PHARMACEUTICAL
`DOSAGE FORMS
`
`Tablets
`
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`VOLUMEl
`
`EDITED BY
`
`Herbert A. Lieberman
`H.H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`
`Leon Lachman
`Lachrnan Consultant Services
`Westbury, New York
`
`Joseph B. Schwartz
`Philadelphia College of Pharmacy and Science
`Philadelphia, Pennsylvania
`
`MARCEL DEKKER, INC.
`
`New York and Basel
`
`1
`
`EX 1014
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`Library of Congress Cataloging-in-Publication Data
`
`Pharmaceutical dosage forms- -tablets I edited by Herbert A. Lieberman.
`Leon Lachman, Joseph B. Schwartz. - - 2nd ed. , rev. and expanded.
`p.
`cm.
`Includes index.
`ISBN 0-8247-8044-2 (v .. 1 : alk. paper)
`1. Tablets (Medicine) 2. Drugs--Dosage forms.
`I. Lieberman,
`II. Lachman, Leon.
`Ill. Schwartz, Joseph B.
`Herbert A.
`[DNLM: 1. Dosage Forms.
`2. Drugs- -administration & dosage. QV
`785 P535]
`RS201.T2P46 1989
`615'.191--dcl9
`DNLM/DLC
`for Library of Congress
`
`89-1629
`CIP
`
`Copyright © 1989 by MARCEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in
`any form or by any means, electronic or mechanical, including photo(cid:173)
`copying, microfilming, and recording, or by any information storage
`and retrieval system, without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`10 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Prei
`
`Severa
`Forms;
`have t
`facturE
`vised
`n
`livery
`tablet
`is sug1
`intesti
`tabletE
`release
`chew al
`descril
`In
`the se
`tablets
`ad di tic
`drug l
`suranc
`Tl
`second
`on sul:
`the ph
`Formul
`been r
`There
`of imp•
`Tl:
`tion ar
`previo
`
`2
`
`

`
`Cenfignis
`
`"iireface
`Contributors
`Contents of Pharmaceutical Dosage For-ms: Tablets, Second Edition
`Volumes 2 and 3
`Contents of Pharmaceutical Dosage Forms: Parenteral Medicatiens,
`Volumes 1 and 2
`Contents of Pharmaceuticcd Dosage For-ms: Disperse Systems,
`Volumes I and 2
`
`Chapter 1.
`
`Preformulafion Testing
`Deedatt A. Wadke, Abu T. M. Serufuddin, and
`Harold Jacobson
`I .
`Introductien
`31. Grganoleptic Properties
`111. Parity
`IV. Particie Size, Shape, and Surface Area
`V.
`Soiability
`V1. Dissulution
`VII. Parameters Affecting Absorption
`V111. Crystal Properéies and Poiymorphism
`IX. Stability
`X. Miscelianeous Pmperties
`XI. Examples of Preformuiation Studies
`References
`
`Chapter 2. Tablet Formulation and Design
`Garnet E. Peck, George J. Buley, Vincent E. Mcflurdy,
`and Gilbert 3. Banker
`
`Introduction ,
`1.
`P:-eformulation Studies
`II.
`EH. A Systematic and Modern Approach to
`Tablet Product Design
`.
`IV. Tablet Components and Additives
`V. Regulatory Requirements for Excipients in
`the United States
`’
`VI . References
`
`3
`
`

`
`Cozlients
`
`13}
`
`Ccmprsssed Tablets by Wet Granulation
`Fred J. Butndeiin
`
`i. Properties of Tablets
`IL E‘o:°mulation 01‘ Tablets
`Hi. Tablet Manufacture
`EV . Gramzlation
`V.
`Ex-nignients and Fcxtcmulation
`V1. Multiiayer Tablats
`VIE.
`Prolonged Reiease ’.'i.‘abie‘:‘_s
`VIE}. Manufacturing Problems
`References
`
`Chapter =1.
`
`Compressed ’£‘a¥:>Ee*z3 by Direct Compression
`Rcziph Shflngraw
`E.
`1r:'ttoducti<m and History
`ii. Advantages and Disadvantages of the We‘:
`Granuiation Process
`:11. The Diracbcorsrpression ?1:'0r:ess
`IV. Direct-Compression Filler Binders
`V.
