Modern .
`Pharmaceutics
`
`Christopher T. Rhodes
`
`fillll‘lll ffliliflll, HBViSBfl and EXflflflflBfl
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`edited by
`Gilbert 8. Banker
`
`MYLAN EXHIBIT 1010
`
`MYLAN EXHIBIT 1010
`
`

`

`Modern Pharmaceutics
`
`Fourth Edition. Revised and Expanded
`edited by
`
`Gilbert S.Banker
`
`University of Iowa
`Iowa City, Iowa
`
`Christopher T.Rhodes
`University of Rhode Island
`Kingston, Rhode Island
`
`
`
`
`
`2
`
`
`
`
`
`

`

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`

`

`013
`
`XP009184716
`
`10
`
`Tablet Dosage Forms
`
`Edward M. Rudnlc
`Pharmavene, Inc., Rockville, Maryland
`Mary Kathryn Kottke
`Autoimmune, Inc., Lexington, Massachusetts
`
`I.
`
`INTRODUCTION
`
`During the past three and a half decades, the pharmaceutical industry has invested vast amounts
`of time and money in the study of tablet compaction. This expenditure is quite reasonable
`when one considers how valuable tablets, as a dosage form, are to the industry. As oral dosage
`forms can be self-administered by the patient, they are obviously more profitable to manufac(cid:173)
`ture than parenteral dosage forms, which usually must be administered 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 with
`other oral dosage forms, tablets are the manufacturers' dosage form of choice because of their
`relatively low cost of manufacturing, packaging, and shipping; increased stability, and virtual
`tamper resistance (i.e., most tampered tablets either become discolored or disintegrate).
`
`II. DESIGN AND FORMULATION OF COM~RESSED TABLETS
`A. General Considerations
`
`The most common solid dosage. forms in contemporary practice are tablets, which may be
`defined as unit forms of solid medicaments prepared by compaction. 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 is formulated
`to allow dissolution or dispersion in water before administration. 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 formulated to be effervescent, and their main advantages include rapid
`release of medicament and minimization of gastric irritation.
`Some tablets are designed to be masticated (chewed). This type of tablet is often used when
`absorption from the buccal cavity is desired, or to enhance dispersion before swallowing.
`
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`.1 •• \
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`334
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`XP009184716
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`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 are 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 fentanyl was developed for pediatric use.
`There are now many types of tablet formulations that provide· for the release of the niedi(cid:173)
`cament. to be delayed or to control the rate of the drug's availability. Some ofthese preparations
`are highly sophisticated and are rightly referred to as complete "drug-delivery systems.';
`"Sustained-release" tablets can encompass a broad range of tt;chnologies. Since the con(cid:173)
`cepts of prolonged 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
`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 these, 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 surely make matters worse. To solve such a problem, the formu(cid:173)
`lators would have to turn to other types of water-insoluble materials, such as polymers, to
`achieve drug release and tableting goals.
`Some tablets combine sustained-release characteristics with a rapidly disintegrating tablet.
`Such products as K-Dur (Key Pharmaceuticals) combine coated potassium chloride (KCl) crys(cid:173)
`tals in a rapidly releasing tablet. In this particular instance, the crystals are coated with ethyl(cid:173)
`cellulose, a water-insoluble polymer and are then incorporated in a rapidly disintegrating mi(cid:173)
`crocrystalline cellulose matrix. The purpose of this tablet is to minimize GI ulceration,
`commonly seen with KCl therapy. This simple, but elegant, formulation is a masterpiece of
`solid dosage form strategy 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 achieve developmental objec(cid:173)
`tives. To do this properly, the formulator must know the properties of the drug, the materials
`to be coformulated 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(cid:173)
`punch press), or when the upper and lower punches squeeze together (rotary press), the powder
`is forced into a tablet. Despite that' powder compaction has been observed for millennia, sci(cid:173)
`entists still debate the exact mechanisms behind this phenomenon.
`Perhaps the most significant factor in the tableting process arises from 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 commen(cid:173)
`surate with modern tablet press operation is impossible. This requirement immediately places
`demands on the physical characteristics of the feed and on the design of the tablet press itself.
`In the former, precompression treatment of the granulation is one of the most common ways
`of minimizing difficulties arising from this source.
`The great paradox in pharmaceutical tableting is the need to manufacture a compact capable
`of reproducibly releasing the drug that is of sufficient. mechanical strength to wi~hstand the
`rigors of processing and packaging. Usually, the release of the drug is produced by the· pene-
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`XP009184716
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`Tablet Dosage Forms
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`335
`
`tration 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 oftablets.
`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, th.e flow
`properties of the mixed ingredients, and the tendency of the granulation to segregate .. Currently,
`there are also two. conflicting considerations that tend to play a major role in this choice. These
`are the relqctance 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 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, whereas the tiend for new prod(cid:173)
`ucts is to use direct compression procedures. Although many steps are eliminated when using
`direct compression, some formulators have found that wet granulated products are more mbust
`and able to accommodate variability in raw materials. Thus, for some companies, the trend is
`reverting to· the formulation of tablets by wet granulation.
`
`B. Desirable 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 are necessary. To
`produce accurate, 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.
`Particle 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
`are enhanced by using regular-shaped, smooth particles with a narrow size distribution, tqgether
`with an optimum proportion of "fines" (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 [l]. In fact, it has been suggested that, for sue~
`drugs, standards for specific surface areas and the number of particles per unit weight shouid
`be developed. However, the difficulty in handling very fine powders, as well as the possibility
`of altering the material in other ways, has shifted the emphasis towards producing an optimum,
`rather than a minimum, particle size. For instance, several researchers have found that decreas(cid:173)
`ing particles size produces tablets of increased strength, as well as reduced tendency for lam-·
`ination [2-Sl, This is probably due to the minimization of any adverse influences that a par(cid:173)
`ticular crystal structure may have on the bonding mechanism. On the other hand, samples of
`milled digoxin crystals prepared by various size-reduction techniques have been reported to
`elicit different equilibrium solubilities [1 ]. This suggests that the method of grinding may well
`affect the dissolution behavior of certain medicaments.
`The effect of particle size on the compaction characteristics of two model sulfonamide drugs,
`one exhibiting·brittle fracture and the other being compressed chiefly by plastic deformation,
`has been reported [3]. In particular, the tensile strength of tablets made from the brittle material
`
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`

