7ores
`
`16.
`
`EDITION
`
`Remingtons
`
`ARTHUR OSOL
`
`Editor, and Chairman
`of the Editorial Board
`
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`
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`aeenrentsete
`
`
`
`
`
`Pharmaceutical
`
`Sciences
`
`1980
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`MSN EXHIBIT 1010 - Page 2 of 36
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`

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`Entered according to Act of Congress, in the year 1885 by Joseph P. Remington,
`in the Office of the Librarian of Congress, at Washington, D.C.
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P. Remington
`
`Copyright 1926, 1936, by Joseph P. Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy andScience
`
`Copyright © 1956, 1960, 1964, 1970, 1975, 1980, by The Philadelphia College of Pharmacy
`and Science
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912374-02-9
`
`The use of portions of the text of USP XX and NF XVis by permission of the USP
`Convention. The Conventionis not responsible for any inaccuracyof quotation
`or for anyfalse or misleading implication that mayarise fromseparationof
`excerpts from the original context or by obsolescence resulting from publication
`of a supplement.
`
`NoTicE—This text is not intended to represent, nor shall it be interpreted to bi, the
`equivalent of or a substitute for the official United States Pharmacopeia(USP)
`and/or the National Formulary (NF). In the event of any difference or
`discrepancy between the currentofficial USP or NF standardsof strength,
`quality, purity, packaging andlabeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
`
`Printed in the United States of America by the Mack Printing Company, Easton, Pennsylvania
`
`MSN EXHIBIT1010 - Page 3 of 36
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`RemingtonHistorical / Biographical Data
`
`The following is a record of the editors and the dates of publication of successive editions of this book, prior to the 13th
`Edition known as Remington's Practice of Pharmacy and subsequently as Remington's Pharmaceutical Sciences.
`
`First Edition, 1886
`Second Edition, 1889
`Third Edition, 1897
`Fourth Edition, 1905
`
`Fifth Edition, 1907
`Sixth Edition, 1917
`
`Seventh Edition, 1926
`
`Eighth Edition, 1936
`
`Ninth Edition, 1948
`
`Tenth Edition, 1951
`
`Eleventh Edition, 1956
`
`Twelfth Edition, 1961
`
`Joseph P. Remington
`
`Joseph P. Remington
`Assisted by
`E. Fullerton Cook
`
`Editors
`E. Fullerton Cook
`Charles H. LaWall
`
`Editors
`E. Fullerton Cook
`Charles H. LaWall
`Associate Editors
`lvor Griffith
`
`Adley B. Nichols
`Arthur Osol
`
`Editors
`E. Fullerton Cook
`Eric W. Martin
`
`Editors
`E. Fullerton Cook
`Eric W. Martin
`
`Editors
`Eric W. Martin
`E. Fullerton Cook
`Associate Editors
`E. Emerson Leuallen
`Arthur Osol
`Linwood F. Tice
`Clarence T. Van Meter
`
`Editors
`Eric W. Martin
`E. Fullerton Cook
`E. Emerson Leuallen
`Arthur Osol
`Linwood F. Tice
`Clarence T. Van Meter
`Assistant to the Editors
`John E. Hoover
`
`Thirteenth Edition, 1965 Editor-in-Chief
`Eric W. Martin
`Editors
`Grafton D. Chase
`Herald R. Cox
`Richard A. Deno
`Alfonso R. Gennaro
`Stewart C. Harvey
`Robert E. King
`E. Emerson Leualien
`Arthur Osol
`
`Ewart A. Swinyard
`Clarence T. Van Meter
`
`Managing Editor
`John E. Hoover
`
`Fourteenth Edition, 1970 Chairman, Editorial Board
`Arthur Osol
`Editors
`Grafton D. Chase
`Richard A. Deno
`Alfonso R. Gennaro
`Melvin R. Gibson
`Stewart C. Harvey
`Robert E. King
`Alfred N. Martin
`
`Fifteenth Edition, 1975
`
`Ewart A. Swinyard
`Clarence T. Van Meter
`Bernard Witlin
`
`Managing Editor
`John E. Hoover
`
`Chairman, Editorial Board
`Arthur Osol
`Editors
`John T. Anderson
`Cecil L. Bendush
`Grafton D. Chase
`Alfonso R. Gennaro
`Melvin R. Gibson
`C. Boyd Granberg
`Stewart C. Harvey
`Robert E. King
`Alfred N. Martin
`
`Ewart A. Swinyard
`Managing Editor
`John E. Hoover
`
`MSN EXHIBIT1010 - Page 4 of 36
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`ix
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`

`

`
`
`
`
`ff
`
`H a2
`
`(ai
`
`Seas
`
`wkoaieeeeei
`
`Tablets, Capsules, and Pills
`
`Robert E. King, PhD Professor of Industrial Pharmacy, Philadelphia College of
`Pharmacyand Science, Philadelphia, PA 19104
`
`tablets
`compressed
`formulas
`molded
`capsules
`hard gelatin
`soft gelatin
`pills
`other solid
`dosage forms
`
` Chapter 89
`
`Drug substances are most frequently administered orally
`by means ofsolid dosage forms such as tablets and capsules.
