`
`HD
`
`
`
`osage ie
`Tablets voume:
`
`Bea PoP
`
`TeCOMEtseeLe
`
`COMPRESSION CYCL _TM TL SR
`
`.——f 4
`
`i|Ss
`|SS
`
`=
`
`a raedei
`
`LI
`
`u
`I
`q|
`SS-
`
`| | ||
`
`
`‘bagSfPSOG[EONNIIeULIEY OTeee
`«Sorel.
`
`—y
`.
`-:\
`
`f|||
`
`|
`
`!
`
`. volume1
`
`Second Edition |
`Revised
`and
`Expanded-
`
`Lieberman |
`Lachman
`Schwartz
`fo
`if
`Ly a7] 4
`
`|) 89 |
`_|)
`Dekker =
`
`COMPRESS
`
`ey..
`
`~
`
`aaa)cae eSranAX
`
`ran
`
`pata a
`
`IPR2018-00390
`
`Page 1 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 1 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`‘i‘]
`ia.tii
`bags
`iteret
`
`about the first edition...
`“||, representsthe most comprehensive effort ever made in compiling technological, preformulation, and
`formulation concepts related to pharmaceutical tablets, .
`.
`. reviews the literature in a well-organized, highly
`cogent, andeasilyreadablemanner.”
`_PharmaceuticalTechnology
`“ |, the editors haveprovided valuable information which is difficult to find elsewhere. Usually these unique
`tablet formsare treated very superficially or not at all in pharmaceutics textbooks.”
`_—American Journalof.Pharmaceutical Education
`
`about the second edition...
`
`Focusing on recent innovations in the field, the Second Edition continues to provide in-depth, authoritative
`information onthe science and technology oftabletformulation, manufacture, and testing.
`aceutical Dosage Forms: Tablets, Second Edition :
`contains newmaterialon theformulation ofsustainedorprolongedreleasetablets by wetgranulation, fluidized
`Combining the work of 14 experts, Pharm
`bed granulating, long-acting and controlled-release buccal tablets, vaginal and rectal tablets, and inclusion
`complexes and molecular complexes.
`the Second Edition also offers revised and updated coverage on such topics as drug
`substance purity, dissolution, partition coefficient, the permeability concept, miscellaneous pharmaceutical
`- Expanding its scope,
`properties of solids, the developmentof prototype formulas, direct compression excipients, effervescent
`technology,stability testing and shelf-life, testing for airtightness of sealed packets, microencapsulation and
`
`spray coating, and more.
`
`about the editors ..-
`
`Hersert A. LIEBERMAN is President of H. H. Lieberman Associates,Inc. in Livingston, New Jersey. Hewas for
`many years Vice-President of Proprietary Products Research and Director of Proprietary/Toiletry Product
`DevelopmentatWarner-LambertCompany,Inc. WithKennethE, AvisandLeonLachman he coedited the two-
`volume Pharmaceutical Dosage Forms: Parenteral Medications, and with Martin M.Rieger arid Gilbert S.
`Systems (both titles, Marcel
`Bankerhe coedited the first volume of Pharmaceutical Dosage Forms: Disperse
`Dekker,Inc.). Di. Lieberman received his undergraduate and graduate degrees in chemistry and pharmacy from
`ColumbiaUniversity and thePh.D. degree in pharmaceutical chemistry from Purdue University.
`LronLacuMan is President of Lachman Consultant Services, Inc. in Westbury, New York. Dr. Lachman has
`over 30 years’ industrial experiencein pharmaceutical science,including Director of Pharmacy Research and
`Developmentat CIBA Pharmaceutical Company and Vice President of Development and Control at DuPont
`Pharmaceuticals. Presently he is visiting professor at Rutgers University College ofPharmacy. Dr. Lachman
`has coedited, with Herbert A.LiebermanandJosephL. Kanig, threeeditions ofthe textbook TheoryandPractice
`ofIndustrial Pharmacy. He was honored with the Doctorof Science honoris causa (1976) from Columbia
`University and the Academy ofPharmaceutical Sciences Research Achievement Award (1979). Dr. Lachman
`receivedthe B.Sc. degree in pharmacy andM.Sc. degree in industrial pharmacy from ColumbiaUniversity, and
`Ph.D, degree in pharmaceutics from the University ofWisconsin.