`

`XP009184716
`
`336
`
`Rudnlc and Kottke
`
`were more sensitive to the drug's particle size than that of tablets made from the plastically
`deforming material. In addition, larger granules possess better flow, whereas small aggregates
`deform during compaction (e.g., spray-dried lactose) [6].
`An alternative approach aimed at reducing the segregation tendencies of medicaments and
`excipients involves miUing the former to a small particle size and, then, physically absorbing
`it uniformly onto the surface of the larger particles of an excipient substrate. By these means
`ordered, as opposed to random, mixing is realized, and dissolution is enhanced as a result of
`the fine dispersion [7].
`
`Moisture Content
`One of the most significant parameters contributing to the behavior of many tablet formulations
`is 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 evidence
`to suggest that moisture levels may be very critical in minimizing certain faults, such as lam(cid:173)
`ination, 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. 1 illustrates the
`effect of moisture content on the compactibility of anhydrous lactose (8]. As the moisture
`content increases, it is absorbed by the lactose, thereby converting it from the anhydrous to
`the hydrous form. During this transformation, the 13-form of lactose most probably changes to
`the a-form and, thus, produces changes in compactibility.
`Accelerated aging and crystal transformation rates have also been traced to high residual
`moisture content. Ando et al. studied the effect of moisture content on the crystallization of
`anhydrous theophylline in tablets [9]. Their results also indicate that anhydrous materials con(cid:173)
`vert to hydrates at high levels of relative humidity. In addition, if hygroscopic materials [e.g.,
`polyethylene glycol (PEG) 6000] are also contained in the formulation, needlelike crystals
`form at the tablet surface and significantly reduce the release rate of the theophylline.
`In many products, it seems highly probable that there is a narrow range of optimum moisture
`content that should be maintained. More specifically, the effect of moisture on microcrystalline
`
`300
`
`250
`
`...
`'"200
`!.
`e 150
`= " ..,
`e c. 100
`
`50
`
`0
`
`1
`
`5.13%
`
`3.53%
`1.93%
`
`0.33%
`
`3
`
`7
`5
`Hardness (kg)
`
`9
`
`11
`
`fig. 1 The effect of moisture content on the compactibility of anhydrous '3-lactose tablets. (From
`Ref. 8.)
`
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`
`

