Pharmaceutical Dosage Forms: Tablets, Third Edition (Three-Volume Set): Pharmaceutical Dosage Forms: Tablets, Third Edition Volume 2: Rational Design and Formulation

570 Pages·2008·8.04 MB·English

by  Larry L. Augsburger

Pharmaceutical Science
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about the book…
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The ultimate goal of drug product development is to design a system that maximizes the 2 dM DOSAGE FORMS: TABLETS
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therapeutic potential of the drug substance and facilitates its access to patients. Pharmaceutical R itA
Dosage Forms: Tablets, Third Edition is a comprehensive treatment of the design, formulation, a io
manufacture, and evaluation of the tablet dosage form. With over 700 illustrations, it guides tio nC
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pharmaceutical scientists and engineers through difficult and technical procedures in a simple n Third Edition
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easy-to-follow format. l
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New to the Third Edition: e I
(cid:115) developments in formulation science and technology s C
i Volume 2:
(cid:115) changes in product regulation g A
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(cid:115) streamlined manufacturing processes for greater efficiency and productivity L
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n Rational Design
Pharmaceutical Dosage Forms: Tablets, Volume Two examines: d D
(cid:115) formulation examples for stability, facilitating, and manufacturability F O
(cid:115) systematic approaches to design formulation and optimization of dosage forms or S and Formulation
(cid:115) immediate release and modified release tablets m A
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about the editors... l G
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LARRY L. AUGSBURGER is Professor Emeritus, University of Maryland School of Pharmacy, i
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Baltimore, and a member of the Scientific Advisory Committee, International Pharmaceutical n F
Excipients Council of the Americas (IPEC). Dr. Augsburger received his Ph.D. in Pharmaceutical O
Science from the University of Maryland, Baltimore. The focus of his research covers the design
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and optimization of immediate release and extended release oral solid dosage forms, the
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instrumentation of automatic capsule filling machines, tablet presses and other pharmaceutical
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processing equipment, and the product quality and performance of nutraceuticals (dietary
:
supplements). Dr. Augsburger has also published over 115 papers and three books, including

Pharmaceutical Excipients Towards the 21st Century published by Informa Healthcare. T
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STEPHEN W. HOAG is Associate Professor, School of Pharmacy, University of Maryland, Baltimore.
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Dr. Hoag received his Ph.D. in Pharmaceutical Science from the University of Minnesota,
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Minneapolis. The focus of his research covers Tablet Formulation and Material, Characterization,
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Process Analytical Technology (PAT), Near Infrared (NIR) Analysis of Solid Oral Dosage Forms,
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Controlled Release Polymer Characterization, Powder Flow, Thermal Analysis of Polymers, Mass
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Transfer and Controlled Release Gels. Dr. Hoag has also published over 40 papers, has licensed

four patents, and has written more than five books, including Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms, Third Edition and Excipient Development for Pharmaceutical,
Biotechnology, and Drug Delivery Systems, both published by Informa Healthcare.
Augsburgerr
Printed in the United States of America
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Hoag
(cid:36)(cid:43)(cid:25)(cid:16)(cid:17)(cid:21)
Edited by
Larry L. Augsburger
Stephen W. Hoag
Pharmaceutical
Dosage Forms: taBlets

Pharmaceutical
Dosage Forms: taBlets
Third Edition
Volume 2:
Rational Design and Formulation
Edited by
Larry L. Augsburger
University of Maryland
Baltimore, Maryland, USA
Stephen W. Hoag

University of Maryland
Baltimore, Maryland, USA
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1.Tablets(Medicine)2. Drugs–Dosageforms. I.Augsburger,LarryL.II.Hoag,StephenW.III.
Title:Tablets.
[DNLM:1. Tablets–pharmacology.2. DrugCompounding.3. DrugDesign.4. Drug
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To my loving wife Jeannie,
the light and laughter in my life.
—Larry L. Augsburger
To my dear wife Cathy and my children Elena
and Nina and those who helped me
so much with my education:
My parents Jo Hoag and my late father
Jim Hoag, Don Hoag, and Edward G. Rippie.
—Stephen W. Hoag