`co,
`JoserH B. SCHWARTZis the LinwoodF, Tice Professor of Pharmaceutics and Director of Industrial Pharmacy
`ResearchatthePhiladelphiaCollege ofPharmacy and ScienceinPhiladelphia,Pennsylvania. During 13 years at
`MerckSharp & DohmeResearch Laboratories, Dr. Schwartz was involved in the developmentofdrug products,
`from the preliminary stages through scale-up and production. His research interests and publications have been
`in the areas of solid dosage form technology and processing, controlled release, and formulation and process
`optimization. Theeditor oftheJournalofParenteral Science and Technology, Dr. Schwartz is aFellow ofthe
`AcademyofPharmaceutical Sciences and the American Association ofPharmaceutical Scientists. He received
`the B.S. degree fromthe Medical College ofVirginia School ofPharmacy,and the M.S. and Ph.D. degrees from
`ISBN: 0—-8247—8044—2
`
`the University of Michigan.
`
`_ Printed in the United States ofAmerica
`
`marcel dekker, inc./new york - basel-
`
`
`
`
`
`
`
`IPR2018-00390
`
`Page 2 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 2 of 120
`
`I-MAK 1009
`
`
`
` be ct ASFE£ RERPoAAIS +
`
`
`
`; TERENCE .
`ANDIhTHFORMATON SERVIC.
`SSECES
`
`
`
`PHARMACEUTICAL
`-DOSAGE FORMS
`
`|
`Tablets
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`VOLUME 1
`
`‘EDITED BY
`
`Herbert A. Lieberman
`H.H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`
`Leon Lachman
`~ Lachman Consultant Services
`Westbury, New York
`
`Joseph B. Schwartz
`Philadelphia College of Pharmacy and Science
`_ Philadelphia, Pennsylvania
`
`MARCEL DEKKER, INC.
`
`New York and Basel-
`
`IPR2018-00390
`
`Page 3 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 3 of 120
`
`I-MAK 1009
`
`
`
`
`
`Library of Congress Cataloging-in-Publication Data
`
`
`
`
`
`
`
`
`
`
`
`
`Pharmaceutical dosage forms--tablets / edited by Herbert A. Lieberman,
`Leon Lachman, Joseph B. Schwartz. -- 2nd ed., rev. and expanded.
`.
`em.
`:
`Includes index.
`ISBN 0-8247-8044-2 (v. i: alk. paper)
`I. Lieberman,
`1. Tablets (Medicine)
`2. Drugs--Dosage forms.
`Herbert A.
`II, Lachman, Leon.
`III. Schwartz, Joseph B.
`°.
`{[DNLM:
`1. Dosage Forms.
`2. Drugs--administration & dosage. QV
`785 P535)
`RS201.T2P46
`615'.191--del9
`DNLM/DLC ©
`for Library of Congress
`
`.
`
`89-1629
`CIP
`
`1989
`
`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-
`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):
`109876543 21
`
`
`
`
`
`
`
`
`
`
`
`PRINTEDIN THE UNITED STATES OF AMERICA ~
`
`
`
`IPR2018-00390
`
`Page 4 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 4 of 120
`
`I-MAK 1009
`
`
`
` 3C
`
`ompressed Tablets by Wet Granulation
`
`Fred J. Bandelin
`
`Schering-Plough Corporation and University of Tennessee, Memphis,
`Tennessee
`:
`
`Compressed tablets are the most widely used of all pharmaceutical dosage
`forms for a number of reasons. They are convenient, easy to use, portable,
`‘and less expensive than other oral dosage forms. They deliver a precise
`‘dose with a high degree of accuracy. Tablets can be made in a variety. of
`shapes and sizes limited only by the ingenuity of the tool and die maker
`(i.e. round, oval, capsule-shaped,. square, triangular, etc.).
`’
`Compressed tablets are defined as solid-unit dosage forms made by com-
`paction of a formulation containing the drug and certain fillers or excipients
`selected to aid in the processing and properties of the drug product.
`There are various types of tablets designed for specific uses or func-
`tions. These include tablets to be swallowed per se; chewable tablets form-
`ulated to be chewed rather than swallowed, such as some antacid and vita-
`min tablets; buccal tablets designed to dissolve slowly in the buccal pouch;
`and sublingual tablets for rapid dissolution under the tongue. Effervescent
`tablets are formulated to dissolve in water with effervescence caused by the
`reaction of citric acid with sodium bicarbonate or some other effervescent
`combination that produces effervescence in water. Suppositories can be
`made by compression of formulations using a specially designed die to pro-
`duce the proper shape.