`

`Tablet Dosage Forms
`
`XP009184716
`
`337
`
`cellulose (MCC)-containing tablets has been the subject of an investigation that demonstrates
`the sensitivity of this important excipient to moisture content [10). Differences exist in both
`the cohesive pature and the moisture content of two commercial brands of MCC [10]. A very
`useful report on the equilibrium moisture content of some 30 excipients 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 Pharmaceutical Excipients [12].
`
`Crystalline 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)
`phenicol esters produce little clinical response [13]. There is also a significant difference in the
`bioavailability of anhydrous and hydrated forms of ampicillin [14]. 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 Doelker reviewed several drugs
`that undergo polymorphic transformation when triturated in a mortar and pestle [16]. Some of
`their conclusions are listed in Table 1 and illustrated in Fig. 2. In 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 naproxen crystals that had been spherically agglomerated with different
`solvents and found that signiftcant differences existed between the various types of agglom(cid:173)
`erates (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 growth rate of the stable form (22]. These polymorphic changes may have a profound
`effect on tablet performance in terms of processing, in vitro dissolution, and in vivo absorption.
`In fact, a major clinical failure of generic carbamazepine tablets can be directly linked to
`
`Table 1 Some Drugs That Undergo Polymorphic Transition When
`Triturated
`
`Number of polymorphs
`before trituration
`
`Number of polymorphs after
`trituration
`
`2
`2
`3
`2
`2
`3
`4
`4
`3
`2
`2
`
`1
`1
`2
`3
`1
`1
`5
`3
`2
`1
`1
`
`Drug
`
`Barbi tone
`Caffeine
`Chlorpropamide
`Clenbuterol HCl
`Dipyridamole
`Maprotiline HCI
`Mebendazole
`Nafoxidine HCI
`Pentobarbitone
`Phenobarbitone
`Sulfabenzamide
`
`Source: Ref. 16.
`
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`

