Slallllil
`
`1
`
`1 SecondEdition,RevisedandExpanded
`1 Hired by Herberr A. Lieberman,
`'
`leon luchman, and legend: B. Schwartz _
`
`‘ii
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`V
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`ii‘i
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`“W.
`2K,.u
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`.
`
`about the first edition .
`
`. represents‘the 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, andeasilyreadable manner."
`-—Phannaceutical Technology
`“ .
`.
`. the editors have provided valuable information which is difficult to find elsewhere. Usually these unique
`tablet formsare treated very superficially or not at all in pharmaceutics textbooks.”
`——American Journal ofPharmaceutical Education
`
`about the second edition .
`
`.
`
`.
`
`Focusing on recent innovations in the field, the Second Edition continues to provide in-depth, authoritative
`information on the science and technology of tablet formulation, manufacture, and testing.
`Combining the work of 14 experts. Pharmaceutical Dosage Forms; Tablets, Second Edition
`containsnew material on the formulation ofsustained or prolonged release tablets by wet granulation, fluidized
`bed granulating, long-acting and controlled-release buccal tablets, vaginal and rectal tablets, and inclusion
`complexes and molecular complexes.
`pe, the Second Edition also offers revised and updated coverage on such topics as drug
`t, miscellaneous pharmaceutical
`Expanding its sco
`substance purity, dissolution, partition coefficient, the permeability concep
`properties of solids, the development of prototype formulas. direct compression excipients, effervescent
`technology. stability testing and shelf-life, testing for airtightness of scaled packets, microencapsulation and
`spray coating, and more.
`.
`
`about the editors .
`.
`.
`HERBERT A. LiaaERMAN is President of H. H. Lieberman Associates, Inc. in Livingston, New Jersey. He .was for
`many years Vice-President of Proprietary Products Research and Director of Proprietary/1‘oiletry Product
`Development atWamer-Lambert Company, Inc. With Kenneth E. Avis and Leon Lachman he coedited the two-
`volume Pharmaceutical Dosage Farms: Parenteral Medications. and with Martin M. Rieger and Gilbert S.
`Bankerhe coedited the first volume of Pharmaceutical Dosage Form: Dirperse Systems (both titles. Marcel
`Dekker. Inc.). Dr. Lieberman received his undergraduate and graduate degrees in chemistry and pharmacy from
`ColumbiaUniversity and the Ph.D. degree irt pharmaceutical chemistry from Purdue University.‘
`LEON human is President of Lachman Consultant Services, Inc. in Westbury, New York: Dr. Lachman has
`over 30 years‘ industrial experience in pharmaceutical science, including Director of Pharmacy Research and
`Development at 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. Lieberman andJoseph L. Kanig. three editions ofthe textbook Theory and Practice
`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
`received the B.Sc. degree in pharmacy and M.Sc. degree in industrial pharmacy from Columbia University, and
`PhD. degree in pharmaceutics from the University ofWisconsin.
`losarn B. SCHWARTZ is the Linwood F. Tice Professor of Pharmaceutics and Director of Industrial Pharmacy
`Research at the Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania. During 13 years at
`Merck Sharp & Dohme Research 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. The editor of the Journal ofParenteral Science and Technology, Dr. Schwartz is a Fellow of the
`Academy ofPharmaceutical Sciences and the American Association of Pharmaceutical Scientists. He received
`the B.S. degree from the Medical College ofVirginia School ofPharmacy, and the MS. and PhD. degrees from
`the University of Michigan.
`- Printedinthe UnitedStatesofAmerica
`
`ISBN2_ 0—8247—8044—2
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`morcel dekker, inc./ new york - bosel '
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`' SCIENCE "RE-‘E-R‘ENCE Ii
`NDEH‘ORMA’I‘flN SER‘JK _
`
`
`2272';c'#19891:
`
`Tablets
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`
`VOLUME 1
`
`EDITED BY
`
`Herbert A. Lieberman
`H.H. Lieberman Associates, Incl
`Consullant 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 -
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`
`
`Library of CongreSs 'Cataloging—in—Publication Data
`
`Pharmaceutical dosage forms-—tab1ets / edited by Herbert A. Lieberman,
`Leon Lachman, Joseph B.- Schwartz.