`,
`ot
`:
`,
`The function of tablets is determined by their design..Multilayer tab-
`lets are made by multiple compression. These are called layer tablets and
`. usually consist of two and sometimes three layers. They serve several
`purposes:
`to separate incompatible ingredients by formulating them in
`separate layers, to make sustained or dual-release products, or merely for-
`appearance where the layers are colored differently. Compression-coated
`tablets are made by compressing a tablet within a tablet’ so that the outer
`coat becomes the coating. As many as two coats can be compressed around
`a core tablet. As with layer tablets, this technique can also be used to
`separate incompatible ingredients and to make sustained or prolonged
`'
`
`
`
`
`
`
`
`
`IPR2018-00390
`
`Page 5 of 120
`
`I-MAK 1009
`
`131
`
`IPR2018-00390
`
`Page 5 of 120
`
`I-MAK 1009
`
`
`
`132
`,
`Bandelin
`release tablets. Sugar-coated tablets are compressed tablets with a sugar
`coating. The coating may vary in thickness and color by the addition of
`dyes to the sugar coating. Film-coated tablets are compressed tablets with
`a thin film of an inert polymer applied in a suitable solvent and dried.
`Film coating is today the preferred method of making coated tablets.
`It is
`the most economical and involves minimum time,
`labor, expense, and. expo-
`sure of the tablet to heat and solvent. Enteric-coated tablets are compressed
`tablets coated with an inert substance which resists solution in- gastric fluid,
`but disintegrates and releases the medication in the intestines.
`Sustained
`or prolonged release tablets are compressed tablets especially designed to
`release the drug over a period of time.
`Most drugs cannot be compressed directly into tablets because they
`lack the bonding properties necessary to form a tablet. The powdered
`drugs, therefore, require additives and treatment to confer bonding and
`free-flowing properties on them to facilitate compression by a tablet press.
`This chapter describes and illustrates how this is accomplished by the
`versatile wet granulation method.
`
`I.
`
`PROPERTIES OF TABLETS
`
`Whatever method of manufacture is used, the resulting tablets must meet a
`number of physical and biological standards. The attributes of an accept-
`able tablet are as follows:
`
`1. The tablet must be sufficiently strong and resistant to shock and
`abrasion to withstand handling during manufacture, packaging,
`shipping, and use. This property is measured by two tests,
`the
`hardness and friability tests.
`2. Tablets must be uniform in weight and in drug content of the in-
`dividual tablet. This is measured by the weight variation test and _
`the content uniformity test.
`3. The drug content of the tablet must be bioavailable. This property
`is also measured by two tests, the disintegration test and the dis-
`solution test. However, bioavailability of a drug from a tablet, or
`other dosage form,
`is a very complex problem and the results of
`these two tests do not of themselves provide an index of bioavail-
`ability. This must be done by blood levels of the drug.
`4. Tablets must be elegant in appearance and must have the charac-
`teristic shape, color, and other markings necessary to identify the
`product. Markings are usually the monogram or logo of the manu-
`facturer. Tablets often have the National Drug Code number print-
`ed or embossed on the face of the tablet corresponding to the official
`listing of the product in the National Drug Code Compendium of the
`Food and Drug Administration. Another marking that may appear.
`on the tablet is a score or crease across the face, which is intended
`to permit breaking the tablet into equal parts for the administration |
`of half a tablet. However,
`it has been shown that substantial vari-
`ation in drug dose can occur in the manually broken tablets.
`5. Tablets must retain all of their functional attributes, which include
`drug stability and efficacy.
`
`_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IPR2018-00390
`
`Page 6 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 6 of 120
`
`I-MAK 1009
`
`
`
` Compressed Tablets by Wet Granulation
`
`11,
`
`FORMULATION OF TABLETS
`
`The size and, to some extent, the shape of the tablet are determined by ~
`the active ingredient(s). Drugs having very small doses in the microgram
`range (e.g., folic acid, digitoxin, reserpine, dexamethasone, etc.) require
`the addition of fillers also called excipients to be added to produce a mass or
`or volume of material that can be made into tablets of a size that is con-
`venient for patients. A common and convenient size for such low-dosage
`drugs is a 1/4-in. round tablet or equivalent in some other shape.
`It is
`difficult for some patients to count and handle tablets smaller than this.
`Tablets of this size ordinarily weigh 150 mg or more depending on the den- .
`sity of the excipients used to make up the tablet mass.
