Modern
`Pharmaceutics
`Fourth Edition, Revised and Expanded
`
`edited by
`Gilbert $. Banker
`University of lowa
`lowa City, fowa
`
`Christopher T. Rhodes
`University of Rhode Island
`Kingston, Rhode island
`
`MARCEL
`
`a
`
`Marcer Dexxer, Inc.
`
`DEKKER
`
`New York « Baser
`
`
`
`Hopewell EX1065
`Hopewell v. Merck
`IPR2023-00480
`
`Hopewell EX1065
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`ISBN: 6-8247-0674-9
`
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`PRINTED IN THE UNITED STATES OF AMERICA
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`2
`
`

`

`Chapter 10
`
`Tablet Dosage Forms
`
`Mary Kathryn Kottke
`
`Cubist Pharmaceuticals, Inc., Lexington, Massachusetts
`Edward M. Rudnic
`
`Advancis Pharmaceutical Corp., Gaithersburg, Maryland
`
`I.
`
`INTRODUCTION
`
`During the past four decades, the pharmaceutical in-
`dustry has invested vast amounts of time and moneyin
`the study of tablet compaction. This expenditure is
`quite reasonable when one considers how valuable
`tablets, as a dosage form, are to the industry. Because
`oral dosage forms can be self-administered by the pa-
`tient,
`they are obviously more profitable to manu-
`facture than parenteral dosage forms that must be
`administered, in most cases, by trained personnel. This
`is reflected by the fact that well over 80% of the drugs
`in the United States that are formulated to produce
`systemic effects are marketed as oral dosage forms.
`Compared to other oral dosage forms, tablets are the
`manufacturer’s dosage form of choice because of their
`relatively low cost of manufacture, package, and
`shipment;
`increased stability and virtual tamper re-
`sistance (most
`tampered-with tablets either become
`discolored or disintegrate).
`
`Il. DESIGN AND FORMULATION
`OF COMPRESSED TABLETS
`
`A. General Considerations
`
`in con-
`The most common solid dosage forms
`temporary use are tablets, which may be defined as
`
`unit forms of solid medicaments prepared by com-
`paction. Most consist of a mixture of powders that are
`compacted in a die to produce a single rigid body. The
`most common types of tablets are those intended to be
`swallowed whole and then disintegrate and release
`their medicaments in the gastrointestinal tract (GIT).
`A less common type of tablet that is rapidly gaining
`popularity in the United States is formulated to allow
`dissolution or dispersion in water prior to adminis-
`iration. Ideally, for this type of tablet all ingredients
`should be soluble, but frequently a fine suspension has
`to be accepted. Many tablets of this type are for-
`mulated to be effervescent, and their main advantages
`inelude rapid release of drug and minimization of
`gastric irritation.
`Some tablets are designed to be masticated {i.c.,
`chewed). This type of tablet is often used when ab-
`sorption from the buceal cavity is desired or to en-
`hance dispersion prior to swallowing. Alternatively, a
`tablet may be intended to dissolve slowly in the mouth
`(e.g., lozenges) so as to provide local activity of the
`drug. A few tablets are designed to be placed under the
`tongue (i.¢., sublingual) or between the teeth and gum
`(i.c., buccal} and rapidly release drug into the blood-
`stream. Buceal or sublingual absorption is often
`desirable for drugs liable to extensive hepatic meta-
`bolism by the first-pass effect
`(e.g., nitroglycerin,
`
`287
`
`3
`
`