`Factors in Fax-muiation Development
`‘VI. Morphalogy of Direcbflompression Fillers
`Vii. Coprocessed Active Ingredients
`VIII.
`l\-iudiflcation and Entagration of Direct-
`Cempression and Granulation Processes
`Future -sf i)irect—Comp:-essien Tableting
`Formulations for Direct Compression
`Glossary of Traée Names and Manufacturers
`References
`
`Chapter 5.
`
`Compre.=;.=si1>n—Coated and Layer Tablets 7
`William C. Gunsel and Robert G. Buss!‘
`
`;
`1. Compression Coating
`I1.
`Formulations {Compression Coating)
`HI.
`Iniay Tablets
`IV. Layer Tablets
`V.
`Formuiations (Layer)
`References
`
`Chapter 6. Effervescent Tablets
`Raymond Mohrle
`I .
`Introduction
`H. Raw Materials
`Hi. Prqeessing
`IV. Maxpzfaeturing Operations
`V. Tablet Evajeuation
`
`4
`
`

`
`Contents
`
`Chapter 7.
`
`VI.
`VII .
`VIII.
`
`Effervescent Stability
`Effervescent Formulations
`References
`
`Special Tablets
`James W. Canine and Michael J’. Pilcai
`I.
`II.
`III.
`
`Drug Absorption ThI‘0ugi1_'th9 Oral Niucosa
`Molded Sublingual Tablets
`Special Problems with Molded Nit:-oglycerin
`Tablets
`
`IV.
`V.
`VI.
`V1}.
`VIII.
`IX.
`
`Compressed Sublingual Tablets
`Buccal Tablets
`Vaginal Tablets
`Rectal Tablets
`flispensing Tablets
`Tablets for Miscellaneous Uses
`References
`
`Chayter 8.
`
`Chewable Tablet S
`
`Robert W. Menzies, Aloysius O. Anuebonam, and
`Juhan B. Duruwalu
`I.
`Introduction
`I1.
`Formulation Factors
`III.
`i~‘ormuiati_on Techniques
`IV.
`Excipients
`V.
`Flavoring
`Colorants
`VI.
`VII.
`Manufacturing
`VIII.
`Evaluation of Chewable Tablets
`IX.
`Summary
`References
`
`Chapter 9.
`
`Medicated Lozenges
`David Peters
`
`I.
`13.
`III.
`IV.
`V.
`VI.
`VII.
`VIII.
`EX.
`X.
`X].
`
`Hard Candy Lozenges
`Processing
`Formulations (Hard Candy Lazenges)
`Centaz-«Filled Hard Candy Lozenges
`Formuiations (Center Filled Lozenges)
`Packaging
`Chewy or Caramel Base Medicated Tablets
`Formulations {Chewy Based Confections)
`Compressed Tablet Lozenges
`Manufacturing: Compression Sequence
`Typical Formulations (Compressed-Tablet
`Lozenges)
`
`5
`
`

`
`XII. Quality Central Proeedure$
`References
`
`Suggested Reading
`
`Ccmtenfs
`
`56'?
`576
`S80
`
`6
`
`

`
`end Jacobson
`
`Preformulation Testing
`
`s
`
`observing the melting point, especially with a hot-stage microscope. More
`quantitative information can be obtained by using quantitative differential
`scanning calorimetry or by phase-rule solubility analysis.
`As important to a compound's chemical characteristic are its physical
`ones. Crystalline form (including existence of solvates) is of fundamental
`importance, and for complete documentation of the compound X-ray powder
`diffraction patterns for each batch is desirable. This is simple to execute
`and provides useful information for later comparison and correlation to
`other properties.
`
`IV. PARTICLE SIZE, SHAPE, AND SURFACE AREA
`
`Various chemical and physical properties of drug substances are affected
`by their particle size distribution and shapes. The effect is not only on
`the physical properties of solid drugs but also, in some instances, on their
`biopharmaceutical behavior. For example, the bioavailability of griseofulvin
`and phenacetin is directly related to the particle size distributions of these
`drugs [ 3, 41 .