`.
`As the dose increases, so does the size of the tablet. Drugs with a
`dose of 100 to 200 mg may require tablet weights of 150 to 300 mg and
`‘round die diameters of 1/4 to 7/16 in.
`in diameter depending on the density
`and compressibility of the powders used. As the dose of the active ingredi-
`ent(s) increases, the amount of the excipients and the size of the tablet
`may vary considerably depending on requirements of each to produce an
`acceptable tablet. While the diameter of the tablet may in some cases be
`fixed, the thickness is variable thus allowing the formulator: considerable
`latitude and flexibility in adjusting formulations.
`the formu-
`As the dose, and therefore the size, of the tablet increases,
`_ lator uses his expertise and knowledge of excipients to keep the size of the
`tablet as small as possible without sacrificing its necessary attributes.
`Form-
`ulation of a tablet,
`then, requires the following considerations:
`
`
`
`1.
`Size of dose or quantity of active ingredients
`2. Stability of active ingredient(s)
`3. Solubility of active ingredient(s)
`4. Density.of active ingredient(s)
`5. Compressibility of active ingredient(s)
`6.
`Selection of excipients
`7, Method of granulation (preparation for compression)
`8. Character of granulation
`;
`9. Tablet press, type, size, capacity
`10. Environmental conditions (ambient or humidity control)
`11. Stability of the final product
`12. Bioavailability of the active drug content of the tablet
`
`The selection of excipients is critical in the formulation of tablets. Once
`the formulator has become familiar with the physical and chemical properties
`‘of the drug,
`the process of selecting excipients is begun. The stability of
`the drug should be determined with each proposed excipient. This can be
`accomplished as follows:
`In the laboratory,-prepare an intimate mixture of
`the drug with an excess of each individual excipient and hold at 60°C for
`72 hr in a glass container. At the end of this period, analyze for the
`drug using a stability-indicating assay.. The methods of accelerated testing
`of pharmaceutical products have been extensively reviewed by Lachman et
`al in The Theory and Practice of Industrial Pharmacy, 3rd Ed., Lea and
`Febiger (1986).
`
`
`
`
`
`IPR2018-00390
`
`Page 7 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 7 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`134
`
`Bandelin
`
`Table 1
`
`Suggested Excipient /Drug Ratio in Compatibility Studies
`
`Excipient
`Alginic acid
`Avicel
`Cornstarch
`Dicalcium phosphate
`dihydrate =»
`‘
`Lactose
`Magnesium carbonate
`Magnesium stearate
`Mannitol
`Methocel-
`PEG 4000
`PVP
`Sta-Rx?
`Stearic acid
`Tale
`
`Weight excipient per unit weight drug
`(anticipated drug dose, me)
`an
`1
`5-10
`25-50
`75-150
`150
`24
`24
`9
`9
`9
`24
`9
`9
`9
`4
`24
`9
`4
`2
`2
`34
`34
`9
`9
`9
`
`.
`
`34
`24
`1
`24
`2
`9
`4
`1
`1
`1
`
`9.
`24
`1
`9
`2
`9
`4
`1.
`1.
`1
`
`4
`9 -
`1 .
`4
`2
`4
`2
`1
`1
`1
`
`2
`9
`1
`2
`2
`4
`1
`1.
`1
`1
`
`1
`4
`1.
`1
`1
`(2
`“t
`1
`1
`1
`
`-
`.
`8Now called starch 1500.
`Source: Modified from Akers, M. J., Can. J. Pharm. Sci., 11:1 (1976).
`Reproduced with permission of the Canadian Pharmaceutical Association.
`
`The suggested ratio of excipient to drug is given in Table 1. Excipients
`are specified according to the function they perform in the tablet.
`. They
`are classified as follows:
`.
`
`Fillers (diluents) ©
`Binders
`Disintegrants
`Lubricants -
`Glidants
`Antiadherents
`
`These additives are discussed in detail later in this chapter..
`
`
`
`IPR2018-00390
`
`Page 8 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 8 of 120
`
`I-MAK 1009
`
`
`
` Compressed Tablets by Wet Granulation
`
`(it. TABLET MANUFACTURE
`
`A. Tablet Presses
`
`The basic unit of any tablet press is a set of tooling consisting of two ,
`punches and a die (Fig. 1) which is called'a station. The die determines
`the diameter or shape of the tablet; the punches, upper and lower, come
`together in the die that contains the tablet formulation to form a-tablet.
