Encyclopedia of
`Pharmaceutical Technology
`
`Second Edition
`Volume 3
`Ped-Z
`Pages 2045-3032
`
`edited by
`James Swarbrick
`President
`PharmaceuTech, Inc., Pinehurst, North Carolina
`and
`Vice President for Scientific Affairs, aaiPharma, Inc.
`Wilmington, North Carolina, U.S.A.
`and
`James C. Boylan
`Pharmaceutical Consultant
`Gurnee, Illinois, U.S.A.
`
`MARCEL
`
`DEKKER
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`MARCEL DEKKER, INC.
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`NEW YORK • BASEL
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`MYLAN EXHIBIT 1013
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`

`

`TABLET FORMULATION
`
`Larry L. Augsburger
`University of Maryland, Baltimore, Maryland
`
`Mark J. Zellhofer
`University Pharmaceuticals of Maryland, Inc., Baltimore, Maryland
`
`INTRODUCTION OBJECTIVES
`OF TABLET FORMULATION
`
`The best new therapeutic entity in the world is of little
`value without an appropriate delivery system. Tableted
`drug delivery systems can range from relatively simple
`immediate-release formulations to complex extended- or
`modified-release dosage forms. The most important role of
`a drug delivery system is to get the drug "delivered" to the
`site of action in sufficient amount and at the appropriate
`rate; however, it must also meet a number of other
`essential criteria. These include physical and chemical
`stability, ability to be economically mass produced in a
`manner that assures the proper amount of drug in each and
`every dosage unit and in each batch produced, and, as far
`as possible, patient acceptability (for example, reasonable
`size and shape, taste, color, etc. to encourage patients to
`take the drug and thus comply with the prescribed dosing
`regimen).
`The discovery of new therapeutic entities always
`initiates excitement, but the contributions of the
`formulation specialist are either not well understood or
`are often taken for granted and thus remain "unsung."
`However, the drug and its delivery system cannot be
`separated. The general design criteria for tablets are given
`as follows
`
`1. Optimal drug dissolution and, hence, availability from
`the dosage form for absorption consistent with intended
`use (i.e., immediate or extended release).
`2. Accuracy and uniformity of drug content.
`3. Stability, including the stability of the drug substance,
`the overall tablet formulation, disintegration, and the
`rate and extent of drug dissolution from the tablet for an
`extended period.
`4. Patient acceptability. As much as possible, the finished
`product should have an attractive appearance, includ(cid:173)
`ing color, size, taste, etc., as applicable, in order to
`maximize patent acceptability and encourage compli(cid:173)
`ance with the prescribed dosing regimen.
`
`Encyclopedia of Phannaceutical Technology
`Copyright © 2002 by Marcel Dekker, Inc. All rights reserved.
`
`5. Manufacturability. The formulation design should
`allow for the efficient, cost-effective, practical pro(cid:173)
`duction of the required batches.
`
`That tablets can be formulated to uniquely meet these
`criteria accounts for their emergence as the most prevalent
`oral solid dosage form. Although several different types of
`tablets may be distinguished, they are mostly made by
`compression, intended to be swallowed whole and
`designed for immediate release. This paper presents a
`systematic approach to the design and formulation of
`immediate-release compressed tablets.
`
`MODERN TABLET FORMULATION DESIGN
`AND MANUFACTURE
`
`Tablet dosage forms have to satisfy a unique design
`compromise. The desired properties of rapid or controlled
`disintegration and dissolution of the primary constituent
`particles must be balanced with the manufacturability and
`esthetics of a solid compact resistant to mechanical attrition.
`Excipients are critical to the design of the delivery
`system and play a major role in determining its quality and
`performance (1). They may be selected to enhance
`stability (antioxidants, UV absorbers), optimize or modify
`drug release ( disintegrants, hydrophilic polymers, wetting
`agents, biodegradable polymers), provide essential man(cid:173)
`ufacturing technology functions (binders, glidants, lubri(cid:173)
`cants), enhance patient acceptance (flavors), or aid in
`product identification (colorants). Thus a tablet formu(cid:173)
`lation is not a random combination of ingredients, but
`rather a carefully thought out, rational formulation
`designed to satisfy the above criteria.
`A long list of possible excipients is available to the
`formulation scientist, but certain external factors such as
`cost, functional reliability, availability, and international
`acceptance govern their selection. For example, although
`the official compendia provide standards for identity and
`purity of excipients, monographs may not provide tests to
`
`2701
`
`