`It is now generally recognized that poorly soluble drugs
`showing a dissolution rate-limiting step in the absorption process will be
`more readily bioavailable when administered in a finely subdivided state
`than 8s a coarse material. Very fine materials are difficult to handle [5];
`but many difficulties can be overcome by creating solid solution of a material
`of interest in a carrier, such as a water-soluble polymer. This represents
`the ultimate in size reduction, since in a (solid) solution, the dispersed
`material of interest exists as discrete molecules or agglomerated molecular
`bundles of very small dimensions indeed.
`Size also plays a role in the homogeneity of the final tablet. When
`large differences in size exist between the active components and excipients,
`mutual sieving ( demixing) effects can occur maldng thorough mixing diffi(cid:173)
`cult or, if attained, difficult to maintain during the subsequent processing
`steps. This effect is greatest when the diluents and active raw materials
`are of significantly different sizes. Other things being equal, reasonably
`fine materials interdisperse more readily and randomly. However, if materials
`become too fine, then undersirable properties such as electrostatic effects
`and other surface active properties causing undue stickiness and lack of
`flowability manifest. Not only size but shape too influences the flow and
`mixing efficiency of powders and granules.
`Size can also be a factor in stability: :fine materials are relatively more
`open to attack from atmospheric oxygen, heat, light, humidity, and inter(cid:173)
`acting exipients than coarse materials. Weng and Parrott [ 6] investigated
`influence of particle size of sulfacetamide on its reaction with phthalic an(cid:173)
`hydride in 1: 2 molar compacts after 3 hr at 95°C. Their data, presented
`in Table 2, clarly demonstrate greater reactivity of sulfacetamide with de(cid:173)
`creasing particle size.
`Because of these significant roles , it is important to decide on a desired
`size range, and thence to maintain and control it. It is probably safest to
`grind most new drugs having particles that are above approximately 100 µm
`in diameter.
`If the material consists of particles primarily 30 µm or less in
`diameter, then grinding is unnecessary, except if the material exists as
`needles-where grinding may improve flow and handling properties, or if
`the material is poorly water-soluble where grinding increases dissolution
`rate. Grinding should reduce coarse material to, preferably, the 10- to
`
`rimental drug.
`
`'£ chromato(cid:173)
`anses due to
`ypieally, the
`graphic proce-
`response due
`1 shows an
`:ermination
`detector.
`on time of
`M?aks are due
`l. Thus, II
`1).8515 =
`
`In
`
`lated procedure
`In
`TLC.
`e to impurities
`. of the main
`ities [1,2].
`iSP are not
`~. • molecular
`s assumed to
`analysis re(cid:173)
`'JJY preparation
`;t always un-
`
`m.ia1 and
`? a qualitative
`resence of sol(cid:173)
`!Cterizing the
`appearance
`be indicative
`ersted by
`
`---------
`
`7
`
`

`
`6
`
`Wadke, Serajuddin, and Jacobson
`
`Influence of Particle Size
`Table 2
`on Conversion of Sulfacetamide
`
`Particle size of
`sulfacetamide
`(µm)
`
`128
`
`164
`
`214
`
`302
`
`387
`
`% Conversion
`±SD
`
`21.54 ± 2. 74
`19. 43 ± 3.25
`
`17.25 ± 2.88
`
`15.69 ± 7. 90
`
`9.34 ± 4.41
`
`Source: Modified from Weng, H. ,
`and Parrott, E. L., J. Pharm. Sci.,
`73: 1059 ( 1984). Reproduced with
`the permission of copyright owner.
`
`40- µm range. Once this is accomplished, controlled testing can be per(cid:173)
`formed both for subsequent in vivo studies and for in-depth preformulation
`studies. As the studies proceed, it may become apparent that grinding is
`not required and that coarser materials are acceptable. At that time, it
`is conceptually simpler to omit that step without jeopardizing the information
`already developed. The governing concept is to stage the material so that
`challenges are maximized.
`There are several drawbacks to grinding that may make it inadvisable.
`Some are of lesser importance. For example, there are material losses when
`grinding is done. Sometimes a static electricity buildup occurs, making the
`material difficult to handle. Often, however, this problem, if it exists, may
`be circumvented by mixing with excipients such as lactose prior to grinding.