`Large-scale production methodsused for their preparation
`as described later in the chapter require the presence of other
`materials in addition to the active ingredients. Additives may
`also be included in the formulations to enhance the physical
`appearance, improvestability, and aid in disintegration after
`administration. These supposedly inert ingredients, as well
`as the production methods employed, have been shown in
`some cases to influence the release of the drug substances.!
`Therefore care must be taken in the selection and evaluation
`of additives and preparation methods to ensure that the
`physiological availability and therapeutic efficacy of the active
`ingredientwill not be diminished.
`In a limited numberofcases it has been shownthat the drug
`substance’s solubility and other physical characteristics have
`influenced its physiological availability from a solid dosage
`form. These characteristics includeits particle size, whether
`it is amorphousor crystalline, whetherit is solvated or non-
`solvated, and its polymorphic form. Afterclinically effective
`formulations are obtained, variations among dosage units of
`a given batch, as well as batch-to-batch differences, are re-
`duced to a minimum through properin-process controls and
`good manufacturing practices.
`It is in this area thatsignifi-
`cant progress has been madewiththerealization that large-
`scale production ofa satisfactory tablet or capsule depends
`not only on the availability of a clinically effective formulation
`but also on the raw materials, facilities, personnel, processing
`
`equipment, packaging, and the controls used during and after
`
`preparation (Fig. 89-1).
`
`Fig. 89-1. Tablet press operators checking batch record in confor-
`mance with Current Good Manufacturing Practices (courtesy,Lilly).
`
`Tablets
`
`Tablets may be defined as solid pharmaceutical dosage
`forms containing drug substances with or without suitable
`diluents and prepared either by compression or molding
`methods. They have been in widespread use since the latter
`part of the 19th century and their popularity continues. The
`term compressed tablet is believed to have beenfirst used by
`John Wyeth and Brother of Philadelphia. During this same
`period molded tablets were introducedto be used as “hypo-
`dermic”tablets for the extemporaneouspreparationof solu-
`tions for injection. Tablets remain popular as a dosage form
`because of the advantages afforded both to the manufacturer
`(e.g., simplicity and economyof preparation, stability, and
`convenience in packaging, shipping, and dispensing) and the
`patient (e.g., accuracy of dosage, compactness, portability,
`blandness of taste, and ease of administration).
`Although the basic mechanical approach for their manu-
`facture has remained the same, tablet technology has under-
`gone great improvement. Efforts are continually being made
`to understand more clearly the physical characteristics of
`tablet compression and the factors affecting the availability
`of the drug substance from the dosage form after oral ad-
`ministration. Compression equipment continues to improve
`1553
`
`both as to production speed and the uniformity of tablets
`compressed. Recent advancesin tablet technology have been
`reviewed.?-&
`.
`Although tablets are more frequently discoid in shape, they
`also may be round, oval, oblong, cylindrical, or triangular.
`They may differ greatly in size and weight depending on the
`amountof drug substance present and the intended method
`of administration. They are divided into two general classes,
`whether they are made by compression or molding. Com-
`pressed tablets are usually prepared by large-scale production
`methods while molded tablets generally involve small-scale
`operations. The various tablet types and abbreviations used
`in referring to them arelisted below.
`
`Compressed Tablets (CT)
`These tablets are formed by compression and contain no special coating.
`They are made from powdered,crystalline, or granular materials, alone
`or in combination with binders, disintegrators, lubricants, diluents, and
`in manycases, colorants.
`Sugar-Coated Tablets (SCT)—These are compressed tablets con-
`taining asugar coating. Such coatings may becolored and are beneficial
`in covering up drug substances possessing objectionable tastes or odors,
`and in protecting materials sensitive to oxidation.