`

`2702
`
`assure their functionality. For instance, the NF monograph
`for Compressible Sugar provides no test for compress(cid:173)
`ibility. The monograph for Lactose USP does not address
`the many particle size and tableting grades meeting
`monograph standards. The NF monograph for Pregelati(cid:173)
`nized Starch refers to grades that are "compressible and
`flowable in character," but provides no specifications or
`tests for these properties. Nor do the monograph tests for
`disintegrants and lubricants necessarily relate to their
`functionality. The need to provide functionality tests or
`tests for properties clearly related to functionality may be
`as important as controlling identity and purity (2). This
`point has been made even more apparent in recent years
`with the emergence of multiple sources of such modem
`excipients as direct-compression filler-binders and the
`various classes of "super" disintegrants.
`A major problem currently being faced by multi(cid:173)
`national firms and others who market in the international
`arena, is the lack of universal acceptability of excipients in
`different countries. The selection of excipients for
`international markets is often a compromise between
`functional efficacy, local restrictions, and cost and
`availability in the countries where the product is to be
`made. In recent years, the globalization of the pharma(cid:173)
`ceutical industry has brought about an intense interest in
`developing harmonized pharmacopeial excipient stan(cid:173)
`dards, Good Manufacturing Practices (GMP) for excipient
`manufacture, and safety evaluation guidelines for new
`excipients to eliminate or avoid trade barriers between
`different countries (3). The International Pharmaceuticals
`Excipients Council (IPEC), which consists of producers,
`users, and pharmaceutical scientists, was launched in 1991
`to assist regulatory authorities in the United States, Japan,
`and Europe with harmonization. The separate organi(cid:173)
`zations later formed in the United States (IPEC-Americas),
`Europe (IPEC-Europe), and Japan (JPEC) are now known
`as TriPEC and include, as of 1993, more than 100 excip(cid:173)
`ient and pharmaceutical firms (3).
`
`PREFORMULATION
`
`The objective of preformulation studies is to develop a
`portfolio of information about the drug substance to serve
`as a set of parameters against which detailed formulation
`design can be carried out. Preformulation investigations
`are designed to identify those physicochemical properties
`of drug substances and excipients that may influence the
`formulation design, method of manufacture, and pharma(cid:173)
`cokinetic-biopharmaceutical properties of the resulting
`product.
`
`Tablet Formulation
`
`Following is a generalized preformulation protocol
`appropriate for tablet dosage forms. For certain tests, it is
`assumed that the drug substance is multisourced (a
`previously new chemical entity whose patent has expired
`and which is available to the generic market) for which a
`USP monograph exists.
`
`Identity and Purity
`
`The study of any drug substance must start with the
`determination of identity and purity. Such tests are
`necessary to identify degradents and contaminants and
`may include organoleptic tests for color, odor, and taste.
`Purity tests can be found in the USP for almost all
`marketed compounds. Alternative methods can be
`employed only if they are validated against the USP
`procedure. Tests other than potency, which can help to
`identify or determine the purity of compounds, are melting
`point, specific rotation, pH, heavy metals, residue on
`ignition, etc. Impurities can occasionally affect stability,
`and metal contamination can catalyze chemical reactions.
`Impurities can also alter the color of drug substances.
`Techniques can be utilized to give a quantitative estimate
`of impurities such as the impurity index (II) and the
`homogeneity index (HI). An ordinary impurity test can be
`found in the USP that estimates impurities by thin-layer
`chromatography (TLC).
`
`Crystal Properties and Polymorphism
`
`Many drug substances appear in more than one
`polymorphic form. The form is determined by certain
`conditions during the crystallization step. Occasionally
`drug substances are precipitated in such a way that
`molecules do not organize themselves in any set pattern,
`resulting in an amorphous powder. It is also possible for
`solids to entrap solvents stoichiometrically to form
`solvates.
`Even though they are chemically identical, the different
`polymorphic forms of a compound are associated with
`different free energies, and, therefore, have different
`physical properties that can impact significantly on
`product performance (4). These include differences in
`solubility and dissolution rate (affecting bioavailability),
`solid-state stability (affecting potency), deformation
`characteristics (affecting compactibility), and particle
`size and shape (affecting powder density and flow
`properties). The form with the lowest energy is more
`stable than the others. Although the other polymorphs are
`thus energetically unfavored, if kept dry, they may persist
`indefinitely and are called "metastable." A metastable
`
`

