpiecc of
`solid dosage form strategy to achicve clinical goals.
`Thus. the single greatest challcngc to the tablet formulator is in thc dclinition of thc purposc
`of the formulation and the idcntifkation of suitable materials lo achicve clevclopmcutal objec(cid:173)
`tives. To do this properly, the formulator must know thc propcrtics of the drug, the materials
`to be coformulatcd with the drug, and the important aspccts of the granulation, tableting, and
`coating processes.
`Pharmaceutical compressed tablets arc prepared by placing an appropriate powder mix, or
`granulation, in a metal die on a tablet press. At thc base of thc die is a lower punch, and above
`the dic is an upper punch. When the upper punch is forced down on the powder mix (single(cid:173)
`punch press), or when !he upper and lowcr punches squccze together (rotary prcss), !he powder
`is forced into a 1ablct. Despite that powder compaction has been observed for millennia , sci(cid:173)
`entists still debate the exact mechanisms behind this phenomenon.
`Perhaps the mos! significant factor in the tableting process arises from till: need to produce
`tablets of uniform weight. This is achieved by fccding constant volumes of homogeneous
`material to the dies. Such an approach is necessary because direct weighing at rates commen (cid:173)
`surate with modern tablet press operation is impossible. This requirement immediately places
`demands on thc physical characteristics of the feed and on the design of the tablet press itself.
`In the former, prccompression trcatmcnt of the granulation is one of the most common ways
`of minimizing difficulties arising from this source.
`The great paradox in pharmaceutical t:_1hleting !~ t!1c need to n~anufacturc a com~act capable
`of reproducibly rcleasing the d~ug that 1s of suf hc1cnt m~chan1cal ~trcnglh to w1thsland the
`rigors of processing and packaging. Usually, the release of the drug 1s produced hy the penl'·
`
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`Su.l>ject USCopy,ight La ws
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`Tablet Dosage forms
`
`335
`
`!ration of aqueous fluids into the fine residual pore structure of the tablet and the contact of
`these fluids with components that either swell or release gases.
`The selected precompression treatment, if any, markedly affects the manufacture of tablets.
`In particular, one must determine whether a mixture of powdered ingredients is to be tableted
`directly, or if an intervening wet granulation step is to be introduced. This decision is influenced
`by many factors, including the stability of the medicament to heat and moisture, the flow
`properties of the mixed ingredients, and the tendency of the granulation to segregate. Currently,
`there arc also two conflicting considerations that tend to play a major role in this choice. These
`arc the reluctance to change the traditional methods employed by the company, versus the
`economic advantages of omitting complete stages in the production sequence. In wet granu(cid:173)
`lation, the components of the formulations arc mixed with a granulating liquid, such as water
`or ethanol. to produce granules that will readily compress to give tablets. Wet granulation
`methods predominate in the manufacture of existing products. whereas the trend for new prod(cid:173)
`ucts is to use direct compression procedures. Although many steps arc eliminated when using
`direct compression, some formulators have found that wet granulated products arc more robust
`and able to accomnHHlatc variability in raw materials. Thus, for some companies, the trend is
`reverting to the formulation of tablets by wd granulation.
`
`B. Deslrable Properties of Raw Materials
`
`Most formulations will be composed of one or more medicaments plus a variety of excipients.
`Irrespective of the type of tablet, general criteria for these raw materials arc necessary. To
`prmh1ce acrnrate, reproducible dosage forms it is essential that each component be uniformly
`dispersed within the mixture and that any tendency for component segregation be minimized.
`In addition, the processing operations demand that the mixture be both free-flowing and co(cid:173)
`hesive when compressed.
`
`/'article Size
`In general, the tendencies for a powder mix to segregate can be reduced by maintaining similar
`particle size distribution, shape and, theoretically, density of all the ingredients. Flow properties
`arc enhanced by using regular-shaped, smcH1th particles with a narrow size distribution, together
`with an optimum proportion of "tines" (particles< 50 µm) . If such conditions cannot be met,
`then some form of granulation should be considered.
`Particle size distribution and, hence, surface area of the drug itself, is an important property
`that has received considerable attention in the literature. For many drugs. particularly those for
`which absorption is limited by the rate of dissolution, attainment of therapeutic levels may
`depend on achieving a small particle size j I J. In fact, it has been suggested that, for such
`drugs, standards for specific surface areas and the number of particles per unit weight should
`be developed . llowevcr. the difficulty in handling very line powders, as well as the possibility
`of altering the material in other \vays. has shifted the emphasis towards producing an optimum,
`rather than a minimum, particle size. For instance. several researchers have found that ckcrcas(cid:173)
`ing particles size produces tablets of increased strength, as well as rnluced tendency for lam(cid:173)
`ination 12-.S k This is proh;1bly due to the minimization of any adverse inllucnccs that a par(cid:173)
`ticular crystal structure may ha\'l' on the honding mechanism. On the other hand. samples of
`milled digoxin crystals prepared hy various site-reduction techniques have been reported to
`elicit dilfrrent equilibrium solubilities I 11. This suggests that the method of grinding may well
`affect the dissolution hchavim of cntain medicaments.
`The cffrrl of part irk size 011 the rnmpaction charactcristics of two model sulfonamide drugs,
`one c.xhihiting hrittk fracturl· and the othn being compressed chiclly by plastic deformation,
`has hl'rn rl'portt'd 1-'1· In particular, the IL'nsik slrl'ngth of tablets made from the brittle material
`
`This material was co pieij;
`at the riLM and: may be
`Subject US Copyright Laws
`
`