`
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`1554
`
`CHAPTER 89
`
`Film-Coated Tablets (FCT)—These are compressed tablets which
`are covered with a thin layeror film of a water-soluble material. A number
`of polymeric substances with film-forming properties may be used. Film
`coating imparts the same general characteristics as sugar coating with the
`added advantageof a greatly reduced time period required for the coating
`operation.
`Enteric-Coated Tablets (ECT)—These are compressed tablets coated
`with substancesthatresist solution in gastric fluid but disintegrate in the
`intestine. Enteric coatings can be used for tablets containing drug sub-
`stances whichare inactivated or destroyed in the stomach,for those which
`irritate the mucosa,or as a meansofdelayed release of the medication.
`Multiple Compressed Tablets (MCT)—These are compressed tablets
`made by more than one compressioncycle.
`Layered Tablets—Suchtablets are prepared by compressing additional
`tablet granulation on a previously compressed granulation. The operation
`may be repeated to produce multilayered tablets of two or three layers.
`Special tablet presses are required to makelayered tablets.
`Press-Coated Tablets—Suchtablets, also referred to as dry-coated, are
`prepared by feeding previously compressedtablets into a specialtableting
`machine and compressing another granulation layer around the preformed
`tablets. They have all the advantages of compressedtablets,i-e., slotting,
`monogramming, speed ofdisintegration,etc., while retaining the attributes
`of sugar-coated tablets in masking thetaste of the drug substancein the
`core tablets. An example of a press-coated tablet press is the Manesty
`Drycota. Press-coated tablets can also be used to separate incompatible
`drug substances; in addition, they can provide a meansto give an enteric
`coating to the core tablets. Both types of multiple-compressed tablets
`have been widely used in the design of prolonged-action dosage forms.
`Prolonged-Action Tablets—Compressedtablets can be formulated
`to release the drug substance in a mannerto provide medication over a
`period of time. There are a numberof types which include delayed-action
`tablets in which the release of the drug substance is preventedfor an in-
`terval of time after administration or until certain physiological conditions
`exist; repeat-action tablets which periodically release a complete dose of
`the drug substanceto the gastrointestinal fluids; and the extended-release
`tablets which continuously release increments of the contained drug
`substance to the gastrointestinal fluids. These tablets are discussed in
`Chapter91.
`Tablets for Solution—-Compressed tablets to be used for preparing
`solutions or imparting given characteristics to solutions must be labeled
`to indicate that they are not to be swallowed. Examples of these tablets
`
`are Halazone Tablets for Solution and Potassium Permanganate Tablets
`for Solution.
`Effervescent Tablets—lIn addition to the drug substance, these con-
`tain sodium bicarbonate and an organic acid suchastartaric orcitric.
`In
`the presence of water, these additives react liberating carbon dioxide which
`acts as a distintegrator and produces effervescence. Except for small
`quantities of lubricants present, effervescent tablets are soluble.
`Tableted Suppositories or Inserts—Occasionally vaginal supposi-
`tories, such as Metronidazole Tablets, are prepared by compression.
`In
`this case, as well as for any tablet intended for administration other than
`by swallowing, the label must indicate the manner in whichitis to be
`used.
`Buccal and Sublingual Tablets—Theseare small, flat, oval tablets.
`Tablets intended for buccal administration by inserting into the buccal
`pouch dissolve or erode slowly. Progesterone Tablets may be adminis-
`tered in this way. Sublingual tablets, such as those containingnitro-
`glycerin, isoproterenol hydrochloride, or erythrityl tetranitrate, are placed
`under the tongue. Sublingualtablets dissolve rapidly and the drug sub-
`stances are readily absorbed bythis form of administration.
`
`Molded Tablets or Tablet Triturates (TT)
`Tablet triturates are usually made from moist material usinga triturate
`mold which gives them the shapeofcut sections of a cylinder. Such tablets
`must be completely and rapidly soluble. The problem arising from
`compressionof these tablets is the failure to find a lubricant that is com-
`pletely water-soluble.
`Dispensing Tablets (DT)—These tablets provide a convenient
`quantity of potent drug that can be incorporated readily into powders and
`liquids, thus circumventing the necessity to weigh small quantities. These
`tablets are supplied primarily as a convenience for extemporaneous
`compounding and should never be dispensed as a dosage form.