`

`Tablet Formulation
`
`form may be preferred, particularly for its ability to
`dissolve more rapidly.
`Polymorphic transformation can take place during
`pharmaceutical processing, such as particle size
`reduction, wet granulation, drying, and even during the
`compaction process (5). Tests employed to determine
`crystal properties include differential thermal analysis
`(DTA), differential scanning calorimetry (DSC), and
`X-ray diffraction (4). See also the article Thermal
`Analysis of Drugs and Drug Products by D. Giron in this
`encyclopedia.
`
`Particle Size, Shape, and Surface Area
`
`Probably no characteristics of a drug substance are
`more important than particle characteristics in determin(cid:173)
`ing
`its performance
`in a
`formulation. This
`is
`particularly true in those cases where the drug is a
`poorly soluble nonelectrolyte or a free acid form with
`poor solubility at low pH values. Such drugs are likely
`to exhibit dissolution-rate-limited absorption, and if
`dissolution does not
`take place rapidly enough, a
`therapeutic concentration in the body fluids may never
`be achieved, the peak plasma concentration may be
`significantly delayed, or much of the drug may bypass
`that region of the gastrointestinal (GI) tract where
`absorption
`is best. Particle size reduction (e.g.,
`rnicronization) is often utilized to enhance dissolution
`rate. Small particles present a larger surface area per
`unit weight to the dissolution media and hence dissolve
`more rapidly than large particles. Particle size and
`surface area are two of the most important properties
`determining the solubility rate of a drug and thus
`potentially
`its bioavailability. There are numerous
`examples of bioavailability problems and bioinequiva(cid:173)
`lence due to the inappropriate particle size of the drug
`substance.
`Particle size and shape also play an extremely
`important role in the homogeneity of powder blends and
`the unblending of powders in a mixer. Segregation in
`handling or during the compaction process has a
`significant effect on the content uniformity of the finished
`products. Particle size can also affect the stability of a drug
`substance in that it governs the surface area available for
`oxidation and hydrolysis. Surface area is critical for
`interaction with excipients in tablet dosage forms and can
`greatly affect stability. Methods to determine particle size
`and shape include light microscopy, scanning electron
`microscopy, sieve analysis, and various electronic
`sensing-zone particle counters. Methods available for
`surface area measurement include air permeability and
`various gas adsorption techniques.
`
`2703
`
`Bulk Powder Properties
`
`Bulk powder properties are extremely important in
`pharmaceutical processing (6). Knowledge of the true
`and bulk densities of the drug substance as well as of the
`excipients is extremely useful in
`
`• Providing perspective as to the size of the final tablet
`and the size and type of processing equipment needed,
`• Anticipating problems in the physical mixing of
`powders and the homogeneity of intermediate and
`final products because significant differences in true
`densities can result in segregation,
`• Anticipating problems in flow properties, since that
`property is affected by density, and
`• Identifying differences in different lots and raw
`materials from different suppliers because different
`polymorphic forms can be expected to exhibit different
`true densities.
`
`A comparison of true particle density, apparent particle
`density, and bulk density can provide information on total
`porosity, interparticle porosity, and intraparticle porosity.
`Methods include true particle density measurements via
`helium pycnometry, mercury intrusion porosimetry, and
`poured and tapped bulk density.
`The influence of sorbed moisture on chemical stability
`and the flow and compaction of powders and granulations
`is well established. The moisture content and hygro(cid:173)
`scopicity of excipients is particularly important as total
`product processing as well as finished product stability can
`be affected. Hygroscopicity, moisture-sorption isotherms,
`and equilibrium moisture content can be determined by
`thermogravimetric analysis and Karl Fisher titration
`methods.
`The compactibility of relatively large-dose drug
`substances and formulations is another important property.
`Compactibility is of less concern for smaller-dose drugs for
`which direct compression fillers may be able to compensate
`for a lack of ability to form mechanically strong compacts.
`An instrumented tablet press (7) or compaction simulator
`(8) may be used to assess the relationship between the
`mechanical strength of the compact and the force ( or
`pressure) employed to form the tablet. This relationship is
`the easiest of all compaction measurements to establish and
`provides important information on the ability of the
`material to form practical compacts. Measures of compact
`mechanical strength include hardness ( or crushing force),
`tensile strength, and friability. Other more complex
`studies, more easily and perhaps best done using a
`compaction simulator, include measurement of the work or
`energy of compaction, pressure-density (Athy-Heckel)
`analysis, strain-rate sensitivity, and elastic recovery (9).
`
`--
`
`