`Reduction of the particle size to too small a dimension often leads to aggre(cid:173)
`gation and an apparent increase in hydrophobicity, possibly lowering the
`dissolution rate and making handling more troublesome. When materials are
`ground, they should be monitored not only for changes in the particle size
`and surface area, but also for any inadvertent polymorphic or chemical
`transformations. Undue grinding can destory solvates and thereby change
`some of the important characteristics of a substance. Some materials can
`also undergo a chemical reaction.
`
`A. General Techniques for Determining Particle Size
`
`Several tools are commonly employed to monitor the particle size. The most
`rapid technique allowing for a quick appraisal is microscopy. Microscopy,
`since it requires counting of a large number of particles when quantitative
`information is desired, is not suited for rapid, quantitative size determina(cid:173)
`tions. However, it is very useful in estimating the range of sizes and the
`shapes. The preliminary data can then be used to determine if grinding is
`needed. A photomicrograph should be taken both before and after grinding.
`The range of sizes observable by microscopy is from about 1 µm upward.
`
`ilm' 0
`ma~
`~·to'
`
`~· For· a
`~· ~.iii
`~.
`~,,­
`~
`age {H!Ai
`C~nter}.
`the USP'
`The instr
`eriy msp
`~5
`sor m 1i!!!
`Ot'be!
`a:~­
`fue ~
`The latte
`~·~
`as fue. A!
`settling: 5
`general d
`camnm t.
`~
`teme•
`metric•
`ratio of 11
`
`~
`Sieve
`
`~
`
`Du~
`
`Cen~
`
`p~
`
`light SC'llll
`
`.source:
`4:31{1•
`~
`
`8
`
`

`
`. and Jacobson
`
`Preformulation Testing
`
`7
`
`For optical microscopy, the material is best observed by suspending it
`in a nondissolving fluid (often water or mineral oil) and using polarizing
`lenses to observe birefringence as an aid to detecting a change to an amor(cid:173)
`phous state after grinding.
`For a quantitative particle size distribution analysis of materials that
`range upward frOm about 50 µm, sieving or screening is appropriate, al(cid:173)
`though shape has a strong influence on the results. Most pharmaceutical
`powders, however, range in size from 1 to 120 µm. To encompass these
`ranges, a variety of instrumentation has been developed. There are in -
`struments based on lasers (Malvern), light scattering (Royco), light block(cid:173)
`age' (HIAC), and blockage of an electrical conductivity path (Coulter
`Counter). The instrument based on light blockade has been adopted by
`the USP to monitor the level of foreign particulates in parenteral products.
`The instrument will measure particle size distribution of any powder prop(cid:173)
`erly dispersed in a suspending medium. The concentration of sample sus(cid:173)
`pension should be such that only a single particle is presented to the sen(cid:173)
`sor in unit time, thus avoiding coincidence counting.
`Other techniques based on centrifugation and air suspension are also
`available. Most of these instruments measure the numbers of particles, but
`the distributions are readily converted to weight and size distributions.
`The latter way of expressing the data is more meaningful. A number of
`classical techniques based on sedimentation methods, utilizing devices such
`as the Andreasen pipet or recording balances that continuously collect a
`settling suspension, are also known. However, these methods are now in
`general disfavor because of their tedious nature. Table 3 lists some of the
`common techniques useful for measurement of different size ranges [7].
`There are many mathematical expressions that can be used to charac(cid:173)
`terize an average size. These refer to average volumes or weights, geo(cid:173)
`metric mean diameters, and relationships reflecting shapes, such as the
`ratio of an area to a volume or weight factor [ 8] •
`
`Table 3 Common Techniques for
`Measuring Fine Particles of
`Various Sizes
`
`Technique
`
`Microscopic
`Sieve
`
`SE!dimentation
`Elutriation
`Centrifugal
`Permeability
`
`light scattering
`
`Particle size
`(µm)
`
`1-100
`
`>50
`>1
`1-50
`<50
`>1
`0.5-50
`
`Source: Parrott, E. L., Phann. Mfg.,
`4: 31 ( 1985). Reproduced with the
`permission of. copyright owner.
`
`!8i1 be per(cid:173)
`p:reformulation
`st grinding is
`!lat time, it
`the information
`derial so that
`
`t inadvisable.
`isl losses when
`rs • making the
`f it exists, may
`ior to grinding.