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`

`

`Tablet Dosage Forms
`
`337
`
`cellulose (MCC)-containing tablets has been the subject of an investigation that demonstrates
`the sensitivity of this important cxcipient to moisture content [10]. Differences exist in both
`the cohesive nature and the moisture content of two commercial brands of MCC [10]. A very
`useful report 011 the equilibrium moisture content of some 30 excipicnts has been compiled by
`a collaborative group of workers from several pharmaceutical companies [11 ]. The information
`garnered from this study now appears in the Handbook of l'harmace11tical Excipients [12].
`
`Crysta I I ine Form
`Selection of the most suitable chemical form of the active principle for a tablet, although not
`strictly within our terms of reference here, must be considered. For example, some chloram(cid:173)
`phcnicol esters produce little clinical response [ 13]. There is also a significant difference in the
`bioavailability of anhydrous and hydrated forms of ampicillin [ 14J. Furthermore, different poly(cid:173)
`morphic forms, and even crystal habits, may have a pronounced influence on the bioavailability
`of some drugs. owing to the different dissolution rates they exhibit. Such changes can also
`give rise to manufacturing problems. Polymorphism is not restricted to active ingredients, as
`shown, for example, in a report on the tableting characteristics of five forms of sorbitol [ 15].
`Many drugs have definite and stable crystal habits. Morphological changes rarely occur in
`such drugs as the formulation process is scaled up. However, some drugs exhibit polymor(cid:173)
`phism, or have different identifiable crystal habits. Chan and Doclker reviewed several drugs
`that undergo polymorphic transformation when tritu ratcd in a mortar and pestle [ 16]. Some of
`their conclusions arc listed in Table I and illustrated in Fig. 2. [n addition, several researchers
`have concluded that both polymorph and crystal habit influence the compactibility and me(cid:173)
`chanical strength of tablets prepared from polymorphic materials [ 16-21 ]. York compared the
`compressibility of naproxcn crystals that had been spherically agglomerated with different
`solvents and found that significant differences existed between the various types of agglom(cid:173)
`erates (sec Fig. 3) [21 j. Other investigators have found that, in some instances, there is a
`correlation be tween the rate of reversion to the metastable form during dissolution and the
`crystal growth rate of the stable form [221. These polymorphic changes may have a profound
`cffcct on tablet performance in terms of processing. in 1·itro dissolution, and i11 ifro absorption.
`In fact, a major clinical failure of generic carbamazepinc tablets can be directly linked lo
`
`Table l Some Drugs That Undergo Polymorphic Transi1ion When
`Triluralcd
`
`Drug
`
`Barhilone
`Caffeine
`('hhirpropamide
`Clcnh111erol IICI
`Di py ri1bmo k
`Maprnlilinl' IICI
`~khcnd:11ok
`Naf'oxidim· IICI
`l\·11111l1a1 hih llll'
`l'hc1H 1ha1hih111l'
`Su I f'ahl·111ami1k
`
`S,,,11,·,·: Hd. l<i.
`
`Number of polymmphs
`before 1ri111ra1ion
`
`Numher of polymorphs after
`1ri1urat io11
`
`2
`2
`J
`2
`2
`3
`,I
`,I
`J
`2
`-1
`
`2
`."\
`I
`
`5
`J
`2
`
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`at the NLM and may be
`5:uhje<:.t US ~pyright La ws
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`Tablet Dosage Forms
`
`339
`
`polymorphic changes (dihydrate formation) that led to altered dissolution of the tablets and,
`ultimately, disastrous clinical consequences. Thus, formulators of solid dosage forms must be
`aware of a subject compound's propensity for polymorphic transition so that a rational approach