`Hypodermic Tablets (HT)—Hypodermic tablets are soft, readily
`soluble tablets and were originally used for the preparation of solutions
`to be injected. Since stable parenteral solutionsare now available for most
`drug substances,thereis no justification for the use of hypodermictablets
`for injection. Their use in this manner should be discouraged sincethe
`resulting solutions are not sterile. Large quantities of these tablets con-
`tinue to be madebutfor oral administration. No hypodermictablets have
`ever been recognized by theofficial compendia.
`
`Compressed Tablets (CT)
`
`Basic mechanical unit for tablet compression:
`
`In order for medicinal substances, with or withoutdiluents,
`to be made into solid dosage forms with pressure, using
`available equipment,it is necessary that the material, either
`in crystalline or powdered form, possess a numberof physical
`characteristics. These characteristics include the ability to
`flow freely, cohesiveness, and lubrication. Since most ma-
`terials have none or only some of these properties, methods
`of tablet formulation and preparation have been developed
`to impart these desirable characteristics to the material which
`is to be compressedinto tablets.
`tablet-compression
`in all
`The basic mechanical unit
`equipment includes a lower punch whichfits into a die from
`the bottom and an upperpunch,having a head of the same
`shape and dimensions, which enters the die cavity from the
`top after the tableting materialfills the die cavity. See Fig.
`89-2. The tablet is formed by pressure applied on the punches
`and is subsequently ejected from the die. The weightof the
`tablet is determined by the volume of the material which fills
`the die cavity. Therefore, the ability of the granulation to
`flow freely into the die is important in insuring an uniform fill,
`as well as the continuous movementof the granulation from
`the source of supply or feed hopper. Ifthe tablet granulation
`does not possess cohesive properties, the tablet after com-
`pression will crumble and fall apart on handling. As the
`punches must movefreely within the die and the tablet must
`be readily ejected from the punch faces, the material must
`have a degree of lubrication to minimizefriction and to allow
`for the removalof the compressed tablets.
`(1)
`There are three general methodsof tablet preparation:
`the wet-granulation method; (2) the dry-granulation method;
`and (3) direct compression. The methodof preparation and
`the added ingredients are selected in orderto give the tablet
`formulation the desirable physical characteristics allowing
`
`the rapid compression of tablets. After compression the
`tablets must have a numberof additionalattributes such as
`appearance, hardness,disintegration ability, and uniformity
`whichare also influenced both by the methodofpreparation
`and by the added materials present in the formulation.
`In
`the preparation of compressed tablets the formulator must
`also be cognizant of the effect which the ingredients and
`methods of preparation may have on the availability of the
`active ingredients and hence the therapeutic efficacy of the
`dosage form.
`In response to a request by physicians to change
`a dicumaroltablet in order that it might be moreeasily bro-
`ken, a Canadian companyreformulated to makea largetablet
`with a score. Subsequent use of the tablet containing the
`same amountof drug substanceas the previoustablet, resulted
`in complaints that larger-than-usual doses were needed to
`produce the sametherapeutic response. On the other hand,
`literature reports indicate that the reformulation of a com-
`
`
`
`Fig. 89-2.
`punch, die, and upper punch (courtesy, Vector/Colton).
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`lower
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`

`the same quantity of drug substance, that gave the desired
`clinical response at half its original dose. Methods and
`principles that can be usedto assess the effects of excipients
`and additives on drug absorption have been reviewed.7°8 See
`Chapters 37, 75 and 76.
`
`Tablet ingredients
`
` mercial digoxin tablet resulted in a tablet, although containing
`
`In addition to the active or therapeutic ingredient, tablets
`contain a numberof inert materials. The latter are known
`as additives or “adds.” They may beclassified according to
`the part they play in the finished tablet. The first group
`contains those which help to impart satisfactory compression
`characteristics to the formulation. These include (1) diluents,
`(2) binders, and (3) lubricants. The second group of added
`substances helps to give additional desirable physical char-
`acteristics to the finished tablet.
`Includedin this group are
`(1) disintegrators, (2) colors, and in the case of chewable
`tablets, (3) flavors, and (4) sweetening agents.
`Although the term “inert” has been applied to these added
`materials, it is becoming increasingly apparent that thereis
`an importantrelationship between the properties of the ex-
`cipients and the dosage forms containing them. Preformu-
`lation studies demonstrate their influence on stability, bio-
`availability, and the processes by which the dosage formsare
`prepared. The need for acquiring more information and use
`standards for excipients has been recognized in a joint venture
`of the Academyof Pharmaceutical Sciences and the Council
`of the Pharmaceutical Society of Great Britain. The program
`is called the Codex of Pharmaceutical Excipient Project and
`the Academy’s Industrial Pharmaceutical Technology Section
`has undertaken its organization and implementation.