`eads to aggre(cid:173)
`Ollifering the
`i materials are
`e particle size
`r chemical
`iereby change
`merials can
`
`lre. The most
`Microscopy,
`1 quantitative
`ize determina(cid:173)
`siaes and the
`if gl"inding is
`after grinding.
`:..m upward.
`
`9
`
`

`
`8
`
`Wadke, Serajuddin, and Jacobson
`
`Cumulotlve Weight Percentage at the Indicated Size
`99.9
`99 98 915 90 80 70
`:JO 30
`10 15
`2 I 0.15
`
`99.8
`
`60 40 20
`
`100
`80
`60
`
`40
`30
`
`20
`
`-E
`
`::t.
`It.I 10
`~ 8
`6
`
`f/)
`
`4
`3
`
`2
`
`Figure 2 Log probability plot of the size distribution of a sample of tri(cid:173)
`amcinolone acetonide.
`
`A convenient way to characterize a particle size distribution is to con(cid:173)
`struct a log probability plot. Log probability graph paper is commercially
`available, and particle size distributions resulting from a grinding operation
`with no cut being discarded will give a linear plot. An example is illus(cid:173)
`trated in Figure 2 for a powder sample of triamcinolone acetonide. The
`data used in the construction of Figure 2 are presented in Table 4.
`The numbers of particles in Table 4 are converted into weight fractions
`by assuming them to be spheres and multiplying by the volume of a single
`sphere (particle) calculated from the geometric relationship:
`
`where V is the volume and d the particle diameter (using the average
`value of the range given in the first column of Table 4). The result is
`the total volume occupied by particles in each of the size ranges and is
`given in the third column of the table. The volume is directly related to
`a mass term by the reciprocal of the density. However, since the density
`is constant for all particles of a single species and is rarely known accurate(cid:173)
`ly, it is sufficient to use the volume terms to calculate the weight percent(cid:173)
`ages in each size range by dividing the total volume of all the particles
`into the volumes in each range (column 4 of Table 4).
`If densities were
`used, it is obvious that they would cancel out in this calculation. The
`cumulative weight percentage in each size range is shown in the last column.
`Statistical descriptions of distributions most often give a measure of
`central tendency. However, with powders the distributions are skewed in
`the direction of increasing size. This type of distribution can be described
`by the Hatch-Choate equation:
`
`>~,~~:.!~
`·~£-
`
`ka"'· ... -~
`.........
`........
`•
`.'h.._
`~···
`
`Pm- ti
`piiidide a
`shpe· ten
`• lmem' p
`
`s. Oeler
`
`Tire deter
`~a
`Simple -
`
`Size rangii
`(i.U)
`
`!2.5-26..5
`
`18.5-U.t
`
`14.9-18.I
`
`11.8-14-1
`
`9.4-U...&
`
`7.4-5.'t:
`5.9--'f .. ~;1
`
`10
`
`

`
`Preformulation Testing
`
`f =
`
`I:n
`&1n" g
`
`exp
`
`[
`
`-
`
`9
`
`( 1)
`
`where f is the frequency with which a particle of diameter d occurs, and
`n is the total number of particles in a powder in which the geometric mean
`particle size is M and the geometric standard deviation is crg. Equation (1)
`is succinctly discussed by Orr and Dalla Valle [9].
`The two measures M and crg uniquely characterize a distribution, and
`are readily obtained graphically from a log probability plot in which cumu(cid:173)
`lative weight percentage is plotted against the particle si2e (Fig. 2) . The
`geometric mean diameter corresponds to the 50% value of the abscissa, and
`the geometric standard deviation is given by the following ratios, the values
`for which are taken from the graph.
`
`cr = --,-.....,---
`84.13% size
`50% size
`50% size = 15. 87% size
`g
`
`For the example, the values are 8. 2 and 1. 5 µm for the geometric mean
`particle size and its standard deviation, respectively. The latter is also a
`slope term. For particle size distributions resulting from a crystallization,
`a linear plot can often be obtained using linear probability paper.