`There are two types of presses:
`single-punch and rotary punch. The
`single-punch press has a single station of one die and two punches, and
`is capable of producing from 40 to 120 tablets per minute depending on
`the size of the tablet.
`It is largely used in the early stages of tablet form-
`ulation development. The rotary press has a multiplicity of stations arranged
`.on a rotating table (Fig. 2) in which the dies are fed the formulation pro-
`ducing tablets at production rates of'from a few to many thousands per
`minute. There are numerous models of presses, manufactured by a number
`of -companies, ranging in size, speed, and capacity..
`
`
`
`Figure 1
`(Courtesy of
`Two punches and die, comprises one station.
`Pennsalt Chemical Corporation, Warminster, Pennsylvania.) .
`
`IPR2018-00390
`
`Page 9 of 120
`
`I-MAK 1009
`
`
`
`IPR2018-00390
`
`Page 9 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`136 ©
`
`.
`
`Bandelin
`
`Tablet presses consist of:
`
`1. Hoppers, usually one or two, for storing and feeding the formula-
`tion to be pressed
`Feed frame(s) for distributing the formulation to the dies
`Dies for controlling the size and shape of the tablet
`Punches for compacting the formulation into tablets
`Cams (on rotary presses) that act as tracks to guide the moving
`punches
`
`Om&
`
`All other parts of the press are designed tocontrol the operation of the
`above parts.
`
`B. Unit Operations
`
`There are three methods of preparing tablet granulations. These are (a)
`wet granulation, (b) dry granulation (also called "slugging"), and direct
`compression (Table 2). Each of these methods has its advantages and dis-
`advantages.
`The first two steps of milling and mixing of the ingredients of the form-
`ulation are ‘identical, but thereafter the processes differ. Each individual
`operation of the process is known as a unit operation. The progress or
`flow of materials through the process is shown in the schematic drawing
`(Fig. 3).
`
`pelt)
`
`
`Se
`Chemical Corporation, Warminister, Pennsyovania.)
`
`
`
`
`Figure 2.
`
`Punches and dies on rotary tablet press.
`
`(Courtesy of Pennwalt
`
`IPR2018-00390
`
`Page 10 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 10 of 120
`
`I-MAK 1009
`
`
`
`Compressed Tablets by Wet Granulation
`
`
`
`uotssardwoojoartqg
`
`uolyetnuedsdAIG
`
`
`
`‘woryeTNUuBS19M
`
`(suorjeaedgyun)eanjoeynuepy
`
`
`
`WIAELJOspoyjsMjuserezjiqutsdeyg=zqe
`
`pues3napjoSunnw
`
`
`sS}juatdtoxe-
`
`‘TpusssnapjoBury
`
`
`
`‘TpuesSnipjoSumi-T!
`
`squatdioxa
`
`syuetdioxa
`
`
`
`S}UstpardutjoSux
`
`
`
`uorssaadwoo.jerquy
`
`°ZSdapmodpartujoBurm
`
`*gprey‘oasreyoJUTuoctssardwog
`
`
`
`
`
`
`SaapModpeywjoBury+z“¢depulqjouopeuedarg‘¢Z:
`
`
`
`
`
`:SBn[Spayedsze[qey
`
`worynjos
`
`
`
`yuaseSuryeadayutstp
`
`
`
`puesjusoTaqntUlIMSurxyy
`
`“¢:30MJoBuyusaarasasizeog*G
`
`
`
`ysow-ZT0}-9Sursnssew
`
`SSeWJOMWaIOy
`
`
`
`uotsseadwooGEL
`
`
`
`somueispausszosSure-g
`
`yueaSaqursrp©
`
`
`
`
`
`puejuBoTIqnyyyIM
`
`
`
`UoIssarduiodyaqey°6
`
`yueidaUISIp
`
`
`
`sainueisAapButusaaog+),
`
`
`
`
`
`pueJUBOTIGN]YIM.
`
`
`
`
`
`*9.samuerdysiow8uikaq‘*9
`
`‘sSnjsJoButusaaag
`
`
`
`
`
`
`
`°P,uoTNjosJepulqSure-p
`
`
`
`
`
`0}SanyxtwJapmodyyIM
`
`IPR2018-00390
`
`Page 11 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 11 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`138
`
`Bandelin
`
`ADJUVANT
`
`LIQUIDS
`————
`
`/
`
`:
`
`AGGLOMERATE
`
`LUBRICANT
`
`COMPRESS
`
`TABLET
`
`>
`
`
`
`
`
`;
`
`F SCREEN
` RA
`
`
`(a)
`
`ADJUVANT
`
`
`
`PELLET
`
`.