`

`288
`
`Kottke and Rudnic
`
`testosterone). Recently, a lozenge on a stick, or “lol-
`lipop,” dosage form of fentanyl was developed for
`preoperative sedation in pediatric patients (Oralet®)
`and breakthrough cancer pain in adults (Actiq®).
`Active ingredient is released from the lozenge into the
`bloodstream from the oral nrucosa.
`There are now many types of tablet formulations
`that provide for the release of drug te be delayed or
`control the rate of the drug’s availability. Some of
`these preparations are highly sophisticated and are
`rightly referred to as complete “drug-delivery sys-
`tems.” Since the concepts of controlled drug delivery
`are the subjects of Chapter 15, the strategies of these
`systems will not be discussed here, However, solid
`dosage formulators must be aware of the various op-
`tions available to them.
`For example, when prolonged release of a water-
`soluble drug is
`required, water-insoluble materials
`must be co-formulated with the drug. if the dose of the
`drugis high and it exhibits poor compactibility, purely
`hydrophobic agents, such as waxes, will exacerbate the
`inability of the material to form a compact. In such
`cases, formulators need to turn to other types of water-
`insoluble materials, such as polymers, to achieve both
`drug release and tableting goals.
`Some tablets combine sustained-release and rapid
`disintegration characteristics. Products such as K-
`Dur® (Key Pharmaceuticals) combine coated po-
`tassium chloride crystals in a rapidly releasing tablet.
`In this particular instance, the crystals are coated with
`éthylceliulose, a water-insoluble polymer, and are then
`incorporated into a rapidly disintegrating micro-
`crystalline cellulose (MCC) matrix. The purpose ofthis
`tablet is to minimize GI ulceration, commonly en-
`countered by patients treated with potassium chioride.
`This simple but elegant formulation is an example of a
`solid dosage form strategy used to achieve clinical
`goals.
`Thus, the single greatest challenge to the tablet
`formulator is in the definition of the purpose of the
`formulation and the identification of suitable materials
`to meet development objectives. In order to do this
`properly, the formulator must know the properties of
`the drug, the materials to be co-formulated with the
`drug, and the important aspects of the granulation,
`tableting, and coating processes.
`Pharmaceutical compressed tablets are prepared by
`placing an appropriate powder mix, or granulation, in
`a metal die on a tablet press. At the base of the die is a
`lower punch, and above the die is an upper punch.
`When the upper punch is forced down on the powder
`mix (single station press) or when the upper and lower
`
`punches squeeze together (rotary or multiple station
`press), the powder is forced into a tablet. Despite the
`fact that powder compaction has been observed for
`hundreds of years, scientists still debate the exact me-
`chanisms behind this phenomenon.
`Perhaps the most significant factor in the tableting
`of materials for use as drug products is the need to
`produce tablets of uniform weight. This is achieved by
`feeding constant volumes of homogeneous material to
`the dies. Such an approach is necessary because direct
`weighing at rates commensurate with modern tablet
`press operation is impossible. This requirement im-
`mediately places demands on the physical character-
`istics of the feed and on the design of the tablet press
`itself.
`In the case of the former, precompression
`treatment of the granniation is one of the most com-
`mon ways of minimizing difficulties arising from this
`source.
`The great paradox in pharmaceutical tabletingis the
`need to manufacture a compact of sufficient mechan-
`ical strength to withstand the rigors of processing and
`packaging that is also capable of reproducibly releas-
`ing the drug. In most cases, the release of the drug is
`produced by the penetration of aqueous fluids into the
`fine residual pore structure of the tablet and the con-
`tact of these fluids with components that either swell or
`release gases.
`if any,
`The selected precompression treatment,
`markedly affects the manufacture of tablets. In parti-
`cular, one must determine whether a mixture of pow-
`dered 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 drug to heat and moisture: the flow
`properties of the granulation; and the tendency of the
`granulation to sepregate. At the present time there are
`also two conflicting considerations that tend to play a
`major role in this choice. These are the reluctance to
`change methods employed traditionally by the com-
`pany versus the economic advantages of omitting
`complete stages in the production sequence,
`In wet granulation,
`the componenis of the for-
`mulations are 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,
`while the trend for new products is to use direct
`compression procedures. Although many steps are
`eliminated when using direct compression, some for-
`mulators have found that wet granulated products are
`more robust and able to accommodate variability in
`raw materials and tableting equipment. Thus, for some
`
`4
`
`