`
`Diluents
`
`Frequently the single dose of the active ingredient is small
`and an inert substance is added to increase the bulkin order
`to make the tablet a practical size for compression. Com-
`pressed tablets of dexamethasonecontain 0.75 mg steroid per
`tablet, hence it is obvious that another material must be added
`to make tableting possible. Diluents used for this purpose
`include dicalcium phosphate, calcium sulfate, lactose, kaolin,
`mannitol, sodium chloride, dry starch, and powdered sugar.
`Certain diluents, such as mannitol, lactose, sorbitol, sucrose,
`and inositol, when presentin sufficient quantity, can impart
`properties to some compressed tablets that permit disinte-
`gration in the mouth by chewing. Such tablets are commonly
`called “chewable tablets.” Upon chewing, properly prepared
`tablets will disintegrate smoothly at a satisfactory rate, have
`a pleasant taste and feel, and leave no unpleasantaftertaste
`in the mouth. Diluents used as excipients for direct com-
`pression formulas have been subjected to prior processing to
`give them flowability and compressibility. These are dis-
`cussed under Direct Compression, p. 1563.
`Most tablet formulators tend to use consistently only one
`or two diluents selected from the above groupin their tablet
`formulations. Usually these have been selected on the basis
`of experience and cost factors. However, in the formulation
`of new therapeutic agents the compatibility of the diluent with
`the drug must be considered. Forexample, calcium salts used
`as diluents for the broad-spectrum antibiotic tetracycline have
`been shown to interfere with the drug’s absorption from the
`gastrointestinal tract. When drug substances have low water
`solubility, it is recommended that water-soluble diluents be
`used to avoid possible bioavailability problems. Highly ad-
`sorbent substances, e.g., bentonite and kaolin, are to be
`avoided in making tablets of drugs used clinically in small
`dosage, such as the cardiac glycosides, alkaloids, and the
`synthetic estrogens. These drug substances may be adsorbed
`
`TABLETS, CAPSULES, AND PILLS
`
`1555
`
`to the point where they are not completely available after
`administration. The combination of amine bases with lactose,
`or aminesalts with lactose in the presence of an alkaline lu-
`bricant, results in tablets which discolor onaging.
`Microcrystalline cellulose (Avicel) is usually used as an
`excipient
`in direct compression formulas. However,
`its
`presence in 5-15% concentrations in wet granulations has been
`shown to be beneficial in the granulation and drying processes
`in minimizing case-hardeningof the tablets and in reducing
`tablet mottling.
`
`Binders
`
`Agents used to impart cohesive qualities to the powdered
`material are referred to as binders or granulators. They im-
`part a cohesiveness to the tablet formulation which insures
`the tablet remaining intact after compression, as well as im-
`proving the free-flowing qualities by the formulation of
`granules of desired hardness and size. Materials commonly
`used as binders includestarch, gelatin, and sugars as sucrose,
`glucose, dextrose, molasses, and lactose. Natural and syn-
`thetic gums which have beenused include acacia, sodium al-
`ginate, extractof Irish moss, panwar gum, ghatti gum, muci-
`lage of isapol husks, carboxymethylcellulose, methylcellulose,
`polyvinylpyrrolidone, Veegum, and larch arabogalactan.
`Other agents which maybe considered binders undercertain
`circumstances are polyethylene glycol, ethylcellulose, waxes,
`water, and alcohol.
`The quantity of binder used has considerable influence on
`the characteristics of the compressed tablets. The use of too
`muchbinderor too strong a binder will make a hard tablet
`whichwill not disintegrate easily and which will cause exces-
`sive wear of punches and dies. Differences in binders used
`for CT Tolbutamide resulted in differences in hypoglycemic
`effects observed clinically. Materials which have no cohesive
`qualities of their own will require a stronger binder than those
`with these qualities. Alcohol and water are not binders in the
`true sense of the word; but because of their solvent action on
`some ingredients such as lactose and starch, they change the
`powdered material to granules and the residual moisture re-
`tained enables the materials to adhere together when com-
`pressed.