`
`B. Determination of Surface Area
`
`The determination of the surface areas of powders has been getting in(cid:173)
`creasing attention in recent years. The techniques employed are relatively
`simple and convenient to use, and the data obtained reflect the particle
`
`Table IJ
`Acetonide
`
`Particle Size Distribution of a Ground Sample of Triamcinolone
`
`Size range
`(µm)
`
`No. of
`particles
`
`Volume of
`particles
`-3
`3
`x 10
`(µm )
`
`Weight
`percent
`in range
`
`Cumulative
`weight
`percent
`
`22.5-26.5
`
`18.6-22.0
`
`14.9-18.6
`
`11.8-14.9
`9.4-11.8
`
`7.4-9.4
`
`5. 9-7.4
`
`4. 7-5. 9
`
`3. 7-4. 7
`
`5
`
`54
`
`488
`
`2072
`5376
`
`9632
`
`12,544
`
`12,928
`
`13,568
`
`38
`
`237
`
`1212
`
`2552
`3352
`
`2989
`
`1888
`
`1008
`
`526
`
`0.2
`
`1. 7
`
`8.8
`18.5
`24.3
`
`21.7
`
`13.7
`
`7.3
`
`3.8
`
`100.0
`
`99.8
`
`98.1
`
`89.3
`70.8
`
`46.5
`
`24. 8
`
`11.1
`
`3.8
`
`... : .... :~.:.cc.::~=""·==--------------
`
`>"
`
`"•''•~~bed
`
`11
`
`

`
`iabtet
`
`sanitation see Sesign
`
`Garnet E. Peck
`Purdue University
`West Lafayette,
`Indiana
`
`George J. Baley and
`Vmcem E‘ Mccumy
`The Upjohn Company
`Kalamazoo, Michigan
`
`Giibert S. Banker
`University of Minnesota
`Health Sciences Center
`Minneapolis, Minnesota
`
`I.
`
`iNTRDDUC"{'i0N
`
`The §orm:1lation of solid oral dosage forms, and tablets in particular, has
`undergone rapid change and development over the last several decades with
`the emergence of precompression,
`induced tiie feeding, higlwspeeci ano now
`ultrahigh—speed presses, automated weightmontrol systems,
`the availability
`of many new direct compression materials, and the microprocessor control
`of precompression, compression, ejection forces, as weil as upper punch
`tightness on tablet presses.
`Some of the newer tablet presses have tablet
`rejection Systems that are operated by a computer, Computerwcontroiied
`tablet presses onty require an operator to set up the press at the proper
`tablet weight and thickness (or pressure). The computer can then assume
`complete controi of the run. Still other tabiet presses only require the op-
`erator to provide a product itlentifioatiori code to make tablets within speci-
`fications previously estabiished and stored in the computer memory.
`Most recently, new concepts and fedora} reguiations hearing on bio-
`availability and bioequivalence, anti on validation, are impacting on tablet
`formulation, design, and manufacture.
`Once,
`lavish golcihplatecl pills were manufactured and marketed with
`little knowledge of their pharmacological activity. Appearance and later
`stability of the dosage form were the prime requirements of pharmaceutical
`preparations. The introduction of the fricbie pill denoted in part the reaEi—
`zation that solid medicinais rnust——in some fashionwdisintegrate within the
`body for the patient to benefit from the drug. We now reaiize that disin-
`tegration and dissolution alone do not insure therapeutic activity. As only
`one example of this point, Meyer et el
`[1] presented information on 14
`nitrofurantoin products, which were evaluated both in vitro and in vivo.
`All products tested met USP XVIEI specifications for drug content, disin~
`tegration time, and dissotution rate; however, statisticaliy significant difw
`ferences in bioavailability were observed.
`
`12
`
`

`
`75
`
`Peck, Boley, Mccordy, and Banker
`
`The design of a tablet usually involves a series of compromises on the
`part of the formulator, since producing the desired properties {e.g.,
`rew
`sistance to mechanical abrasion or friability, rapid disintegration and disco-~
`lotion} frequently involves competing objectives. The correct selection and
`balance of excipient materials for each active ingredient or ingredient cora-
`‘oination in a tablet formulation to achieve the desired response (i.e., pro~
`{motion of a safe, effective, and highly reliable product) is not in practice
`2. simple goal to achieve. Add to this fact the need today to develop tabiet
`formulations and processing methods which may be {and must in the future
`be) validated, and the complexity of tablet product design is further in-
`creased in contemporary pharmaceutical development.