`

`2704
`
`The Athy-Heckel analysis can provide information on
`deformation mechanism and give an estimate of the mean
`yield pressure of the material (10). A comparison of yield
`pressures determined at different punch speeds can give
`information on the strain-rate sensitivity of the material
`( 11 ). If the major components of the formulation (including
`the drug) are strain-rate sensitive, the tablets produced on a
`high-speed production press may exhibit lamination or
`capping. Excessive elastic recovery may also indicate such
`tablet failure. The Hiestand indices (bonding and brittle
`fracture) may be used to assess the compactibility of
`materials under laboratory conditions (12).
`For the evaluation of flow properties the following test
`methods may be used:
`
`• Angle of repose
`• Minimum orifice diameter,
`• Carr index,
`• Flow rate, and
`• Direct observation of weight variation during tableting
`runs.
`
`The ultimate goal of flow analysis is to identify the
`powder or powder blend that provides the least weight
`variation in the finished tablet. The more fluid the powder
`is, the more efficiently and reproducibly it should fill the
`die cavities of a tablet press. This more efficient and
`reproducible die fill should be reflected in increased tablet
`weights and reduced intertablet weight variation (13).
`
`Solubility and Permeability
`
`In many cases, the rate of dissolution in gastrointestinal
`fluids is the rate-limiting step in absorption. The
`bioequivalence requirements established by the FDA
`define low solubility as " ... <5 mg/mL in water, and slow
`dissolution rate to be <50% in 30 minutes" (14). However,
`the solubility of a drug should be considered together with
`its dose; that is, even a very poorly soluble drug having a
`sufficiently small therapeutic dose may completely
`dissolve under physiological conditions. Thus, Amidon
`et al. (15) have defined a "high solubility" drug as one
`which at the highest human dose is soluble in 250 ml
`(or less) water throughout the physiological pH range
`(1-8) at 37°C. A "low solubility" drug is thus one
`which requires more than 250 ml of water to dissolve
`the largest human dose at any pH within the physio(cid:173)
`logical range. The likelihood of having bioavailability
`problems requires both a consideration of the dose and
`a solubility volume of the drug and its permeability.
`Amidon et al. (15) created a Biopharmaceutics Drug
`Classification System (BCS) based on estimates of these
`two parameters:
`
`Tablet Formulation
`
`1. Class I: High solubility and high permeability
`2. Class II: Low solubility and high permeability
`3. Class III: High solubility and low permeability
`4. Class IV: Low solubility and low permeability
`A jejuna! permeability of at least 2-4 X 10-4 emfs,
`measured in humans by an intubation technique, is
`considered "high permeability." For many substances,
`this permeability corresponds to a fraction absorbed of
`90% or better. The classification system provides a
`logical basis for estimating the risk of bioavailability
`problems. For example, Class I drugs (e.g., propranolol
`HCI, metoprolol tartrate) are expected to exhibit few
`bioavailability problems. On the other hand, Class II
`drugs (e.g., piroxicam) are more
`likely
`to exhibit
`dissolution-rate-limited absorption problems. Class III
`drugs (e.g., atenolol) are more likely to be prone to
`absorption (permeability) rate-limited absorption. Class
`IV drugs (low solubility-low permeability) present
`formidable obstacles to bioavailability. An in vitro-in
`vivo correlation (IVIVC) is expected only in the case of
`Class II drugs. An IVIVC could be expected for Class I
`drugs if the dissolution rate is slower than the gastric
`emptying the rate. With a sufficiently rapidly dissolving
`Class I drug, little or no IVIVC is expected because
`gastric emptying (not dissolution) would be the rate
`limiting step. Little or no IVIVC is expected for Class
`III or Class IV drugs.
`The FDA has adopted the BCS in developing a
`guidance that provides relaxed policies on scale-up and
`postapproval changes of immediate-release oral solid
`dosage forms (SUPAC-IR). For certain changes, require(cid:173)
`ments depend on the drug class, with the most liberal
`policies for Class I drugs, less liberal policies for Classes II
`and III drugs, and the least liberal policies for Class IV
`drugs. First issued as a draft on Nov. 29, 1994 for comment
`(16, 17), a revised version was published in the Federal
`Register on Nov. 30, 1995.
`The intrinsic dissolution rate (IDR) of drugs is
`frequently measured in preformulation tests by the rotating
`disk method or Wood's apparatus (18). An automated IDR
`system, based on a modification of a standard dissolution
`apparatus, allows for attachment to the stirrer of a die in
`which the pure drug has been compressed with the tablet
`face flush with the bottom surface of the die (19). The IDR
`may be used to detect different polymorphs as well as to
`judge the risk of a drug exhibiting dissolution-rate-limited
`absorption. Kaplan (20) suggested that an IDR of higher
`than 1 mg cm - 2min -l indicated that dissolution-related
`absorption problems were unlikely, whereas an IDR lower
`than 0.1 mg cm - 2min -l indicated dissolution-rate-limited
`absorption.
`
`