`

`289
`
`The effect of particle size on the compaction char-
`acteristics of two model sulfonamide drugs, one ex-
`hibiting brittle fracture and the other being compressed
`chiefly by plastic deformation, has been reported [3]. In
`particular,
`it was shown that the tensile strength of
`tablets made from the brittle material were more sen-
`sitive to the drug’s particle size than that of tablets
`made from the plastically deforming material. In ad-
`dition, larger granules possess better fiow, while small
`ageregates deform during compaction (¢.g., spray-
`dried lactose) [6].
`reducing the
`An alternative approach aimed at
`segregation tendencies of medicaments and excipients
`involves milling the former to a small particle size and
`then physically absorbingit uniformly onto the surface
`of the larger particles of an excipient substrate. By
`these means “ordered,” 2s opposed to ‘‘random,”
`mixing is realized and dissolution is enhanced as a
`result of the fine dispersion [7].
`
`Moisture Content
`
`One of the mostsignificant parameters contributing to
`the behavior of many tablet formulationsis the level of
`moisture present during manufacture as well as that
`residual in the product. In addition to its role as a
`granulation fluid and its potentially adverse effects on
`stability, water has some subtle effects that should not
`be overlooked. For example, there is increasing evi-
`dence fo suggest that moisture levels may be very cri-
`tical in minimizing certain faults, such as lamination,
`that can occur during compression. Moisture levels can
`also affect the mechanical strength of tablets and may
`act as an internal lubricant. For example, Fig.
`| illus-
`
` 1
`
`3
`
`7
`5
`Hardness (kg)
`Fig. 1 The effect of moisture content on the compactibility
`of anhydrous beta lactose tablets. rom Ref. 8.)
`
`3)
`
`11
`
`qablet Dosage Forms
`
`companies, the trend isreverting to the formulation of
`ablets by wet granulation.
`
`B. Desirable Properties of Raw Materials
`Most formulations are composed of one or more
`medicaments plus a variety of excipients. Irrespective
`of the type Of tablet, general criteria for these raw
`materials are necessary. Jn order to produce accurate
`reproducible dosage forms, it is essential that each
`component be uniformly dispersed within the mixture
`and that any tendency for component sepregation be
`minimized, In addition, the processing operations de-
`mand that the mixture be both free-flowing and co-
`hesive when compressed.
`
`Particle Size
`
`In general, the tendencies for a powder mix to segre-
`gate can be reduced by maintainingsimilarparticle size
`distribution, shape, and, theoretically, density ofall the
`ingredients. Flow properties are enhanced by using
`regular-shaped, smooth particles with a narrow size
`distribution together with an optimum proportion of
`“fines” (particles 50 ym). 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 re-
`ceived considerable attention in the literature. For
`many drugs, particularly those whose absorption is
`limited by the rate of dissolution, attainment of ther-
`apeutic levels may depend upon achieving a small
`particle size [1]. 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 devel-
`oped. However,
`the difficulty in handling very fine
`powders, as well as the possibility of altering the ma-
`terial in other ways, has shifted the emphasis towards
`producing an optimum, rather than a minimum, par-
`ticle size, For instance, several researchers have found
`that decreasing particle size produces tablets of in-
`Creased strength that also have 4 reduced tendency for
`lamination [2-5]. This is probably due to the mini-
`mization of any adverse influences that 2 particular
`crystal structure may have on the bonding mechanism.
`On the other hand, samples of milled digoxin crystals
`Prepared by a number of size-reduction techniques
`have been reported to elicit different equilibrium 80-
`lubilities [1]. This suggests that the method of grinding
`i well affect the dissolution behavior of certain
`
`Tugs,
`
`5
`
`