`to formulation can be followed.
`
`H icstand Tableting Indices
`Materials that do not compress will produce soft tablets; brittle crystalline materials will yield
`brittle tablets. Hiestand was the first pharmaceutical scientist to quantify rationally the com(cid:173)
`paction properties of pharmaceutical powders [23-28). The results of this work arc three
`indices known as the Hiestand Tableting Indices. The strain index (SI) is a measure of the
`internal entropy. or strain, associated with a given material when compacted. The bonding
`index (Bl) is a measure of the material's ability to form bonds and undergo plastic transfor(cid:173)
`mation to produce a suitable tablet. The third index, the brittle fracture index (BF!), is a measure
`of the hrilllcness of the material and its compact. 1:1blc 2 lists these indices for several drugs
`and cxcipients. For most materials, the strength of the tablet is a result of competing processes.
`For example, erythromycin is a material known for its tendency to cap and laminate when
`tableted. On the basis of its l3l value, one might expect relatively good bonding. However, the
`very high strain index associated with this drug appears to overcome its bonding abilities.
`Microcrystallinc cellulose, on the other hand, has very high strain index, but its bonding index
`is exceptionally high and compensates for this effect.
`Other investigators have evaluated the potential for these indices. In their studies, Williams
`and McGinnity have concluded that evaluation of single-material systems should precede binary
`or tertiary powder systems l29J. A full discussion of compaction mechanisms is given later in
`this chapter.
`
`Variability
`The eff cct of raw material variability of tablet production [2,30,31} and suggestions for im(cid:173)
`proving tableting quality of starting materials [21] have been the subject of recent publications.
`Table 3, which lists the characteristics of different sources of magnesium stearate, clearly
`illustrates the variability of this material [32]. Phadkc and Eichorst have also confirmed that
`significant diff ercnces can exist between different sources, and even different lots, of magnc(cid:173)
`situn stearate [ 33 ]. Given that the effectiveness of magnesium stearate is primarily due to its
`large surface area, these variations should not be overlooked. In addition, studies assessing raw
`material variability emphasize the need for physical, as well as chemical. testing of raw ma(cid:173)
`terials to ensure uniformity of the final product.
`Purity
`Raw material purity, in general, must also be given careful altcntion. Apart from the obvious
`reasons for a high level of integrity, as recognized by the regulatory requirements, we should
`he aware of more subtle implications that arc perhaps only just beginning to emerge. For
`instance, small proportions of the impurity acctylsalicylic a11hydride reduces the dissolution
`rate of aspirin itself (Fig. ,f) [34 ].
`Another area of interest is that of microbiological contamination of solid dosage forms,
`whid1 is thought to arise chiclly from raw materials, rather than the manufacturing process
`135,3<,]. Ibrahim and Olurinola monitored the effects of production, environment, and method
`of production, as well as microbial llUality of starting materials, 011 the microbial load during
`various stages of tabkt production [ .15 j. Although high levels of rnntamination were present
`during the wet granulation process. thl'sc levels were significantly reduced during the drying
`process. Tl111s, products 1krivcd frn111 natural origins, such as gelatins and starch, arc sometimes
`heavily contaminall'd.
`
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`