`

`Tablet Formulation
`
`Drug-Excipient Compatibility Studies
`
`A knowledge of the interaction of drugs and excipients is
`essential in the initial formulation of a product. It may also
`be necessary later on during processing scale-up, when
`problems arise, to determine if incompatibilities exist
`which affect manufacturing or stability. Drug-excipient
`interactions are often directly related to the moisture
`present in one or another of the components or to the
`humidity to which the formulation is exposed during
`processing or storage. These studies are always carried out
`at accelerated temperature and humidity conditions, even
`though it must be recognized that some interactions are
`physical (melting and volatilization) and not chemical and
`that accelerated aging may not be predictive. Tests for
`excipient-drug interactions are usually conducted on
`blends of the pure drug and excipient in ratios similar to
`those in the final dosage form. For example, excipient-to(cid:173)
`drug ratios are higher for filler-binders than for lubricants
`and disintegrating agents. These studies are often
`performed with the help of a factorial or fractional(cid:173)
`factorial experimental design (21). Powders are physically
`mixed and may be granulated or compacted to accelerate
`any possible interaction. Samples can be exposed in open
`pans or sealed in bottles or vials to mimic product
`packaging. Evaluation of samples includes
`
`1. Visual inspection for changes in color or texture.
`2. Both HPLC and TLC are commonly employed with
`unstressed samples being used as controls. In general,
`only qualitative results are important initially.
`3. Differential thermal analysis is applied and the
`appearance or disappearance of one or more peaks is
`noted. Isothermal microcalorimetry can also be
`employed as well as a thermal activity monitor
`(TAM) technique.
`
`Compatibility studies are essential in characterizing both
`raw materials and finished formulations. It has been argued
`that binary drug-excipient screening studies are inefficient,
`unrealistic, and ignore processing variables. A better
`approach may be to carefully select potential excipients
`based on known chemistry and published compatibility
`data, and perform miniformulation stability studies (22).
`
`Formulation Design
`
`Based on the preformulation information, decisions can be
`made regarding formulation design and process strategy.
`Initial guidance may be provided by the proposed dose.
`Relatively low-dose drugs can often be tableted by direct
`compression, a term that is applied to the process by which
`tablets are compressed directly from blends of the active
`
`I
`'I
`'
`
`2705
`
`ingredient and suitable excipients. No wet or dry granu(cid:173)
`lation is required, although the drug may occasionally be
`sprayed out of solution onto one of the excipients to ensure
`uniform dispersion of drug in very low dosage. Larger
`doses of poorly compactible drugs may be granulated
`prior to tableting. The process steps required and the
`choice of excipients are often governed by other properties
`of the drug.
`
`Analysis of Critical Variables and
`Formulation Development
`
`Based on the analysis of the preformulation data, likely
`excipients are selected and small batches may be
`produced. The number and size of the batches depend on
`the availability of the drug substance. The batches are
`intended to assess the feasibility of the formulation,
`including the types and levels of excipients, as well as the
`process and its operational variables, such as order of
`addition, mixing times, compression force, granulation
`time, etc. The goal is to develop a formulation and process
`that meets the criteria set forth earlier under Objectives.
`
`MANUFACTURE
`
`Traditionally, tablets have been made by granulation, a
`process that imparts two primary requisites to formu(cid:173)
`lations: compactibility and fluidity. Both wet granulation
`and dry granulation (slugging or roll compaction) are used
`(Table 1). Regardless of whether tablets are made by direct
`compression or granulation, the first steps, milling and
`mixing, are the same; the subsequent steps differ.
`The wet massing of powders is typically carried out in
`high-shear mixers prior to wet screening. The wet
`granules are often dried in fluidized-bed equipment,
`enhancing the efficiency of the process. Alternatively, wet
`granulation may be carried out in fluid-bed drier(cid:173)
`granulators in which the liquid phase is sprayed onto
`fluidized powders while the hot air flow dries the granules.
`This process reduces the number of handling steps and the
`time and space needed for granulation; it can be
`automated. The advantages and disadvantages of wet
`granulation are given in Table 2. See also Granulations
`by H.G. Kristensen and T. Schaeffer, Vol. 7 (1st Ed.),
`pp. 121-160, of this encyclopedia.
`Regardless of the granulation method, the comparative
`simplicity of the direct compression process offers obvious
`advantages, such as
`
`1. Economy
`2. Elimination of heat and moisture
`
`