`

`290
`
`trates the effect of moisture content on the cempact-
`ibility of anhydrous lactose [8]. As the moisture con-
`tent increases, it is adsorbed by the lactose, thereby
`converting it from the anhydrousto the hydrous form.
`During this transformation, the B-form oflactose most
`probably changes to the o-form and thus produces
`changes in compactibility.
`Accelerated aging and crystal transformation rates
`have also been traced to high residual moisture con-
`tent. Andoet al. studied the effect of moisture content
`on the crystallization of anhydrous theophylline in
`tablets [9]. Their results also indicate that anhydrous
`materials convert to hydrates at high levels of relative
`humidity. In addition, if hygroscopic materials {e.g.,
`polyethylene glycol 6000) are also contained in the
`formulation, needle-like crystals form at
`the tablet
`surface and significantly reduce the release rate of the
`theophylline.
`In many products it seems highly probable that
`there exists a narrow range of optimum moisture
`contents that should be maintained. More specifically,
`the effect of moisture on MCC-containingtablets has
`been the subject of an investigation that demonstrates
`the sensitivity of this important excipient to moisture
`content [10]. These researchers found that differences
`exist in both the cohesive nature and the moisture
`content to two commercial brands of MCC. A very
`useful report on the equilibrium moisture content of
`some 30 excipients has been compiled by a collabora-
`tive group of workers from several pharmaceutical
`companies and appears in the Handbook af Pharma-
`ceutical Excipients [11,12].
`
`Crystalline Form
`
`Selection of the most suitable chemical form of the
`active principle for a tablet, while not strictly within
`our terms of reference here, must be considered. For
`example, some chloramphenicol esters produce little
`clinical response [13]. There is also a significant dif-
`ference in the bioavailability of anhydrous and hy-
`drated forms of ampicillin [14]. Furthermore, different
`polymorphic forms, and even crystal habits, may have
`a pronounced influence on the bioavailability of some
`drugs due to the different dissolution rates they exhibit.
`Such changes can also give rise to manufacturing
`problems. Polymorphism is, of course, not restricted to
`active ingredients, as shown, for example, in an eva-
`fuation of the tableting characteristics of five forms or
`sorbitol [15].
`Many drugs have definite and stable crystal habits.
`Morphological changes rarely occur in such drugs as
`
`Kottke and Ruduic
`
`Table 1 Some Drugs That Undergo Polymorphic Transi-
`tion When Triturated
`
`Numberof
`Number of
`polymorphs
`polymorphs
`Drug
`before trituration
`after trituration
`
`
`Barbitone
`Caffeine
`Chiorpropamide
`Clenbuterol HCI
`Dipyridamole
`Maprotiline HC!
`Mebendazole
`Nafoxidine HC]
`Pentobarbitone
`Phenobarbitone
`Sulfabenzamide
`
`Source: Ref. 16.
`
`2
`2
`3
`2
`2
`3
`4
`4
`3
`2
`2
`
`I
`1
`2
`3
`i
`1
`5
`3
`2
`I
`i
`
`the formulation process is scaled up. However, some
`drugs exhibit polymorphism or have different identifi-
`able crystal habits. Chan and Doelker reviewed a
`number of drugs that undergo polymorphic transfor-
`mation when triturated in a mortar and pestle [16].
`Some of their conclusions are listed in Table 1 and ii-
`lustrated in Fig. 2.
`In addition, a number of re-
`searchers have concluded that both polymorph and
`crystal habit
`influence the compactibility and me-
`chanical strength to tablets prepared from poly-
`morphic materials
`[16-21]. York compared the
`compressibility of naproxen crystals that had been
`spherically agglomerated with different solvents and
`found that significant differences existed between the
`various types of agglomerates (see Fig. 3) [21]. Other
`investigators have found that, in some instances, there
`is a correlation between the rate of reversion to the
`metastable form during dissolution and the crystal
`growthrate of the stable form [22]. These polymorphic
`changes may have a profound effect on tablet perfor-
`mance in terms of processing, in vitro dissolution and
`in vive absorption. Thus, formulators of solid dosage
`forms must be aware of a subject compound’s pro-
`pensity for polymorphic transition so that a rational
`approach to formulation can be followed.
`
`Hiestand Tableting Indices
`
`Materials that do not compress well produce soft ta-
`Diets. In addition, brittle crystalline materials will yield
`brittle tablets. Hiestand was the first pharmaceutical
`scientist to quantify rationally the compaction prop-
`erties of pharmaceutical powders [23-28]. The results
`
`6
`
`