`340
`
`Rudnlc and Kottke
`
`Table 2 Hiestand Compaction Jmfa:cs for Some Drugs and Excipients
`
`Matcrial
`
`I3onding index
`
`Brittle fracture
`index
`
`S!rain index
`
`Aspirin
`Caffeine
`Croscarmellosc sodium NF
`Dicalc:ium phosphate
`Erylhromycin dihydrate
`Hydroxypropyl cellulose
`Ibuprofen
`A
`B
`C
`Lactose USP
`Anhydrous
`Hydrous Fast-Flo
`J lydrous bolled
`Hydrous spray process
`Spray dried
`A
`B
`
`Mannitol
`A
`B
`Mt:thenarnine
`Methyl cellulose
`Microcrystalline cellulose NF
`Aviccl PII !02 (coarse)
`Aviccl Pl! IOI (line)
`Povidone USP
`Sorbilol NF
`Slarch NF
`Corn
`l'regclatinized
`Pregelatinized compressible
`Modified (starch 1500)
`Su1:rosc NF
`A
`B
`C
`
`Sourct': Refs. 2.'.l-28.
`
`1.5
`1.3
`2.7
`1.3
`1.9
`1.6
`
`1.9
`1.8
`2.7
`
`0 .8
`0.4
`0 .6
`0.6
`
`0.(1
`0.5
`
`0.8
`0.5
`I.(,
`4.5
`
`4.3
`3.3
`1.7
`0. IJ
`
`0.4
`1.8
`1.2
`1.5
`
`1.0
`0.8
`0.5
`
`0.16
`0.34
`0.02
`0.15
`0.98
`0.04
`
`(l.()5
`0.57
`0.45
`
`0.27
`0. ( I)
`0 .12
`0..15
`
`0. 18
`0 . 12
`
`0.19
`0.15
`0 .1)8
`0.0(,
`
`0.0-1
`<HJ.I
`0 .42
`0.1 (,
`
`0 .2<,
`0 .14
`0.02
`0.27
`
`0 .35
`0.42
`0.53
`
`I. I I
`2. 19
`3.79
`1.13
`2. 13
`2. 10
`
`O.IJ8
`1.51
`1.21
`
`1.40
`1.70
`2. 1(1
`2.12
`
`l.·17
`1.81
`
`2. 18
`2.2<,
`08.l
`3.02
`
`2.20
`2.37
`3.70
`l.70
`
`2.·18
`2.02
`2.08
`2.30
`
`1.45
`I . 79
`1.55
`
`Compatibility
`One final area that should be considered when choosing the cxcipicnls to he used in the tablet
`formulation is thal of drug-excipient interactions. There is still much dehale ahoul whl'thcr
`cxcipient compatibility testing should be conducted before formulation j.37 -J<J J. Thl'se tl'sh
`most often involve the trituration of small amounts of the active ingredient with a variety of
`excipicnts. Critics of these small-scale studies argue that their predictive value has yet lo he
`established and, indeed, !hey do not reflect actual processing conditions [J7J . lnstcacl. lhl·y
`
`Th is ma te,ria l w as copied,
`at the N:LM an,d m ay bi!·
`Subject US Co,pyright L3ws
`
`