`Binders are used both as a solution and in a dry form de-
`pending onthe other ingredients in the formulation and the
`methodof preparation. The same amountof binderin so-
`lution will be more effective thanif it were dispersed in a dry
`form and moistened with the solvent. By the latter procedure
`the binding agentis not as effective in reaching and wetting
`each of the particles within the mass of powders. Each of the
`particles in a powder blend has a coating of adsorbed air on
`its surface, and it is this film which must be penetrated before
`the powders can be wetted by the binder solution. Since
`powdersdiffer with respect to the ease with which they can
`be wetted, it is preferable to incorporate the binding agent in
`solution. By this techniqueit is often possible to gain effec-
`tive binding with a lower.concentration of binder.
`The direct compression method for preparing tablets (see
`page 1563) requires a material that not onlyis free-flowing but
`also sufficiently cohesive to act as a binder. This use has been
`described for a numberof materials including microcrystalline
`cellulose, microcrystalline dextrose, amylose, and polyvinyl-
`pyrrolidone.
`It has been postulated that microcrystalline
`cellulose is a special form ofcellulose fibril in which the indi-
`vidual crystallites are held together largely by hydrogen
`bonding. The disintegration of tablets containing the cellu-
`lose occurs by breaking the intercrystallite bonds by thedis-
`integrating medium.
`Starch Paste—Cornstarchis widely used asa binder. The
`concentration may vary from 10 to 20%.
`It is usually prepared
`as it is to be used by dispersing corn starchin sufficient cold
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`1556
`
`CHAPTER 89
`
`purified water to make a 10% w/w solution and warmingina
`water bath with continuousstirring until a translucent paste
`forms.
`Gelatin Solution——Gelatin is generally used as a 10-20%
`solution; gelatin solutions should be freshly prepared as
`needed and used while warm or they will solidify. The gelatin
`is added to cold purified water and allowed to stand until it
`is hydrated.
`It is then warmed in water bath to dissolve the
`gelatin and the solution is madeup to the final volume on a
`weight basis to give the concentration desired.
`Glucose Solution—Generally a 25-50% solution is used.
`Glucose does not dry out well and is therefore not suitable
`wherethe tablets are subject to humid conditions. These
`solutions are not true 25 and 50% solutions since the corn
`syrup contains only approximately 80% solids. To prepare
`the binder solution, the corn syrup is weighed and dissolved
`in purified water. Sufficient purified water is added to give
`the concentration desired on a weight basis.
`If clarification
`is desirable, it can be strained through cloth.
`It is used ef-
`Ethylcellulose—This is insoluble in water.
`fectively as a binder when dissolved in alcohol, or as a dry
`binder in a granulation whichis then wetted with alcohol. As
`a binderin solutionit is usually used as a 5% solution.
`It is
`widely used as a binder for moisture-sensitive materials. To
`make the solution, ethylcellulose is dissolved in anhydrous
`denatured alcohol and madeupto the final volume on a weight
`basis.
`It will be noted that binder solutions are usually made up
`to weight rather than volume. This is to enable the formu-
`lator to determine the weight of the solids which have been
`addedto the tablet granulation in the binding solution. This
`becomespart ofthe total weight of the granulation and must
`be takeninto consideration in determining the weight of the
`compressed tablet which will contain the stated amountof the
`therapeutic agent.
`
`Lubricants
`
`Lubricants have a numberoffunctions in tablet manufac-
`ture. They improvethe rate offlow ofthe tablet granulation,
`prevent adhesionof the tablet material to the surface of the
`dies and punches, reduce interparticle friction, and facilitate
`the ejection of the tablets from the die cavity. Commonly
`used lubricants include talc, magnesium stearate, calcium
`stearate, stearic acid, and hydrogenated vegetable oils. Most
`lubricants with the exception of talc are used in concentrations
`less than 1%. When used alone, tale may require concentra-
`tions as high as 5%. Lubricants are in most cases hydrophobic
`materials. Poor selection or excessive amounts can result in
`“waterproofing” the tablets, resulting in poor tablet disinte-
`gration and dissolution of the drug substance.
`The addition of the proper lubricant is highly desirable if
`the material to be tableted tendsto stick to the punches and
`dies.
`Immediately after compression most tablets have the
`tendency to expand and will bind andstickto the side ofthe
`die. The choice of the properlubricantwill effectively over-
`come this.
`The methodof. adding a lubricant to a granulation is im-
`portant if the material is to perform its function satisfactorily.