`

`2706
`
`Tablet Formulation
`
`Table 1 Typical unit operations involved in wet granulation, dry granulation, and direct compression
`
`Wet granulation
`
`Milling and mixing of drugs
`and excipients
`Preparation of binder solution
`Wet massing by addition of
`binder solution or granulating solvent
`Screening of wet mass
`Drying of the wet granules
`Screening of the dry granules
`Blending with lubricants and disintegrant
`to produce "running powder"
`Compression of tablets
`
`Dry granulation
`
`Direct compression
`
`Milling and mixing of drugs
`and excipients
`Compression into slugs or roll compaction
`Milling and screening of slugs
`and compacted powder
`Mixing with lubricant and disintegrant
`Compression of tablets
`
`Milling and mixing of drugs
`and excipients
`Compression of tablets
`
`3. Optimization of tablet disintegration
`4. Stability
`
`The most obvious advantage of direct compression is its
`greater economy, owing to reduced processing time, less
`equipment and space required, less process validation, and
`lower energy utilization. Generally, only blending and
`compression are required, although prior micronization of
`the drug may be needed. Unlike wet granulation,
`processing does not require heat or moisture, which can
`be detrimental to drug stability. Moreover, direct
`compression avoids the high pressures associated with
`slugging or roll compaction. In addition, disintegration is
`optimized because directly compressed tablets produce
`primary particles upon disintegration, rather than granules,
`which must deaggregate to liberate primary particles.
`Finally, direct compression tablets often exhibit fewer
`long-term problems of chemical stability or changes in
`dissolution.
`
`Although there are many significant advantages of
`direct compression over granulation, there also are
`important limitations:
`
`1. Uniform blending and prevention of unblending of low(cid:173)
`dose drugs
`2. Fillers often are costlier than fillers used in granulation
`3. Physical properties and functional specifications are
`more critical; properties of raw materials must be
`defined and carefully controlled
`4. Limitations in producing colored tablets
`5. Dust problems
`6. Limitations in the dilution capacity of fillet-binders
`7. More sensitive to lubricant softening and overmixing
`than granulations
`
`Limitations in the dilution capacity of excipients can
`make the direct compression of large-dose, poorly
`compactible drugs impractical. Lubrication is often
`
`Table 2 Advantages and disadvantages of wet granulation
`
`Advantages
`
`Disadvantages
`
`Enhances fluidity and compactibility. suitable for high-dose
`drugs with poor flow and/or compactibility
`Reduces air entrapment
`
`Reduces dustiness
`Provides for the addition of a liquid phase (wet granulation)
`suited to dispersion of low-dose drugs in solution to ensure
`content uniformity
`Enhances wettability of powders through
`hydrophilization (wet granulation)
`Permits handling of powders without loss of blend quality
`
`Each unit process brings its own set of complications
`