`
`CRUSH
`
`LUBRICANT
`
`TABLET
`
`
`
`(b)
`Figure 3 Unit operations in ‘three methods of tablet manufacture:
`granulation, (b) dry granulation, and (c) direct compression.
`
`,(2) wet |
`
`
`
`IPR2018-00390
`
`Page 12 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 12 of 120
`
`I-MAK 1009
`
`
`
` Compressed Tablets by Wet Granulation
`
`
`
`
`ADJUVANTS
`
`TABLET
`
`
`
`DRUG
`
`* GRIND
`
`(c)
`
`Figure 3)
`
`(Continued)
`
`“This chapter is devoted to the first of these processes—the wet granu-
`lation process.
`The preliminary step of particle size reduction ean be accomplished by
`a variety of mills or grinders such as shown in Figure 4. The next step
`is powder blending with a planetary mixer (Fig. 5) or a twin-shell blender
`' (Fig. 6). The addition of the liquid binder to the powders to produce the
`wet mass requires equipment with a strong kneading action such as a sigma
`blade mixer (Fig. 7) or a planetary mixer mentioned above. The wet mass
`is formed into granules by forcing through’‘a screen in an oscillating gran-
`‘ulator (Fig.. 8) or through a perforated steel plate in a Fitzmill (Fig. 9).
`The granules are then dried in an oven or a fluid bed dryer after which
`they are reduced in size for compressing by again screening in an oscilla-
`tor or Fitzmill with a smaller orifice. The granulation is then transferred
`to a twin shell or other suitable mixer where the lubricant, disintegrant,
`and glidant are added and blended... The completed granulation is then
`ready for compression into tablets.
`Fluid bed dryers have been adapted to function as wet granulators as
`|
`depicted by the schematic drawings Figs.
`10 and 11.
`In the latter, pow-
`ders are agglomerated in the drying chamber by spraying the liquid binder
`onto the fluidized powder causing the formation of agglomerates while the
`hot-air flow simultaneously dries the agglomerates by vaporizing the liquid
`phase. This manner of wet granulation has the advantage of reducing
`handling and contamination by dust and offers savings in both process
`time and space [1-3].
`It also lends itself to automation; however, by its
`- nature it has the disadvantage of being limited to a batch-type operation.
`Unlike the wet-massing method, fluidized.granulation is quite sensitive to
`small variations in binder and processing. Conversion of granule prepara-
`tion from the wet massing to the fluid bed method is not feasible without
`extensive and time-consuming reformulation [{4—8].
`In one study it was noted that fluidized bed tablets were more friable
`than wet-massed tablets of the same tensile strength and attributes .this to
`uneven distribution of the binder in the fluidized bed powders leading to
`drug-rich, friable areas on the surface and edges of the tablets causing
`breaking and chipping [9].
`
`
`
`
`
`IPR2018-00390
`
`Page 13 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 13 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`Figure 4
`iWarm
`nis
`
`Tornado mill.
`1a.
`ter,
`Pennsylvan
`
`(Courtesy of Pennwalt Chem
`)
`
`1c
`
`al Corporat:
`
`ion,
`
`140
`
`IPR2018-00390
`
`Page 14 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 14 of 120
`
`I-MAK 1009
`
`
`
`
`Compressed Tablets by Wet Granulat
`
` ton
`
`Ross HDM 40 sanitary double planetary mixer.
`Figure 5
`Charles Ross & Son Co., Happauge, New York.)
`
`(Courtesy of
`
`IPR2018-00390
`
`Page 15 of 120
`
`I-MAK 1009
`
`4
`ral
`
`IPR2018-00390
`
`Page 15 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`
`
`
`142 :
`
`Bandelin
`
`
`
`Twin-shell blender.
`Figure 6
`East Strousberg, Pennsylvania.)
`
`(Courtesy of Patterson-Kelley Company,
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In the past few years considerable improvements have been made in
`equipment available for fluidized bed drying. These have reduced the
`risk of channeling by better design of the fluid bed,
`improved design
`from a Good Manufacturing Practices viewpoint, and by means of in-place
`washing together with automatic controls:
`Several other methods of granulating not extensively used in the phar-
`maceutical industry but worthy of investigation are the following.