`

`338
`
`30
`
`XP009184716
`
`' Rudnfc and Kottke
`
`o;-~-.-~--,.--~....-~-..-~--...~~..-~
`150
`250
`50
`350
`Pressure (MPa)
`Lower Surface
`-
`Middle Region
`-
`Upper Surface
`-
`--+-Side
`
`Fig. 2 Percentage of caffeine "form A" transformed versus applied pressure. (From Ref. 16.)
`
`15
`
`10
`
`O+-~-.-~~.--..,..-......--........... _,.~.---.--~-.
`2500
`1000
`1500
`2000
`500
`3000 3500
`Pressure (lbs)
`
`- Control
`- Octanol
`
`--0-- Hexanol
`
`- -0 - - Toluene
`
`Fig. 3
`Intrinsic compressibility of nonagglomerated naproxen (control) and of naproxen t4at has been
`spherically agglomerated with different solvents. (From Ref. 21.)
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`XP009184716
`
`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 appfoach
`to formulation can be followed.
`
`Hiestand 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 are 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 (BI) is a measure of the material's abili•y to form bonds and undergo plastic travsfor(cid:173)
`mation 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 several drugs
`and excipients. 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 t.he basis of its BI value, one might expect relatively good bonding. However, the
`very high strain index associated with this drug appears to overcome its bonding abilities.
`Microcrystalline cellulose, on the other hand, has very high strain index, but its bonding index
`is exceptionally high and compensates for this effect.
`Other investiga.tors 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 (29]. A full discussion of compaction mechanisms is given later in
`this chapter.
`
`Variability
`The effect of raw material variability of tablet production [2,30,31] and suggestions for im(cid:173)
`proving tableting quality of starting materials {21 l 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 [32l Phadke and Eichorst have also confirmed that
`significant differences can exist between different sources, and even different lots, of magne(cid:173)
`sium stearate (33]. Given that the effectiveness of magnesium stear.ate is primarily due to its
`large surface area, these variations should not be overlooked. Ii:i 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 attention. Apart from the obvious
`reasons for a high level of integrity, as recognized by the regulatory requirements, we should
`be aware of more subtle implications that are perl!aps only just beginning to emerge. For
`instance, small proportions of the impurity acetylsalicyllc anhydri,de reduces the dissolution
`rate of aspirin itself (Fig. 4) (34] .
`. Ariotber area of interest is tha.t of microbiological contamination of solid dosage forms,
`which is thought to arise chiefly from raw materials, rather than the manufacturing process
`[35,36]. Ibrahim and Olurinola monitored the effects of production, environment, and method
`of production, as well as microbial quality of starting materials, on the microbial load during
`various stages of tablet production [35]. Although high levels of contamination were present
`during the wet granulation process, these levels were significantly reduced during the drying
`process. Thus, products derived from natural origins, such as gelatins and starch, are sometimes
`heavily contaminated.
`·
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`