`Increased competition
`among manufacturers (brand versus generic, generic versus generic, and
`brand versus brand) has necessitated that products and processes be cost“
`efficient. Thus cost of a raw material or a particular processing step must
`be considered before a finai tablet formulation or manufactoring process is
`seiected.
`Tablet formulation and design may he described as the process whereby
`the formulator insures that the correct amount of drug in the right form
`is delivered at or over the proper time at the proper rate and in the cle~
`sired location, while having its chemical integrity protected to that point.
`Theoreticaiiy, a validated tablet formulation and production process is one
`in which the range in the variation of the component specifications and
`physical properties of the tablet product quaiity properties is known from
`a cause and effect basis.
`It is further known that raw materials specifica-
`tions, at their limits, and when considered as interaction effects of the
`worst possible combinations, cannot produce a product that is out of speci~
`fication from any standpoint. Likewise a validated tablet—manufacturing
`process is one which, when all the operating variables are considered, at
`any extremes which could ever be encountered in practice, and under the
`worst possible set of circumstances, will produce products that are within
`specifications. Total validation of a tabiet product includes all combination
`effects involving formulation, raw materials variables, and processing vari-
`ables, as well as their interaction effects,
`to assure that any system pro-
`duced will be within total product specifications.
`The amount or quantity of a drug which is sufficient to elicit the re-
`quired or desired therapeutic response can be affected by several factors.
`In the case of compendial or official drugs,
`the dosage levels have been
`predetermined. With certain drugs (e.g. , gr-iseofulvin),
`the efficiencjr of
`absorytion has been shown to depend on the particle size and specific sur-
`face area of the drug. By reducing the particle size of such drugs, the
`dosage level may be reduced by one~half or more and still produce the same
`biological response.
`The form in which the drug is absorbed can affect its activity. Most
`drugs are normally absorbed in solution from the gut. Since the absorp-
`tion process for most orally administered drugs is rapid, the rate of solu-
`tion of the drug will be the rate—limiting step from the point of View of
`blood level and activity.
`Thus, we must consider the contribution and influence of the active
`components and nonactive componentsmboth separately and together—to
`measure their impact on the pharmacological response of any tablet system.
`The timing of administration may effect when and how 9. drug will act (and
`to a certain extent where it acts) as will be discussed further in Section
`
`13
`
`

`
`Tablet Formulation and Design
`
`7?’
`
`l’v‘.A. Also, the timing of administration may be crucial in order to reduce
`gastric irritation (uncoated strong electrolytes are often given following
`food};
`to reduce drug interactions with food (formation of insoluble com-
`plexes between the calcium of milk and several antibiotics), reducing their
`bioavailability; or to enhance the solubility and bioavailability of certain
`drugs in foods (notably fats) by their administration with foods (e.g.,
`griseofulviu). Depending on such timing factors plus the relationship and
`rationale of fast, intermediate, or slow drug release as well as other re-
`lease considerations, a particular design and tablet formulation strategy is
`often indicated.
`‘Many excellent review articles have been written on tablet technology,
`including various formulation aspects. Cooper [23 presented a review mono-
`graph on the contributions from 1964 to 1968 in the areas of tablet formun
`lation, processing, quality standards, and biopharrnaceutics. Later, Cooper
`and Rees £3] continued the review and included similar topics covering the
`period 13359 to 1971. Recent book chapters on tablets include those by
`Banker [4] and Sadik [5].
`The present chapter will detail the general considerations of tablet
`product design; will describe a systematic approach to tablet design,
`in-
`eluding the practical use of preformulation data; wfll describe the commonly
`used tablet excipients with particular emphasis on their advantages and liar
`itations or disadvantages; and will present some general tablet formulation
`approaches. Extensive references to the literature should provide the
`reader with directed reading on topics where additional information may be
`obtained. While it is impossible to exhaustively cover as broad a topic as
`tablet formulation and design in one chapter of a book, it is the goal of
`this chapter to cover the major concepts and approaches, including the
`most recent thought bearing on validation, optimization, and programmatic
`methods related to the formulation, design, and processing of compressed
`tablets.
`
`H.