`

`Tablet Dosage Forms
`
`291
`
`350
`
`30
`
`Zz 2
`
`10
`
`E:R
`
`0
`
`50
`
`undergo plastic transformation to produce a suitable
`tablet. The third index, the brittle fracture index (BFI),
`is a measure of the brittleness of the material and its
`compact, Table 2 lists these indices for a number of
`drugs and excipients. For most materials, the strength
`of the tablet is a result of competing processes. For
`example, erythromycin is a material known forits
`tendency to cap and laminate when tableted. On the
`basis of its BI value, one might expect relatively good
`bonding. However, the very high strain index asso-
`ciated with this drug appears to overcomeits bonding
`abilities. MCC, on the other hand, has very high strain
`index, but its bonding index is exceptionally high and
`compensates for this effect.
`250
`450
`Other investigators have evaluated the potential for
`Pressure (MPa}
`—w— Lower Surface
`these indices. In their studies, Williams and McGinnity
`~e— Middle Region
`have concluded that evaluation of single-material sys-
`oood
`a~wa—- Upper Surlace
`tems should precede binary or tertiary powder systems
`Side
`(29}. A full discussion of compaction mechanisms is
`piven later in this chapter.
`
`Fig. 2 Percentage of caffeine “form A” transformed vs.
`applied pressure, (From Ref. 16.)
`
`of this work are three indices known as the Hiestand
`Tableting Indices. The strain index (SDis a measure of
`the internal entropy, or strain, associated with a given
`material when compacted. The bonding index (BD is a
`measure of the material’s ability to form bonds and
`
`15
`
`oh Qo
`
`on
`
`Hardness{kq)
`
`“500
`
`7000
`
`3000 350
`
`2500
`2000
`1500
`Pressure {ibs}
`—e- Control
`—w Hexanot
`— Octarat
`—o— Tolusne
`
`Intrinsic compressibility of nonagglomerated na-
`Fig. 3
`proxen (control) and of naproxen that has been spherically
`agglomerated with different solvents. (From Ref. 21.)
`
`Variability
`
`The effect of raw material variability on tablet pro-
`duction [2,30,31] and suggestions for improving ta-
`bleting quality of starting materials [21] has been the
`subject of several pubiications. Table 3, whichlists the
`characteristics of different
`sources of magnesium
`stearate, clearly illustrates the variability of this ma-
`terial [32]. Phadke and Eichorst have also confirmed
`that significant differences can exist between different
`sources, and even different lots, of magnesium stearate
`[33]. Given the fact that the effectiveness of magnesium
`stearate is due, in large part, 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
`materials to ensure uniformity of the final product.
`
`Purity
`Raw material purity, in general, must also be given
`careful attention, Apart from the obvious reasonsfor a
`high level of integrity, as recognized by the regulatory
`requirements, one should be aware of more subtle
`implications that are perhaps only just beginning to
`emerge, For instance, small proportions of the im-
`purity acetylsalicylic anhydride have been shown to
`reduce the dissolution rate of aspirin itself (see Fig. 4)
`134].
`Another area of interest is that of microbiological
`contamination of solid dosage forms, which is thought
`to arise chiefly from raw materials rather than the
`
`7
`
`