`Pan granulating is achieved by spraying a liquid binder onto powders
`in a rotating pan such ‘as that used in tablet coating. The tumbling action
`of the powders in the pan produces a fluidizing effect as the binder is
`impinged on the powder particles. The liquid (water or solvent} is evapor-:
`ated in the heated pan by a current of hot air and the vaporsare carried
`off by a vacuum hood over the upper edge of the pan opening..
`Although pan granulation has found extensive application in ‘other in-
`dustries (e.g., agricultural chemicals), it has not found favor in the phar-
`maceutical industry. One reason may be the lack of acceptable design.
`Spray drying can serve as a granulating process. The drying process
`changes the size, shape, and bulk density of the dried product and:lends
`itself to large-scale production [10]. The spherical particles produced
`usually flow better than the same product dried by other means because
`the particles are more uniform in size and shape. Spray drying can also
`‘be used to dry: materials sensitive to heat or oxidation without degrading
`them. The liquid feed is dispersed into droplets, which are dried in-:sec- '
`onds, and the product is kept cool by the vaporization of the liquid.
`Seager and others describe a process for producing.a variety of drug form-
`ulations by spray drying [11-13].
`:
`Extrusion,
`in which the wet mass is forced through holes in a steel
`plate by a spiral screw (similar to a meat grinder), is an excellent method
`of granulating and dénsifying powders.
`
`It lends itself to efficient,
`
`IPR2018-00390
`
`Page 16 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 16 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`Figure7Sigmablademixer.(CourtesyofJ
`
`H
`
`DayCompany,
`
`Cincinnati,Ohio.)
`
`IPR2018-00390
`
`Page 17 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 17 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`Figure 8 Oscillating granulator.
`tion, Warminister, Ohio.)
`.
`
`(Courtesy of Pennsalt Chemical Corpora-
`
`
`
`IPR2018-00390
`
`Page 18 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 18 of 120
`
`I-MAK 1009
`
`
`
`Compressed Tablets by Wet Granulation
`
`Figure 9
`Illinois.)
`
`Fitzmill,
`
`(Courtesy of The Fitzpatrick Company, Elmhurst,
`
`IPR2018-00390
`
`Page 19 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 19 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`;
`
`Bandelin
`
`146
`
`
`
`Fluid bed dryer.
`Figure 10
`ville, New Jersey.)
`
`(Courtesy of Aeromatic, Inc., South Somer-
`
`large-scale production as part of an enclosed continuous .wet-granulating
`system protected from airborne contamination.
`The extruder can also act as a wet-massing mixer by providing a con-
`tinuous flow of the binder into the screw chamber, allowing the spiral screw
`to act as the massing instrument ‘as it moves the powder, infusing it with
`the liquid to form a wet mass that is then extruded to form granules. _The
`extruder has the added advantage of being a ‘Small unit as compared with
`other mixers, and has a high production capacity for its size.
`It is easily
`cleaned and is versatile in its ability to produce granules of various size
`depending on the size of the plate openings used.
`,
`Pellets can be prepared by spheroidization of the wet mass after ex-
`,
`trusion [14~16].
`The transfer of wet granulation technology from lab batches to produc
`tion equipment, generally known as "scale-up," is a critical step because
`
`TOP SPRAY
`GRANULATOR
`
`FILTER HOUSING
`
`EXPANSION CHAMBER
`
`
`
`
`
`
`
`
`
`
`‘LOWER PLENUM
`
`PARTICLE FLOW
`PATTERN
`
`meanenseneneeeences
`
`\
`
`SPRAY NOZZLE
`
`PRODUCT CONTAINER
`
`AIR INLET.
`
`Spray granulator.
`Figure 11
`Ramsey, New Jersey.)
`
`(Courtesy of Glatt Air Techniques, Inc.,
`.
`
`IPR2018-00390
`
`Page 20 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 20 of 120
`
`I-MAK 1009
`
`
`
` Compressed Tablets by Wet Granulation
`
`of the increased mass of the larger batches and different conditions in
`larger equipment.
`To attempt to anticipate granulation variation due to
`scale-up, intermediate pilot equipment facilitates the step-up to production
`quantities. This permits the use of various types of equipment or unit
`operations to determine which produces the best end result of the granu-
`lation process. Often, however, scale-up is limited to the available equip-
`ment, which limits, or locks in,
`the process.