Foreword
We are delighted to have the privilege of continuing the tradition begun by Herb
Lieberman and Leon Lachman, and later joined by Joseph Schwartz, of providing the
onlycomprehensivetreatmentofthedesign,formulation,manufactureandevaluationof
the tablet dosage form in Pharmaceutical Dosage Forms: Tablets. Today the tablet
continues to be the dosage form of choice. Solid dosage forms constitute about two-
thirds of all dosage forms, and about half of these are tablets.
Philosophically,weregard thetabletasadrugdeliverysystem. Likeanydelivery
system, the tablet is more than just a practical way to administer drugs to patients.
Rather,weviewthetabletasasystemthatisdesignedtomeetspecificcriteria. Themost
important design criterion of the tablet is how effectively it gets the drug “delivered” to
thesiteofactioninanactiveforminsufficientquantityandatthecorrectratetomeetthe
therapeutic objectives (i.e., immediate release or some form of extended or otherwise
modified release). However, the tablet must also meet a number of other design criteria
essential to getting the drug to society and the patient. These include physical and
chemical stability (to assure potency, safety, and consistent drug delivery performance
over the use-life of the product), the ability to be economically mass produced in a
manner that assures the proper amount of drug in each dosage unit and batch produced
(to reduce costs and provide reliable dosing), and, to the extent possible, patient
acceptability (i.e., reasonable size and shape, taste, color, etc. to encourage patient
compliancewiththeprescribeddosingregimen). Thus,theultimategoalofdrugproduct
development is to design a system that maximizes the therapeutic potential of the drug
substance and facilitates its access to patients. The fact that the tablet can be uniquely
designedtomeet these criteria accounts foritsprevalence asthe mostpopularoral solid
dosage form.
Although the majority of tablets are made by compression, intended to be
swallowedwholeanddesignedforimmediaterelease,therearemanyothertabletforms.
Theseinclude,forexample,chewable,orallydisintegrating,sublingual,effervescent,and
buccal tablets, as well as lozenges or troches. Effervescent tablets are intended to be
takenafter firstdroppingthem inwater.Some modified releasetablets maybedesigned
todelayreleaseuntilthetablethaspassedthepyloricsphincter(i.e.,enteric).Othersmay
be designed to provide consistent extended or sustained release over an extended period
oftime,orforpulsedrelease,colonicdelivery,ortoprovideauniquereleaseprofilefora
specific drug and its therapeutic objective.
SincethelasteditionofPharmaceuticalDosageForms:Tabletsin1990,therehave
been numerous developments and enhancements in tablet formulation science and
technology,aswellasproductregulation.Scienceandtechnologydevelopmentsinclude
new or updated equipment for manufacture, new excipients, greater understanding of
excipient functionality, nanotechnology, innovations in the design of modified release
v
vi Foreword
tablets, the use of artificial intelligence in formulation and process development, new
initiatives in real time and on-line process control, and increased use of modeling to
understand and optimize formulation and process parameters. New regulatory initiatives
include the Food and Drug Administration’s SUPAC (scale up and post approval
changes)guidances,itsrisk-basedPharmaceuticalcGMPsforthe21stCenturyplan,and
its PAT (process analytical technology) guidance. Also significant is the development,
throughtheInternationalConferenceonHarmonizationofproposals,foraninternational
plan for a harmonized quality control system.
Significantly, the development of new regulatory policy and new science and
technology are not mutually exclusive. Rather, they are inextricably linked. The new
regulatory initiatives serve as a stimulus to academia and industry to put formulation
design, development, and manufacture on a more scientific basis which, in turn, makes
possible science-based policies that can provide substantial regulatory relief and greater
flexibilityformanufacturerstoupdateandstreamlineprocessesforhigherefficiencyand
productivity. The first SUPAC guidance was issued in 1995 for immediate release oral
soliddosageforms(SUPAC-IR).Thatguidancewasfollowedin1997withSUPAC-MR
whichcoveredscale-upandpostapprovalchangesforsolidoralmodifiedreleasedosage
forms. These guidances brought much needed consistency to how the Food and Drug
Administration deals with post approval changes and provided substantial regulatory
relief from unnecessary testing and filing requirements. Major underpinnings of these
tworegulatorypolicieswereresearchprogramsconductedattheUniversityofMaryland
underacollaborativeagreementwiththeFoodandDrugAdministrationwhichidentified
and linked critical formulation and process variables to bioavailability outcomes in
human subjects. The Food and Drug Administration’s Pharmaceutical cGMPs for the
21st Century plan seeks to merge science-based management with an integrated quality
systemsapproachandto“createarobustlinkbetweenprocessparameters,specifications
and clinical performance”1 Thenew PATguidance proposesthe useofmodern process
analyzers or process analytical chemistry tools to achieve real-time control and quality
assurance during manufacturing.2 The Food and Drug Administration’s draft guidance
on Q8 Pharmaceutical Development3 addresses the suggested contents of the pharma-
ceutical development section of a regulatory submission in the ICH M4 Common
Technical Document format.
Acommonthreadrunningthroughthesenewerregulatoryinitiativesisthebuilding
inofproductqualityan dthedevelopmentofmeaningfulproductspecificationsbasedon
a high level of understanding of how formulation and process factors impact product
performance.
Stillotherdevelopmentssince1990aretheadventoftheinternetasaresearchand
resource tool and a decline in academic study and teaching in solid dosage forms.
Together, these developments have led to a situation where there is a vast amount of
formulationinformationwidelyscatteredthroughouttheliteraturewhichisunknownand
difficultforresearchersnewtothetabletingfieldtoorganizeanduse.Therefore,another
objectivetothisbooktointegrateacritical,comprehensivesummaryofthisformulation
information with the latest developments in this field.
Thus, the overarching goal of the third edition of Pharmaceutical Dosage Forms:
Tabletsistoprovideanin-depthtreatmentofthescienceandtechnologyoftabletingthat
1J.Woodcock, “QualitybyDesign:AWayForward,”September17,2003.
2http://www.fda.gov/cder/guidance/6419fnl.doc
3http://www.fda.gov/cder/guidance/6672dft.doc
Foreword vii
acknowledges its traditional, historical database but focuses on modern scientific,
technological, and regulatory developments. The common theme of this new edition is
DESIGN. Thatis,tabletsaredeliverysystemsthatareengineeredtomeetspecificdesign
criteria and that product quality must be built in and is also by design.
No effort of this magnitude and scope could have been accomplished without the
commitment of a large number of distinguished experts. We are extremely grateful for
their hard work, dedication and patience in helping us complete this new edition.
Larry L. Augsburger
Stephen W. Hoag