`
`PREFORMULATION STUDVES
`
`The first step in any tablet design or formulation activity is careful conm
`sideratioh of the preformulation data.
`It is important that the formulator
`have a complete physicoohemical profile of the active ingredients available,
`prior to initiating a formulation development activity. Compilation of this
`information is known as preformulation.
`It is usually the responsibility of
`the pharmaceutical chemistry research area to provide the data shown below
`on the drug substances.
`
`temperature, humidity
`light,
`1. Stability (solid state):
`2. Stability (solution):
`excipient~drug stability (differential thermal
`analysis or other accelerated methods)
`Physicomechonical properties:
`particle size, bulk and tap density,
`crystalline form, compressibility, photomicrographs, melting point,
`taste, color, appearance, odor
`Physicochemical properties:
`solubility and pll profile of solutionl
`dispersion (water, other solvents)
`In vitro dissolution: pure drug, pure drug pellet, dialysis of pure
`drug, absorbability, effect of excipients and surfactants
`'
`
`14
`
`

`
`Y8
`
`Peck, Bailey, McCurdy, and Banker
`
`The basic purposes of the prefoi-mulation activity are to provide a
`rational basis for the formulation approaches,
`to maximize the chances of
`success in formulating an acceptable product, and to ultimately provide a
`basis for optimizing drug product quality and performance.
`From a tablet
`formulatox-‘s perspective, the most important preformulation information is
`the drug-excipient stability study. The question then,
`for a new drug, or
`a drug with which the formulator lacks experience, is to select excipient
`materials that will be both chemically and piiysicaliy compatible with the
`drug.
`The question is compounded by the fact that tablets are compacts; and
`while powder mixtures may be adequately stable, the closer physical contact
`of particles of potentially reactive materials may lead to instability. The
`typical preformulation profile of a new drug is usually of limited value to
`the formulator in assuring him or her that particular drug-excipient com-
`binations will produce adequate stability in tablet form. An added problem
`is that the formulator would like to identify the most compatible excipient
`candidates within days of beginning work to develop a new drug into a tab-
`let dosage form rather than to produce a series of compacts, place them on
`stability, and then wait weeks or months for this information.
`Simon [6}, in reporting on the development of preformulation systems,
`suggested an accelerated approach, utilizing thermal analysis,
`to identify
`possibly compatible or incompatible drug-excipient combinations.
`In his
`procedure, mixtures are made of the drug and respective excipient materi~
`ale in a 1:1 ratio and subjected to differ-entiai thermal analysis. A 1:1 ratio
`is used, even though this is not the ratio anticipated for the final dosage
`form,
`in order to maximize the probability of detecting a physical or chemi-
`cal reaction, should one occur. The analyses are made in visual cells, and
`physical observations accompany the thermal analysis. The thermograms
`obtained with the dz-ug—excipient mixtures are compared to thermograms for
`the drag alone and the excipient alone. Changes in the termograms of the
`mixture, such as unexpected shifts, depressions, and additions to or losses
`from peaks are considered to be significant.
`Simon [6] has given an ex-
`ample of the type of information which may be obtained from such a study '
`by the data shown in Figure l. The thermal peak due to the drug alone
`was lost when the thermal analysis was run on the drug in combination with
`the commonly used lubricant, magnesium stearate. This was strong evidence
`for an interaction between these materials.
`It was subsequently confirmed
`by other elevated-temperature studies that the drug did decompose rapidly
`in the presence of magnesium stearate and other basic compounds.
`Simon
`has concluded the differential thermal analysis can aid immensely in the
`evaluation of new compounds and in their screening for compatibility with
`various solid dosage form excipients. The combination of visual and physical
`data resulting from differential thermal analysis of drugs with excipients is
`suggested as a programmatic approach to the very rapid screening of the
`drug‘-excipient combinations for compatibility.
`Following receipt of the pi-eformuiation information, the formuiator may
`prepare a general summary statement concerning the drug and its properties
`relative to tablet formulation. This statement must often also take into ac-
`count general or special needs or concerns of the medical and marketing
`groups for that drug. A typical statement might be as follows.
`Compound X is a white crystalline solid with a pyridine odor and bitter
`taste, which may require a protective coating (film or sugar).
`It displays
`excellent compressing properties