`The lubricant should be finely divided by passingit through
`a 100-mesh nylon cloth onto the granulation.
`In production
`this is called “bolting” the lubricant. After adding the lu-
`bricant the granulation is tumbled or mixed gently to coat the
`individual granules without breaking them down tofiner
`particles. Prolonged blending of lubricant with a granulation
`can materially affect the hardness anddisintegration time for
`the resultant tablets. The quantity of lubricant varies, being
`as low as 0.1%, and in some cases as high as 5%. Lubricants
`have been added to the granulating agents in the form of
`suspensions or emulsions. This technique serves to reduce
`
`the numberof operational procedures and thus reduce the
`processing time.
`In selecting a lubricant, proper attention mustbe given to
`its compatibility with the drug agent. Perhaps the most
`widely investigated drug is acetylsalicylic acid. Differenttalcs
`varied significantly the stability of aspirin. Tale witha high
`calcium content and a high loss on ignition was associated with
`increased aspirin decomposition. From a stability standpoint,
`the relative acceptability of tablet lubricants for combination
`with aspirin was found to decrease in the following order:
`hydrogenated vegetable oil, stearic acid, talc, and aluminum
`stearate.
`The primary problem in the preparation of a water-soluble
`tablet is the selection of a satisfactory lubricant. Soluble
`lubricants reported to be effective include sodium benzoate,
`a mixture of sodium benzoate and sodium acetate, sodium
`chloride, leucine, and Carbowax 4000. However, it has been
`suggested that formulations used to prepare water-soluble
`tablets may represent a number of compromises between
`compression efficiency and watersolubility. While magne-
`sium stearate is one of the most widely used lubricants,its
`waterproofing properties can retard disintegration and dis-
`solution. To overcome these waterproofing characteristics
`sodium laury] sulfate is sometimes included. One compound
`found to have the lubricating properties of magnesium stea-
`rate without its disadvantages is magnesium laurylsulfate.
`Its safety for use in pharmaceuticals has not yet been estab-
`lished,
`
`MSNv. Bausch - IPR2023-00016
`
`Disintegrators
`
`A disintegrator is a substance, or a mixture of substances,
`added to a tablet to facilitate its breakup or disintegration
`after administration. The active ingredient mustbe released
`from the tablet matrix as efficiently as possible to allow for
`its rapid dissolution. Materials serving as disintegrants have
`been chemically classified as starches,clays, celluloses, algins,
`or gums.
`The most popular disintegrators are corn and potato starch’
`which have been well-dried and powdered. Starch has a great
`affinity for water and swells when moistened, thus facilitating
`the rupture of the tablet matrix. However, others have sug-
`gested that its disintegrating action in tablets is due to cap-
`illary action rather than swelling; the spherical shape ofthe
`starch grains increases the porosity of the tablet, thus pro-
`moting capillary action. Starch, 5%, is suggested, but if more
`rapid disintegration is desired, this amount may be increased
`to 10 or 15%. Although it might be expected that disinte-
`gration time would decrease as the percentageofstarch in the
`tablet increased, this does not appearto be the casefortol-
`butamide tablets.
`In this instance, there appears to be a
`critical starch concentration for different granulations of the
`chemical. Whentheir disintegration effect is desired, starches
`are added to the powderblendsin the dry state. Starch pastes
`which are useful as binding agents will generally not be ef-
`fective as disintegrating agents.
`In addition to the starches a large variety of materials have
`been used and are reported to be effective as disintegrators.
`This group includes Veegum HV, methylcellulose, agar,
`bentonite, cellulose and wood products, natural sponge,cat-
`ion-exchangeresins, alginic acid, guar gum, citrus pulp, and
`carboxymethylcellulose. Sodium lauryl sulfate in combina-
`tion with starch also has been demonstratedto be aneffective
`disintegrant.
`In some cases the apparent effectiveness of
`surfactants in improving tablet disintegration is postulated
`as being due to an increase in the rate of wetting.
`The disintegrating agent is usually mixed with the active
`ingredients and diluents prior to granulation.
`In somecases
`it may be advantageousto divide the starch into two portions;
`one part is added to the powdered formula prior to granula-
`MSN EXHIBIT 1010 - Page 8 of 36
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`Incorporated in this manner the starch
`prior to compression.
`serves a double purpose; the portion added to the lubricant
`rapidly breaks the tablet down to granules, and the starch
`mixed with the active ingredients disintegrates the granules
`into smaller particles. Veegum has been shown to