`340
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`XP009184716
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`Rudnic and Kottke
`
`Table 2 Hiestand Compaction Indices for Some Drugs and Excipients
`
`Material
`
`Bonding index
`
`Brittle fracture
`index
`
`Strain index
`
`Aspirin
`Caffeine
`Croscarmellose sodium NF
`Dicalcium phosphate
`Erythromycin dihydrate
`Hydroxypropyl cellulose
`Ibuprofen
`A
`B
`c
`Lactose USP
`·Anhydrous
`Hydrous Fast-Flo
`Hydrous bolted
`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
`c
`Source: Refs. 23-28.
`
`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
`
`0.6
`0.5
`
`0.8
`0.5
`1.6
`4.5
`
`4.3
`3.3
`1.7
`0.9
`
`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
`
`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
`0.42
`0.16
`
`0.26
`0.14
`0.02
`0.27
`
`0.35
`0.42
`0.53
`
`1.11
`2.19
`3.79
`1.13
`2.13
`2.10
`
`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
`
`2.48
`2.02
`2.08
`2.30
`
`1.45
`1.79
`1.55
`
`Compatibility
`One final area that should be considered when choosing the excipients to be used in the tablet
`formulation is that of drug-excipient interactions. There is still much debate about whether
`· excipient compatibility testing should be conducted before formulation [37-39]. These tests
`most often involve the trituration of small amounts of the active ingredient with a variety of
`excipients. Critics of these small-scale studies argue that their predictive value has yet to be
`established and, indeed, they do not reflect actual processing conditions [37]. Instead, they
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`Table 3 Average Particle Data for Different Sources of Magnesium Stearate
`
`Source
`
`United States
`Great Britain
`Germany
`Italy
`
`Source: Ref. 32.
`
`Size (µ,m)
`
`1.5-3.2
`2.1-5.2
`4.1-6.9
`5.5-9.l
`
`Surface area (m2/g)
`
`Pore radius (A)
`
`0
`
`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,,
`formulation" studies as a preferable method for investigation of drug-excipient interactions.
`
`C. Tablet Components
`
`Conventional solid dosage forms can be 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 are 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 as "non-controlled(cid:173)
`release." This term is a misnomer, since, with the aid of modern tablet disintegrants and other
`excipients, 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 are 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
`
`y = 1.3094 - 0.30351x R"2 = 0.978
`
`a:
`c
`
`1.0
`
`.. '1il
`-2 ...
`.. .. Q
`0 0.8
`
`0.6
`
`0.4
`0
`
`2
`% Acetylsalicylic Anhydride
`
`3
`
`Fig. 4 Effect of acetylsalicylic anhydride impurity on the dissolution rate of aspirin tablets. (From
`Ref. 34.)
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`342
`
`Intact Tablet .
`
`DRUG IN
`BLOODSTREAM
`
`/7 Biological
`
`Membrane
`
`DRVGIN
`SOLUTION
`
`Fig. 5 Absorption of a drug from an intact tablet.
`
`drug is maximized. Very often, this means that disintegration of the tablet must be followed
`by granular disintegration (Fig. 5) to promote rapid dissolution and, hence, absorption.
`The ingredients, or excipients, used to make compressed tablets are numerous. They can be
`classified by their use, or function, as in Table 4. Keep in mind, however, that not all formu(cid:173)
`.lations need contain all the types of ingredients listed in this table. Certain excipients, such as
`antioxidants and wetting agents, are used only in situations for which they are expressly needed
`to assure the stability and solubility of the active ingredients. Other excipients, such as dis(cid:173)
`solutiOn modifiers, are used primarily in controlled-release formulations. In fact, by reducing
`the number of ingredients in a formulation, one will generally reduce the number of problems
`that may arise in the manufacturing process. Hence, many formulators adhere to the motto
`·
`"Keep' it simple."
`
`- ~ ' .,
`
`Table 4
`
`Ingredients Used in Tablet Formulation
`
`Active Ingredient (drug)
`f'.illers
`Binders (dry and wet)
`Disintegrants
`Dissolution retardants
`· Lubricants
`Glidants
`
`Antiadherants
`Wetting agents
`Antioxidants
`Preservatives
`Coloring agents
`Flavoring agents
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`'
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`.. ,'
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`
`Because of the nature of modem 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 excipient will
`produce is often dependent on the concentration in which it is used. For example, Table 5 lists
`some multiuse excipients and the corresponding concentration ranges required for their various
`applications.
`
`Active Ingredients
`The dose of the drug to be administered has a profound effect 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 does
`the effect of the drug's attributes on the tablet.
`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 number of drugs are 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 diluents should meet important criteria, including low cost and good-tableting qualities.
`
`. ~ ...
`
`·,._
`
`.......
`
`Table 5 Some Multiple-Use Excipients for Tablet Formulation
`
`Excipient/concentration in formula (%)
`
`Use
`
`Glyceryl behenate
`0-5
`5-30
`Hydroxypropylmethyl cellulose
`(HPMC), low viscosity
`0-5
`5-20
`5-26
`Microcrystalline cellulose (MCC)
`0-8
`5-15
`5-95
`Polyethylene glycol
`0-10
`5-40
`Polyvinylpyrrolidone (PVP)
`0-15
`5-10
`5-30
`10-35
`Starch
`0-5
`5-10
`5:...20
`
`Lubricant
`Controlled-release excipient
`
`Wet binder
`Film former
`Controlled-release excipient
`
`Improve adhesion of film coat to core
`Disintegrant
`Binder/filler
`
`Lubricant
`Controlled-release excipient
`
`Wed binder
`Coating excipient
`Disintegrant
`Controlled-release excipient
`
`Intragranular binder/disintegrant
`Wet binder
`Disintegrant
`
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`

`344
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`XP009184716
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`Rudnlc and Kottke
`
`It may be possible, in some instances, to combine the role of diluent with a different property,
`such as a disintegrant or flavoring agent.
`Commonly used fiJ!ers and binders and their comparative 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 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
`Bolhuis and Lerk [40] and Shangraw et al. [6] bas demonstrated that all lactoses are not