`

`Tablet Dosage Forms
`
`341
`
`Table 3 Average Particle Data for Different Sources of Magnesium Stearale
`
`Source
`
`United States
`Great Uritain
`Germany
`Italy
`
`Solll'C<': Ref. 32.
`
`Size (µm)
`
`1.5-3.2
`2.1-5.2
`4.1-6.9
`5.5-9.1
`
`Surface area (m 1/g)
`
`Pore radius (A)
`
`13.4
`12.2
`7.4
`4.6
`
`50
`68
`61
`36
`
`suggest a sound knowledge of the chemistry of the materials used in conjuncture with "mini(cid:173)
`formulation" studies as a preferable method for investigation of drug-excipient interactions.
`
`C. Tablet Components
`
`Conventional solid dosage forms can he divided into two classes: those that disintegrate, and
`those that do not. Disintegrating dosage forms release their medicaments by breaking down
`the physical integrity of the dosage form, usually with the aid of solid disintegrating agents or
`gas-releasing effervescent agents. Nondisintegrating tablets arc usually made of soluble drugs
`and excipients that will rapidly dissolve in the mouth or gastrointestinal tract (GIT) on
`ingestion.
`In recent years, the arrival of new prolonged-release dosage forms has caused some phar(cid:173)
`maceutical scientists to consider conventional disintegrating dosage forms ;is "non-controllcd(cid:173)
`rclease.'' This term is a misnomer, since, with the aid of modern tablet disintcgrants and other
`cxcipicnts, the disintegration of these dosage forms can be controlled, both quantitatively and
`qualitatively. Moreover, there are still many drugs in which rapid attainment of therapeutic
`levels, rather than controlled release, is required. Analgesics, antibiotics, and drugs for the
`immediate treatment of angina pectoris arc prime examples. These tablets need to be designed
`so that the drug is liberated from the dosage form in such a manner that dissolution of the
`
`1.4
`
`1.2
`
`l'
`
`y = 1.3094 · 0.30351x W2 "0.970
`
`.. -:;;
`
`1.()
`
`CI:
`C
`0
`;;
`., ...
`0 O.H
`0
`
`O.G
`
`0'1 - - . - - ,- -- . . - - , - -~
`0
`3
`;>
`
`% Acotyl5:illcyltc Anhydride
`
`Fig. 4 Elfrrl of an·tylsalicylir ;1nhydri,k impurity on lhl· dissolution rate of aspirin tablets. (From
`lkL 3·1.)
`
`Th.is m aterial was copde<I
`at the· Nl.iM: and m ay be
`5.t;bject US Copyrig.ht Laws.
`
`

`

`

`

`Tablet Dosage Forms
`
`343
`
`Because of the nature of modern pharmaceutical systems, formulators have made more
`complete investigations of the materials they use. This interest has identified several materials
`that may have more than one use in tableted systems. The type of effect that an cxcipient will
`produce is often dependent on the concentration in which it is used. For example, Table 5 lists
`some multiusc cxcipicnts and the corresponding concentration ranges required for their various
`applications.
`
`Active Ingredients
`The dose of the drug to be administered has a profound cff cct on the design and formulation
`of a dosage form. Content uniformity and drug stability become very important issues when
`the dose of the drug is very small (e.g., oral contraceptives). However, the effect of the drug's
`properties on the tablet, in this case, is minimal. In general, as the dosage increases, so docs
`the effect of the drug's attributes on the tablct.
`Sometimes processing can affect the particle morphology of the active ingredient. This may
`lead to adverse effects on mixing and tableting operations. In particular, micronization may
`cause crystals to change their shape, even though polymorphism is not evidenced.
`
`Fillers
`An increasing numbcr of drugs arc used in very low dosages. To produce tablets of a reasonable
`size (i.e., minimum diameter of 3 mm), it is necessary to dilute the drug with an inert material.
`Such dilucnts should meet important criteria, including low cost and good-tableting qualities.
`
`Table 5 Some Mulliplc-Use Excipicnls for Tablet Formulation
`
`Excipient/com.:entration in formula (%)
`
`Use
`
`G\yccryl behcnate
`0-5
`5-3()
`l lydroxypropylmclhyl cellulose
`(I ll'MC), low viscosity
`0-5
`5-20
`5-26
`Microcrystalline rellulose (MCC)
`0-8
`5-15
`5-95
`Polyethylene glycol
`0-10
`5-,W
`l'olyvinylpyrrolidoni.: (l'VI')
`0-15
`5-10
`5- ]ll
`lll -- J5
`St:nd1
`11 - 5
`5-- \0
`5 - 20
`
`Lubricant
`Controlled-release excipicnt
`
`Wi.:t hinder
`Film former
`Controllcd-ri.:lcasc cxcipicnt
`
`1 mprnvc adhesion of lilm co;1t lo core
`Disintcgrant
`llimkr/til!cr
`
`l.11hricanl
`( 'ontrollcd-rckasc cxcipicnt
`
`\Vi.:d himkr
`Co;1ting l'Xcipil'llt
`I )isintcgrant
`( '1111t111lkd ·rdl'asc t·xcipicnl
`
`\ ntra~:ra1111\ar hi111lcr/disintcgran1
`Wt·t hi111kr
`l)isintq~rant
`
`Th is. materia l was co·piecl
`att:he 14LM a ndm.ayl>e-
`5tJbj:ect USCo:py;right La,vs
`
`