`-— 2nd ed., rev. and expanded.
`p.
`cm.
`Includes index.
`
`I : elk; paper)
`ISBN 0-8247-8044-2 (v.
`I. Lieberman,
`2. Drugs-—Dosage forms.
`1. Tablets (Medicine)
`Herbert A.
`II. Lachman, Leon.
`III. Schwartz, Joseph B.
`'.
`[DNLM:
`l. Dosage Forms.
`2. Drugs-—administration & dosage. QV
`785 P535]
`‘
`R8201.T2P46
`615'.191--dc19
`DNLM/DLC ’
`for Library of Congress
`
`1989
`
`.
`
`89-1629
`01?
`
`
`
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`
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`
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`
`
`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):
`10
`9
`8
`7
`6
`5
`4
`3
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`PRINTED- IN THE UNITED STATES OF AMERICA ’
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` 3 C
`
`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.
`‘
`'
`‘
`i
`'
`The function of tablets is determined by their design. Multilayer tab-
`lets are made by multiple compression. Theseare called layer tablets and
`.yusually 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
`:
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`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.
`It is
`Film coating is today the preferred method of making coated tablets.
`the most economical and involves minimum time,
`labor, expense, and expo—
`Enteric- coated tablets are compressed
`sure of the tablet to heat and solvent
`tablets coated with an inert substance which resists solution in gastric fluid,
`but disintegratesand 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
`The powdered
`lack the bonding properties necessary to form a tablet.
`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
`
`the' resulting tablets must meet a
`_Whatever method of manufacture is used,
`The attributes of an accept—
`number of physical and biological standards.
`able tablet are as follows:
`
`_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`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.
`’
`'
`
`This prop erty
`3. The drug content of the tablet must be bioavailable.
`
`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
`
`Another marking that may appear.
`Food and Drug Administration.
`
`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.
`
`
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` Compressed Tablets by Wet Granulation
`
`ll.
`
`FORMULATION OF TABLETS
`
`
`
`The size and, to some extent, the shape of the tablet are determined by '
`the active ingredient(s). Drugs havingvery 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 seme 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 ex'cipients 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 cempressibility of the powders used. As the dose of the active ingredi-
`ent(s) increases, the améunt 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 possiblewithout sacrificing its necessary attributes.
`Form-
`ulation of attablet,
`then, requires the following considerations:
`
`fbmdmmuari-I
`
`Size of dose or quantity of active ingredients
`Stability of active ingredient(s)
`Solubility of active .ingredient(s)
`Densityof active ingredienfls)
`Compressibility of active ingredient(s)
`Selection of excipients
`Method of granulation (preparation for compression)
`Character of granulation
`_
`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 laboratoryyprepare 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).
`
`
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`134
`
`Bandelin
`
`Suggested Excipient/Drug Ratio in Compatibility Studies
`Table 1
`_______________________———————
`Weight excipient per unit weight drug
`(anticipated drug dose, mg)
`'
`______________________”’—————~—-V
`
`5- 10
`
`25— 50
`
`75- 150
`
`150
`
`1
`
`24
`24
`24
`34
`
`34
`24
`1
`24
`2
`9
`4
`
`Excipient
`
`Alginic acid
`Avicel
`Cornstarch
`Dicalcium phosphate
`dih'jfdrate n
`'
`Lactose
`Magnesium carbonate
`Magnesium stearate
`Mannitol
`Methocel'
`PEG 4000
`PVP
`
`Sta-Rxa
`
`Stearic acid
`Talc
`
`,
`
`24
`9
`9
`34
`
`_
`
`9
`24
`1
`9
`2 I
`9
`4
`
`9
`9
`4'
`'9
`
`'
`
`4
`h 9
`1 I
`4
`2
`4
`2
`
`1 1.1
`
`1
`1
`
`1.
`1
`
`1
`1
`
`_
`
`9
`9
`2
`9
`
`2
`9
`1
`2
`2
`4
`1
`
`1
`
`1
`1
`
`,
`
`9
`4
`2
`9
`
`1
`4
`1
`14
`1
`' 2
`I 1
`
`1
`
`1
`1'
`
`I
`
`-
`_
`3Now 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..
`
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` Compressed Tablets by Wet Granulation
`
`Ill. 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 lowerh 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
`ofcompanies, ranging in size, speed, and capacity.