`

`292
`
`Kottke and Rudunic
`
`Table 2 Hiestand Compaction Indices for Some Drugs and
`Excipients
`
`Table 3 Average Particle Data for Different Sources of
`Magnesium Stearate
`
`Material
`
`Strain
`Brittle
`Bonding
`index fracture index index
`
`Aspirin
`Caffeine
`Croscarmellose sodium NF
`Dicalcium phosphate
`Erythrorayein dihydrate
`Hydroxypropyl cellulose
`Ibuprofen
`A
`B
`c
`Lactose USP
`Anhydrous
`Hydrous Fast-Flo
`Hydrous beited
`Hydrous spray process
`Spray-dried
`A
`B
`Mannitol
`A
`B
`Methenamine
`Methyl cellulose
`Microcrystalline
`cellulose NF
`Avicel PH 102 (coarse)
`Avicel PH 101 (fine)
`Povidone USP
`Sorbitol NF
`Starch NF
`Corn
`Pregelatinized
`Pregelatinized compressible
`Modified (starch 1500}
`Sucrose NF
`A
`B
`Cc
`
`Source: Refs, 23-28,
`
`15
`13
`2.7
`13
`19
`1.6
`
`1.9
`1.8
`2.7
`
`0.8
`0.4
`0.6
`0.6
`
`0.6
`6.5
`
`0.8
`0.5
`1.6
`4.5
`
`4.3
`3.3
`1.7
`0.9
`
`0.4
`18
`1.2
`1.5
`
`1.0
`0.8
`0.5
`
`0.16 i
`6.34
`2.19
`0,02
`3.79
`0.15
`1.43
`0.98
`2.13
`0.04
`2.10
`
`0.05
`0.57
`0.45
`
`0.27
`0.19
`0.12
`0.45
`
`0.18
`0.12
`
`0.19
`0.15
`0.98
`0.06
`
`0.04
`0.04
`6.42
`6.16
`
`0.26
`6,14
`6.02
`0.27
`
`0.35
`0.42
`0.53
`
`0.98
`1.51
`1.21
`
`1.40
`1.70
`2.16
`2.12
`
`1.47
`1.81
`
`2.18
`2.26
`0.84
`3.02
`
`2.20
`2.37
`3.70
`1.70
`
`248
`2.02
`2.08
`2.30
`
`1.45
`1,79
`1.55
`
`Ibrahim and Olur-
`manufacturing process [35,36].
`inaola monitored the effects of production, environ-
`ment and methed of production, as weil as microbial
`quality of starting materials, on the microbial load
`during various stages of tablet production [35]. Al-
`though high levels of contamination were present
`during the wet granulation process, these levels were
`significantly reduced during the drying process. The
`investigators also found that products derived from
`
`Size
`Surface
`Pore tadius
`Source
`(um)
`area (m”/g)
`(A)
`
`United States
`1.5-3.2
`13,4
`50
`Great Britain
`2.1-5.2
`12.2
`68
`Germany
`41-69
`7A
`6
`
`Italy 36 5.5-9.1 4.6
`
`
`Source: Ref. 32.
`
`natural origins, such as gelatins and starch, can be
`contaminated heavily.
`
`Compatibility
`
`One final area that should be considered when choos-
`ing the excipients to be used in the tablet formulation is
`that of drug-excipient interactions. There is stil! much
`debate as to whether excipient compatibility testing
`should be conducted prior to formulation [37-39].
`These tests most often involve the trituration of smail
`amounts of the active ingredient with a variety of ex-
`cipients. Critics of these small-scale studies argue that
`their predictive value has yet to be established and
`indeed do notreflect actual processing conditions [37].
`Instead,
`they suggest a sound knowledge of the
`chemistry of the materials used in conjuncture with
`“mini-formulation” studies as a preferable method for
`investigation of drug-excipient interactions.
`
` Y= 1.9054 -03035tx F42 = 0.978
`
`DissolutionRate
`
`% Acetylsallcyile Anhydride
`
`Fig. 4 Effect of acetylsalicylic anhydride impurity on the
`dissolution rate of aspirin tablets. (From Ref. 34.)
`
`8
`
`