`

`344
`
`Rudnlc and Kottke
`
`It may be possible, in some instances, to combine the role of diluent with a different property,
`such as a disintcgrant or flavoring agent.
`Commonly used fillers and binders and their comparative properties arc listed in Table 6.
`As can be seen by this list, both organic and inorganic materials arc used as fillers and binders.
`The organic materials used arc primarily carbohydrates because of their general ability to
`enhance the product's mechanical strength as well as their freedom from toxicity, acceptable
`taste, and reasonable solubility profiles.
`One of the most commonly used carbohydrates in compressed tablets is lactose. Work by
`I3olhuis and Lcrk [40] and Shangraw ct al. [6] has demonstrated that all lactoses are not alike,
`chemically, physicochcmically, or functionally. Uesidcs various size grades of normal hydrous
`lactose, one can purchase spray-dried lactose, which is an agglomerate of n-lactosc monohy(cid:173)
`dratc crystals, with up to I 0% amorphous material. Spray-dried lactose has very good flow
`properties, but its poor compression characteristics require the addition of a binder, such as
`microcrystallinc cellulose. I lowcvcr, one particular brand of spherical nystalline/amorphous
`agglomerate, Fast-Flo (NF hydrous), possesses superior compressibility and dissolution char(cid:173)
`acteristics. The spherical nature of the crystals make them more compressible than spray-dried
`agglomerates of lactose [41 ]. One must also give attention to this component's stability, as
`aging may adversely affect these properties. Anhydrous lactose has also been use(! as a diluent,
`particularly in direct compression formulations for which low moisture content is desirable,
`since it has very good stability and a reduced tendency to color with aging. Another advantage
`in the use of anhydrous lactose is that its insensitivity to temperature changes allows it to be
`reworked with relative case. Unfortunately, its flow properties arc no! particularly good, and
`its compressibility is inferior to other forms of lactose.
`Some other sugars arc now being produced in special grades to meet the needs of the
`pharmaceutical industry. Most of these products contain combinations of sucrose with invert
`sugar or modified dcxtrins and arc of particular value in the formulation of chewable tablets.
`Starch is often cited as a fillcr, but it is more commonly uscll in its dry state as a disinte(cid:173)
`grating agent. However, modilicd starches such as StaRx 1500 and National 1551 (partially
`
`Table 6 Comparative Properties of Some Directly Compressible Fillers'
`Compac.:tibility Flowability Solubility Disinh.:gration
`
`Filler
`
`I lygroscopic.:ity
`
`Dextrose
`Spray-Jrie<l
`lactose
`Fast-Flo
`lactose
`Anhydrous
`lactose
`Ern<lcx
`(<lextratcs)
`Sm:rosc
`Stard1
`Starch J 500
`Dicalcium
`phospha!c
`Avic.:d (MCC)
`
`J
`
`3
`
`4
`
`2
`
`5
`4
`2
`3
`
`3
`5
`
`2
`
`5
`
`4
`
`3
`
`4
`3
`I
`2
`
`4
`I
`
`4
`
`4
`
`4
`
`4
`
`5
`5
`()
`2
`
`()
`
`2
`
`3
`
`4
`
`4
`
`3
`4
`4
`4
`
`2
`2
`
`'(iradcd <>II a ,r;,lc from 5 (i,:ood/hii,:h) dow11 to I (poor/ low); 0 means 11011c.
`
`5
`
`4
`3
`3
`
`2
`
`Th.is mate.rial wasco,p ied
`at the WLM andmay t;e.
`'>