`
`DOSAGE FORMS
`
`Tablets
`
`SECOND EDITION, REVISED AND EXPANDED
`
`
`In Three Volumes
`
`VOLUl\/IE 1
`
`EDIIED BY
`
`Herbert A. Lievberinén, .
`I-l.H. Lieberman Associates, lnc._ '-
`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
`
`Amgen Ex. 2003
`
`Complex Innovations v. Amgen
`
`|PR2016-00085
`
`Amgen Ex. 2003
`Complex Innovations v. Amgen
`IPR2016-00085
`
`
`
`Library of Congress Cataloging—in-Publication Data
`
`L—. LIlI.__._I.l'IlFIn-I-|'—-'-
`
`
`
`,,,-;_--._=_.-_._._:
`
`
`
`
`
`
`
`--.,_-._______»»............4;-.--<_..._-_-
`
`
`
`89-1629
`CIP
`
`/1,.
`
`‘
`
`Pharmaceutical dosage forms--tablets / edited by Herbert A. Lieberman,
`Leon Lachman, Joseph B. Schwartz.
`-— 2nd ed., rev. and expanded.
`p.
`cm.
`Includes index.
`: alk. paper)
`1
`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:
`1. Dosage Forms.
`2. Drugs--administration & dosage. QV
`785 P535]
`RS201.T2P46
`615'.19l-—dc19
`DNLM/DLC
`for Library of Congress
`
`1989
`
`;"‘;{’h€553"'
`
`
`
`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
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`
`
`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.
`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
`
`131
`
`
`
`132
`
`Bandelin
`
`Sug‘ar~coated tablets are compressed tablets with a sugar
`release tablets.
`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—
`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 T
`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,
`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,.bioavailabi1ity 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 theirfunctional attributes, which include
`
`drug stability and efficacy.
`
`
`
`Compressed Tablets by Wet Granulation
`
`133
`
`ll.
`
`FORMULATION OF TABLETS
`
`the shape of the tablet are determined by
`to some extent,
`The size and,
`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 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.
`As the dose, and therefore the size, of the tablet increases, the formu-
`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:
`
`Size of dose or quantity of active ingredients
`1.
`2. Stability of active ingredient(s)
`3. Solubility of active ingredient(s)
`4. Density of active ingred)ient(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).
`
`
`
`134
`
`Bandelin
`
`Table 1
`
`Suggested Excipient/Drug Ratio in Compatibility Studies
`
`Excipient
`
`Alginic acid
`
`Avicel
`
`Cornstarch
`
`Dicalcium phosphate
`dihydrate‘ :1
`Lactose
`
`Magnesium carbonate
`
`Magnesium stearate
`
`Mannitol
`
`Methocel
`
`PEG 4000
`
`PVP
`
`Sta—Rxa
`
`Stearic acid
`
`Tale
`
`1
`
`24
`
`24
`
`24
`
`34
`
`34
`
`24
`
`1
`
`24
`
`2
`
`9
`
`4
`
`1
`
`1
`
`1
`
`Weight excipient per unit weight drug
`(anticipated drug dose, mg)
`
`5- 10
`
`25- 50
`
`75- 150
`
`150
`
`24
`
`9
`
`9
`
`34
`
`9
`
`24
`
`1
`
`9
`
`2
`
`9
`
`4
`
`1
`
`1
`
`1
`
`9
`
`9
`
`4
`
`9
`
`_4
`
`9
`
`1
`
`4
`
`2
`
`4
`
`2
`
`1
`
`1
`
`1
`
`9
`
`9
`
`2
`
`9
`
`2'
`
`9
`
`1
`
`2
`
`2
`
`4
`
`1
`
`1
`
`1
`
`1
`
`9
`
`4
`
`2
`
`9
`
`1
`
`4
`
`1
`
`l
`
`1
`
`2
`
`1
`
`1
`
`1
`
`1
`
`'
`
`aNow 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
`classified as follows:
`
`Fillers (diluents)
`Binders
`
`Disintegrants
`Lubricants
`Glidants
`Antiadherents
`
`These additives are discussed in detail later in this chapter.
`
`
`
`Compressed Tablets by Wet Granulation
`
`135
`
`III.
`
`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.
`
`Two punches and die, comprises one station.
`Figure 1
`Pennsalt Chemical Corporation, Warminster, Pennsylvania.)
`
`(Courtesy of
`
`
`
`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 astracks to guide the moving
`punches
`
`U1>DCaOL\3o...
`
`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 or
`flow of materials through the process is shown in the schematic drawing
`(Fig. 3).
`
`!'~r.Itrunt:I-I-1::I=I=
`I
`‘J-"".{§"
`
`Punches and dies on rotary tablet press.
`Figure 2
`Chemical Corporation, Warminister, Pennsyovania.)