`In this situation,
`it is in-
`cumbent on the formulator to utilize his or her expertise and experience
`in selecting excipients and binder which yield the best granulation and
`tablets with the equipment available [17-19].
`:
`Attempts to apply experimental design to scaling up the wet granulation
`process has not been rewarding so that,
`in practice, trial and error re-
`mains the most widely used procedure.
`Wet granulation research has greatly increased and expanded in the
`last decade because of the advent of new types of granulating equipment.
`Notable among these are the Lodige, Diosna, Fielder, and Baker—Perkins
`-mixers. These are equipped with high-speed impellers or blades that ro-
`tate at speeds of 100 to 500 rpm. In addition to merely mixing the powders,
`they produce rapid and efficient wetting and densification of the powders.
`. Most of these mixers are also equipped with a rotating chopper that oper-
`ates at speeds of 1000 to 3000 rpm. This facilitates uniform wetting of the
`powders in a matter of minutes. Granule formation can be achieved by the
`controlled spraying or atomization of the binder solution onto the powders
`- while mixing [20]. While these highly efficient mixers serve to optimize the
`wet granulation process,
`they also demand greater understanding of their
`effects on the individual fillers and binders as processed by the mixers
`.
`[21].
`‘
`Another mixer, blender, and granulator that has found application in
`’ the, pharmaceutical industry is the Patterson—Kelley twin-shell liquid-solids
`Blender (Fig. 12). These twin-shell units are equipped with a jacket for .
`
`’
`
`Suspended
`solids -
`
`Canted discs produce
`wide spray band
`
`
`
`
`Size of aperture
`_ controls spray fineness,
`from a mist to droplets
`
`(Courtesy of Patterson -
`Twin-shell liquid-solid blender.
`Figure 12.
`Kelley Company, East Stroudsburg, Pennsylvania.)
`
`
`
`IPR2018-00390
`
`Page 21 of 120
`
`I-MAK 1009
`
`IPR2018-00390
`
`Page 21 of 120
`
`I-MAK 1009
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`148
`
`Bandelin
`
`heating and cooling, a vacuum take-off, and a liquid dispersion bar
`through which a liquid binder can be added. As the blender rotates,
`liquid is sprayed into the powder charge through the rotating liquid dis-
`persion bar,
`located concentric to the trunnion axis. The bar's dog-eared
`blades, rotating at 3300 rpm, aerates the powder to increase the speed and
`thoroughness of the blend. Granulation can be controlled by the rate of
`binder addition through the dispersion bar. After heating,
`the liquid of
`the binder is removed under reduced pressure. Mixing, granulating,
`heating, cooling, and removal of excess liquid are carried out in a continu-
`ous operation in an enclosed system, thereby protecting the contents from
`contamination and the adjacent area from contamination by the contents.
`|
`Once the granulation process is completed, the remaining excipients can
`be added and blended by the simple rotating action of the blender. . This
`unit is also known as a liquid-solids processor.
`
`IV. GRANULATION
`
`Most powders cannot be compressed directly into tablets because (a) they
`-lack the proper characteristics of binding or bonding together into a com-
`pact entity and (b) they do not ordinarily possess the lubricating and
`disintegrating properties required for tableting. For these reasons, drugs
`must first be pretreated, either alone or in combination with a filler,
`to
`form granules that lend themselves to tableting. This process is known as
`granulation.
`Granulation is any process of size enlargement whereby small particles
`are gathered together into larger, permanent aggregates [22]
`to render
`them into a free-flowing state similar to that of dry ‘sand.
`Size enlargement, also called agglomeration, is accomplished by some
`method of agitation in mixing equipment or by compaction, extrusions or .
`globulation as described in the previous section on unit operations [4,23,
`24).
`The reasons for granulation as listed by Record[23] are to:
`
`1. Render the material free flowing
`
`2. Densify materials
`3. Prepare uniform mixtures that do not separate
`4.
`Improve the compression characteristics of the drug
`5. Control the rate of drug release
`6. Facilitate metering or volume dispensing
`7. Reduce dust
`8.
`Improve the appearance of the tablet
`
`Because of the many possible approaches to granulation, selection of
`a method is of prime importance to the formulator.
`
`A. Wet Granulation -
`
`Wet granulation is the process in which a liquid is added to a powder in a
`vessel equipped with any type of agitation that will produce agglomeration
`or’granules. This process has been extensively reviewed by Record [23],
`Kristensen and Schaefer [26], andCapes [27].
`
`
`
`
`.
`
`IPR20