`

`Tablet Dosage Forms
`
`C. Tablet Components
`
`233
`
`Intact Tablet
`
`SS
`
`DAUG IN
`
`BLOODSTREAM
`
`Coarse
`
`o 2esoRep,Patties
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`5
`T3 hr8
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`slow dissolution
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`Biological
`
`Membrane
`
`Conventional solid dosage forms can be divided into
`two classes: those that disintegrate and those that do
`not. Disintegrating dosage forms release dmg by
`breaking down the physical
`integrity of the dosage
`from, usually with the aid of solid disintegrating agents
`or gas-releasing effervescent agents. Nondisintegrating
`tablets are usually made of soluble drugs and ex-
`cipients that will rapidly dissolve in the mouth or GIT
`upon ingestion.
`With the advent of prolonged-release dosage forms,
`some pharmaceutical scientists have begun to regard
`conventional disintegrating dosage forms as “non—
`controlled-release.” This term is a misnomer since,
`with the aid of “super-disintegrants” and other ex-
`cipients, the disintegration of these dosage forms can
`be controlled, both quantitatively and qualitatively.
`Fine
`.
`Moreover, there are still many drugs in which rapid
`Particles
`.
`ney
`atiainment of therapeuticlevels, rather than controlled
`DRUG IN
`Pees
`a oe ‘s rralSOLUTION
`el te
`pee Dee
`release, is required. Analgesics, antibiotics, and drugs
`>
`as
`egetnest
`for the acute treatment of angina pectoris are prime
`tien stwr
`exarnples, These tablets need to be designed so that the
`drug is liberated from the dosage form in such a
`manner that dissolution of the drug is maximized. Very
`often, this means that disintegration of the tablet must
`be followed by granular disintegration (see Fig. 5) to
`promote rapid dissolution and, hence, absorption.
`The ingredients, or excipients, used to make com-
`pressed tablets are numerous. They can be classified by
`their use, or function, as in Table 4. Keep in mind,
`however, that formulations need not contain all the
`types of ingredients listed in this table, Certain ex-
`cipients, such as antioxidants and wetting agents, are
`used only in situations where they are expressly needed
`to assure the stability and solubility of the active in-
`gredients. Other excipients, such as dissolution modi-
`fiers,
`are
`used
`primarily
`in
`controlled-release
`formulations. In fact, by reducing the number of in-
`gredients in a formulation, one will generally be re-
`ducing the number of problems that can arise in the
`manufacturing process. Hence, many formulators ad-
`here to the motto “Keep it simple.”
`Because of the nature of modern pharmaceutical
`systems, formulators have made more complete in-
`vestigations 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 ex-
`cipient will produce is often dependent upon the con-
`centration in which it is used. For example, Table 5 lists
`some ‘“multiuse” excipients and the corresponding con-
`centration ranges required for their various applications.
`
`eee
`
`dissolution
`
`
`
`Fig. 5 Absorption of a drug from anintact tablet.
`
`A telatively new class of “co-processed” excipients
`now exists. These excipients are essentially a “pre-
`blend” of two or more excipients that are commonly
`used in conjunction with each other.
`
`Active Ingredients
`
`The dose of the drug to be administered has a pro-
`found effect on the design and formulation of a dosage
`form. Content uniformity and drug stability become
`very important issues when dealing with highly potent
`compounds that are delivered in very small doses {e.¢.,
`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 does the effect of
`the drug’s attributes on the tablet.
`
`Table 4 Ingredients Used in Tablet Formulation
`
`Active ingredient (drug)
`Fillers
`Binders (dry and wet)
`Disintegrants
`Antifrictional agents
`Lubricants
`Glidants
`Antiadherants
`
`Dissolution modifiers
`Absorbents
`Flavoring agents
`Coloring agents
`Wetting agents
`Antioxidants
`Preservatives
`
`9
`
`

`

`294
`
`Kottke and Rudnic
`
`Table 5 Some Multiple-Use Excipients for Tablet Formulation
`
`Use
`Excipient/concentration in formula
`
`Wet or dry binder
`Controlled-release coating
`
`Lubricant
`Controlled-release excipient
`
`Wetor dry binder
`Film former
`Controlled-release excipient
`
`Binder
`Disintegrant
`
`Ethylceliulose
`1-3%
`13%
`Glyceryl palmitostearate
`05%
`10-50%
`Hydroxypropylmethy! cellulose (HPMC), low
`viscosity
`2-S%
`2-10%
`5-25%
`Magnesium aluminum silicate
`2-10%
`2-10%
`Microcrystalline cellulose (MCC)
`08%
`0.2-0.5%
`$-20%
`5-20%
`5-95%
`Polyethylene glycol
`0-10%
`G-15%
`5-40%
`Poly(methacrylates)
`2-10%
`$-20%
`10-50%
`5-10%
`Poly(vinyl pyrrolidone) (Povidone, PVP)
`53-15%
`35-10%
`5-30%
`10-35%
`Starch
`315%
`Intragranular binder/disintegrant
`5-25%
`Wet binder
`520%
`Disintegrant
`
`Improve adhesion of film coat to core
`Glidant
`Antiadherant
`Disintepgrant
`Binder/filler
`
`Lubricant
`Thermoplastic filler/binder
`Controlled-release excipient
`
`Film former
`Controlled-release excipient
`Filler
`Coating excipient
`
`Wet binder
`Coating excipient
`Disintegrant
`Controlled-reiease excipient
`
`Sometimes processing can affect the particle mor-
`phology of the active ingredient. This in turn may lead
`to adverse effects on mixing and tableting operations.
`In particular, micronization of a drug may cause
`crystals to change their shape even though poly-
`morphism is not evidenced,
`
`Fillers
`
`An increasing number of drugs are highly potent and
`are thus used in very low dosages. In order to produce
`tablets of a reasonable size G.e., minimum diameter of
`
`3 mm), it is necessary te dilute the drug with an inert
`material. Such diluents should meet importantcriteria,
`including low cost and good tableting qualities. It may
`be possible, in some instances, to combine the role of
`diluent with a different property, such as disintegrant
`or flavoring agent.
`Commonly used fillers and binders and their com-
`parative properties are listed in Table 6. As can be seen
`by this list, both organic and inorganic materials are
`used as fillers and binders. The organic materials used
`are primarily carbohydrates because of their general
`ability to enhance the product’s mechanicalstrength as
`
`10
`
`10
`
`