`
`
`
`
`
`(Courtesy of
`Two punches and die,_ comprises one station.
`Figure 1
`Pennsalt Chemical Corporation, Warminster, Pennsylvania.) ,
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`1 36 ’
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`.
`
`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
`
`0|pr
`
`All other parts of the press are designed to. control 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'br
`flow of materials through the process is shown in the schematic drawing
`(Fig. 3).
`
`
`
`
`
`Punches and dies on rotary tablet press.
`Figure 2
`Chemical Corporation, Warminister, Pennsyovania.)
`
`
`(Courtesy of Pennwalt
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`Compressed Tablets by Wet Granulation
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`
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`138
`
`Bandelin
`
`ADJUVANT
`
`LIQUIDS
`
`
`
`LUBRICANT
`
`COMPR ESS
`
`AGGLOMERATE
`
`PELLET
`
`TABLET
`
`(a)
`
`
`
`
`ADJUVANT
`
`PE LLET
`
`LUBRICANT
`
`(b)
`
`Figure 3 Unit operations in'three methods of tablet manufacture:
`granulation, (b) dry granulation, and (c) direct compression.
`
`,(a) Wet
`
`'
`
`
`
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`Compressed Tablets by Wet Granulation
`
`ADJUVANTS
`
`COMPRESS
`
`
`
`
`
`BLEND
`
`TABLET
`
`DRUG
`
`'
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`- GRIND
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`(C)
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`Figure 3
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`(Continued)
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`‘This chapter is devoted to the first of these processes—the wet granu-
`lation process.
`_
`The preliminary step of particle size reduction can be accomplished by
`a variety of mills orgrinders 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— 7
`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, fluidizedgranulation 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].
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`Courtesy of Pennwalt Chem
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`IC
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`Jon ,
`a] Corporat'
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`)(
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`Tornado mi
`ter ,
`Pennsylvan
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`ia
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`Figure 4
`Warminis
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`140
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` lOT!
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`Figdre 5
`Ross HDM 40 sanitary double planétary mixer.
`Charles Ros‘s & Son 00., Happauge, New York.)
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`(Courtesy of
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`14‘2-
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`Bandelin
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`Twin-shell blender.
`.Figure 6
`East Strousberg, Pennsylvania.)
`
`(Courtesy of Patterson—KelleyCompany,
`
`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-r
`ated in the heated pan by a current of hot air and the vapors are 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
`I 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- ‘
`ends, and the product is kept cool by the vaporization of the liquid.
`Seager’and others describe a process for producinga 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 de'nsifyi'ng powders.
`It lends itself to efficient,
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`lac;u
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`(Courtesy of Pennsélt Chemical Corpora-
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`Figuré 8 Oscillating granulator.
`tion, Warmim‘ster, Ohio.)
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`145
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`M
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`E‘itzmill.
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`.mt.aD.zt.1Fe‘hTf0V.setru0C(
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`pm0C
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`Figure 9
`Illinois . )
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`146
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`Fluid bed dryer.
`Figure 10
`ville, New Jersey.)
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`(Courtesy of Aeromatic,_1nc., South Somer-
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`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 mixerstand 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
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`GRANULATOR
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`FILTER 'HDUSING
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`EXPANSION CHAMBER
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`'LONER PLENUM
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`'-
`PARTICLE FLOW
`pATTERN _ SPRAY NOZZLE
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`PRODUCT CONTAINER
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`AIR INLET-i
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`Spray granulator.
`Figure 11
`Ramsey, New Jersey.)
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`(Courtesy of Glatt Air Techniques. Inc.,
`1
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`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].
`v
`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 proceduret
`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 rpmf In addition to merely mixing the powders,
`they produce rapid and efficient wetting and de‘nsification 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
`l
`[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 A
`
`
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`Canted discs produce
`wide spray band
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`
`
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`size of aperture
`‘ controls spray fineness,
`from a mist lo droplets
`
`(Courtesy of Patterson-
`Twin—shell liquid-solid‘blender.
`Figure 12
`Kelley Company, East Stroudsburg, Pennsylvania.)
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`148
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`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—
`located concentric to the trunnion axis. The bar's dog-eared
`persion bar,
`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], and Capes [27].
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