`
`(Courtesy of Pennwalt
`
`
`
`Compressed Tablets by Wet Granulation
`
`137
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`1 38
`
`Bandelin
`
`DRUG
`
`ADJUVANT
`
`LIQUIDS
`
`
`
`AGGLOME RATE
`
`
`LUBRICANT
`
`COMPRESS
`
`PELLET
`
`gn
`TABLET
`
`(a)
`
`DRUG
`
`ADJUVANT
`
`DRY
`
`\
`
`
`
`GRIND
`
`BLEND
`
`PELLET
`
`CRUSH
`
`LUBRICANT
`
`COMPRESS
`
`TABLET
`
`SCREEN
`
`(b)
`
`‘
`
`Figure 3 Unit operations in three methods of tablet manufacture:
`granulation, (b) dry granulation, and (c) direct compression.
`
`(a) wet
`
`
`
`Compressed Tablets by Wet Granulation
`
`139
`
`DRUG
`
` ADJUVANTS
`
`COMPRESS
`
`
`
`
`TABLET
`
`GRIND
`
`BLEND
`
`(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 can 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 thelpowders 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 for.med 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.
`V
`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 fromithe 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].
`
`
`
`(Courtesy of Pennwalt Chemical Corporation,
`Tornado mill.
`Figure 1!
`Warminister , Pennsylvania. )
`
`140
`
`
`
`4
`
`Compressed Tablets by Wet Granulation
`
`141
`
`Ross HDM 40 sanitary double planetary mixer.
`Figure 5
`Charles Ross 8: Son Co., Happauge, New York.)
`
`(Courtesy of
`
`
`
`
`
`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 liquidbinder 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 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
`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 densifying powders.
`It lends itself to efficient,
`
`
`
`
`
`
`
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`
`Figure 8 Oscillating; granulator.
`tion , Warminister , Ohio . )
`
`(Courtesy of Pennsalt Chemical Corpora-
`
`
`
`Compressed Tablets by Wet Granulation
`
`145
`
`Figure 9
`Illinois.)
`
`Fitzmill.
`
`(Courtesy of The Fitzpatrick Company, Elmhurst,
`
`
`
`
`
`1 46
`
`Bandelin
`
`
`
`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
`
`PARTICLE FLOW
`PATTERN
`
`-----------------« J______.K‘
`
`4-"'O"‘
`
`I:
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`
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`
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`
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`
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`
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`
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`
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`‘:‘:°3‘:':':°:':'3°3
`\.o,o.o.o.o.o_o.o.'
`'9:o:o:o:o:o:o:o:o:o'
`
`Spray granulator.
`Figure 11
`Ramsey, New Jersey.)
`
`(Courtesy of Glatt Air Techniques, Inc.,
`
`
`
`Compressed Tablets by Wet Granulation
`
`147
`
`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 and 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 .[ l7~19].
`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. VGranu1e 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—she1l liquid—solid blender.
`Figure 12
`Kelley Company, East Stroudsburg, Pennsylvania.)
`
`
`
`
`
`.:.._--._'..“'""7-‘Eli
`
`
`
`\\-t1..,,a.,r...,'~»z.'4.:»’,t}.
`
`148
`
`Bandelin
`
`heating and cooling, a. vacuum take—off, and a liquid dispersion bar
`through which a liquid binder can be added. As the blendervrotates,
`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:
`
`%'\'lO§U'lpbC.OL\’Jl—l
`
`....-.-.
`
`Render the material free flowing
`Densify materials
`Prepare uniform mixtures that do not separate
`Improve the compression characteristics of the drug
`Control the rate of drug release‘
`Facilitate metering or volume dispensing
`Reduce dust
`_
`
`Improve the appearance of the tablet
`
`Becauserof 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 liquidis 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].
`
`
`
`Compressed Tablets by Wet Granulation
`
`149
`
`It is the oldest and most conventional method of making tablets. Al-
`though it is the most labor-intensive and most expensive of theavailable
`methods, it persists because of its versatility. The possibility of moisten-
`ing powders with a variety of liquids, which can also act as carriers for
`certain ingredients, thereby enhancing the granulation characteristics,
`. has many advantages. Granulation by dry compaction has many limitations.
`It does not lend itself to all tablet formulations because it depends on the
`bonding properties of dry powders added as a carrier to the drug thereby
`increasing the size of the tablet.
`In ‘wet granulation, the bonding proper-
`ties of the liquid binders available is usually sufficient to produce bonding
`with a minimum of additives.
`The phenomena of adhesion and cohesion may be defined as follows:
`adhesion is the bonding of unlike materials, while cohesion is that of like
`materials. Rumpf [28]
`identified mechanisms by which mechanical links are
`formed between particles. The following are involvedin the bonding
`process:
`
`1. Formation of crystalline bridges by binders during drying
`2. Structures formed by the hardening of binders in drying
`3. Crushing and bonding of particles during compaction
`
`Wet granulation is a versatile process and its application in tablet form-
`ulation is unlimited.