`

`Tablet Dosage Forms
`
`295
`
`Table 6 Comparative Properties of Some Directly Compressible Fillers*tgegnnn
`
`
`
`
`
`Compactibility Flowability Solubility Disintegration Hygroscopicity LwubricityFiller Stabilityieweee
`Dextrose
`3
`2
`4
`2
`]
`2
`3
`Spray-dried lactose
`3
`5
`4
`3
`1
`2
`4
`Fast-Flo lactose
`4
`4
`4
`4
`J
`2
`4
`Anhydrous lactose
`2
`3
`4
`4
`5
`2
`4
`Emdex (dextrates}
`3
`4
`§
`3
`l
`2
`3
`Sucrose
`4
`3
`5
`4
`4
`i
`4
`Starch
`2
`i
`0
`4
`3
`3
`3
`Starch 1500
`3
`2
`2
`4
`3
`2
`4
`Dicaicium phosphate
`3
`4
`1
`2
`i
`2
`5
`
`5 1 0 2 2 4Avicel (MCC) 5
`
`
`
`
`
`
`
`“Graded on a scale from 5 (good/high) downto 1 (poor/low); 0 means none.
`
`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 Bolhuis and
`Lerk [40] and Shangraw et al.
`[6] has demonstrated
`that all lactoses are not equivalent as determined by
`chemical, physiochemical, and functional measure-
`ments. In addition to the various particle-size grades of
`normal hydrous lactose, one can purchase spray-dried
`lactose, which is an agglomerate of a-lactose mono-
`hydrate crystals with up to 10% amorphous material.
`Spray-dried lactose has very good flow properties, but
`its poor compression characteristics require the addi-
`tion of a binder such as MCC. However, one particular
`brand of spherical crystalline/amorphous agglomer-
`ate, Fast-Fio (NF hydrous), possesses superior com-
`pressibility
`and
`dissolution
`characteristics. The
`spherical nature of the crystals make them more
`compressible than spray-dried agglomerates of lactose
`[41]. Anhydrouslactose has also been used as a diluent,
`particularly in direct compression formulations where
`low moisture content is desirable, since it has very
`gocd stability and a reduced tendency to color upon
`aging. Another advantage in the use of anhydrous
`lactose is that its insensitivity to temperature changes
`
`to be reworked with relative ease. Un-
`allows it
`fortunately,
`its flow properties are not particularly
`good and its compressibility is inferior to other forms
`of lactose. Gne mustalso give attention, though,to this
`component’s stability, as aging may adversely affect
`these properties.
`Some other sugars are now being produced in spe-
`cial grades to meet the needs of the pharmaceutical
`industry. Most of these products contain combinations
`of sucrose with invert sugar or modified dexirins and
`are of particular value in the formulation of chewable
`tablets. In addition, crystalline maltose and directly
`co