`The large number of unit processes increases the chances
`of problems
`Difficult to control and validate
`Potential adverse effects of temperature, time, and rate of drying
`on drug stability and distribution during drying
`
`Overall more costly than direct compression in terms of space,
`time, and equipment requirements
`
`

`

`Tablet Formulation
`
`a compromise between the amount and type needed for
`adequate lubrication and their adverse effect on compact(cid:173)
`ibility. Content uniformity is of greater concern in direct
`compression tableting, particularly with low-dose drugs.
`Since the drug is not "locked" into granules, direct
`compression blends are subject to unmixing in subsequent
`processing steps. In addition, drugs are often micronized
`prior to blending to enhance their dissolution rate, and the
`resulting high surface-to-mass ratios may lead to difficulty
`in flowing and mixing due to surface interactions. Another
`important limitation is that unlike granulation, which tends
`to compensate for variability in excipients, direct
`compression is heavily dependent upon reproducible
`properties of the excipients (and the drug). Raw material
`standards must be carefully defined and address function(cid:173)
`ality. Lot-to-lot variations in both the drug and the
`excipients must be avoided. The cost of raw materials and
`their testing is higher in direct compression.
`Thus, direct-compression tableting requires careful
`attention to the choice of excipients, appropriate flow
`properties, and blend homogeneity, and to the interplay of
`formulation and process variables that can affect both
`compactibility and drug dissolution. See also Direct
`Compression Tableting by R.F. Shangraw, Vol.4, (1st Ed.)
`pp. 85-106, of this encyclopedia.
`
`Excipients
`
`The design of the formulation and selection of excipients
`is especially critical in tablet dosage forms. Products can
`vary from a relatively simple aspirin tablet containing
`aspirin and starch to more complex systems that might
`contain fillers, binders, disintegrating agents, glidants,
`lubricants, and coating agents. Modified release introduces
`even more complexity. The appropriate selection of
`excipients and their concentration are clearly critical to
`both the ability to manufacture tablets as well as to their
`performance as a drug delivery system. Since others have
`illuminated the various excipient classes in great detail,
`references are provided in Table 3.
`
`Manufacturability
`
`Excipients function to provide compactibility, lubrication,
`flow properties, disintegration efficiency, wetting, etc. Poor
`choice of excipients may give rise to poor characteristics
`(hardness, appearance), which can be important in
`packaging, storage, and patient acceptance. Problems
`with excipients may arise from variations in source or lot,
`particularly in formulations made by direct compression.
`Examples of excipient problems include variation in
`performance between Hoc cellulose and microcrystalline
`cellulose relative to particle size, flow, and compactibility,
`
`2707
`
`or different polymorphic forms of