`
`B. Advantages of Wet Granulation
`
`1. The cohesiveness and compressibility of powders is improved due
`"to the added binder that coats the individual powder particles,
`causing them to adhere to each other so they can be formed_into
`agglomerates called granules. By this method, properties of the
`formulation components are modified to overcome their tableting
`deficiencies. During the compaction process, granules are fractured
`exposing fresh powder surfaces, which also improves their compres-
`sibility. Lower pressures are therefore needed to compress tablets
`resulting in improvements in tooling life and decreased machine
`wear.
`.
`2. Drugs having a high dosage and poor flow and/or compressibility
`must be granulated by the wet method to ‘obtain suitable flow and
`cohesion for compression.
`In this case, the proportion of the
`binder required to impart adequate compressibility and flow is
`much less than that of the dry binder needed to produce a tablet-
`by-direct compression.
`low—dosage
`3. Good distribution and uniform content for soluble,
`drugs and color additives are obtained if these are dissolved in
`thepbinder solution. This represents a distinct advantage over
`direct compression where the content uniformity of drugs and uni-
`form color dispersion can be a problem.
`A wide variety of powders can be processed together in a single
`batch and in so doing, their individual physical characteristics are
`altered to facilitate tableting.
`5. Bulky and dusty powders can be handled without producing a
`great deal of dust and airborne contamination.
`
`I5
`
`
`
`1 50
`
`Bandeliin
`
`6. Wet granulation prevents segregation of components of a homo-
`geneous powder mixture during processing, transfering, and handl-
`ing.
`In effect,
`the composition of each granule becomes fixed and
`remains the same as that of the powder mixture at the time 0'-f the
`wetting.
`7. The dissolution rate of an insoluble drug may be improved by wet
`granulation with the proper choice of solvent and binder.
`8. Controlled release dosage forms can be accomplished. by the selec-
`tion of a suitable binder and solvent.
`
`C. Limitations of Wet Granulation
`
`The greatest disadvantage of wet granulation is its cost because of the
`space,
`time, and equipment involved. The process is labor—intensive as
`indicated by the following.
`
`2.
`DO
`
`‘
`
`1. Because of the large number of processing steps, it requires a
`large area with temperature and humidity control.
`It requires a number of pieces of expensive equipment.
`It is time consuming, especially the wetting and drying steps.
`4. There is a possibility of material loss during processing due to
`the transfer of material from one unit operation to another.
`5. There is a greater possibility of cross—contamination than with the
`direct—compression method.
`It presents material transfer problems involving the processing
`of sticky masses.
`It can slow the dissolution of drugs from inside granules after tab-
`_ let disintegration if not properly formulated and processed.
`
`6.
`
`7.
`
`A recent innovation in wet granulating, which reduces the time and
`energy requirements by eliminating the drying step, is the melt process.
`This method relies on the use of solids having a low softening or melting
`point which, when mixed with a powder formulation and heated, liquefy to
`act as binders [29,30]. Upon cooling, the mixture forms a solid mass in
`which the powders are bound together by the binder returning to the solid
`state.
`.The mass is then broken and reduced to granules and compressed
`into tablets. Materials used as binders are polyethylene glycol 4000 and
`polyethylene glycol 6000 [3l——33] , stearic acid [30], and various waxes
`[34,35] .
`The amount of binder required is greater than for conventional liquid
`binders (i.e. ,
`-20 to 30% of the starting. material).
`Another advantage of the method is that the waxy materials also act as
`lubricants, although in some cases additional lubricant is required.
`A new variation of.the granulating process known as "moisture—activated
`dry granulation" [36] combines the efficiency of dry blending with the ad-
`vantages of wet granulation. As little as 3% water produces agglomeration.
`The process requires no drying step because any free water is absorbed
`by the excipients used. After granulation, disintegrant and lubricant are
`added and the granulation is ready for compression.
`The complex nature of wet granulation is still not well understood,
`which accounts for the continuing interest in research on the process.
`One significant problem is the degree of wetting or massing of the powders.
`Wetting plays an exceedingly important roll in the compression characteristics
`
`
`
`Compressed Tablets by Wet Granulation
`
`151
`
`of the granules, and also in the rate of drug release from the final tablet.
`Some attempts at standardizing the wetting process have been made, par-
`ticularly in the matter of overwetting [37—39] . Factors that affect wetting
`are
`
`U'|LhCaOl\3l-‘
`
`.....
`
`Solubility of the powders
`Relative size and shape of the powder particles
`Degree of fineness
`Viscosity of the liqui