Chapter 89
`
`Tablets, Capsules, and Pills
`
`Robert E. King, PhD Professor of Industrial Pharmacy, Philadelphia College of
`Pharmacy and Science, Philadelphia, PA 19104
`
`tablets
`compressed
`formulas
`molded
`capsules
`hard gelatin
`soft gelatin
`
`PMS
`other solid
`dosage forms
`
`Drug substances are most frequently administered orally
`by means of solid dosage forms such as tablets and capsules.
`Large-scale production methods used 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, improve stability, 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
`ingredient will not be diminished.
`In a limited number of cases it has been shown that the drug
`substance’s solubility and other physical characteristics have
`influenced its physiological availability from a solid dosage
`form. These characteristics include its particle size, whether
`it is amorphous or crystalline, whether it is solvated or non-
`solvated, and its polymorphic form. After clinically 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 proper in-process controls and
`good manufacturing practices.
`It is in this area that signifi-
`cant progress has been made with the realization that large-
`scale production of a 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 been first used by
`John Wyeth and Brother of Philadelphia. During this same
`period molded tablets were introduced to be used as “hypo-
`dermic” tablets for the extemporaneous preparation of solu-
`tions for injection. Tablets remain popular as a dosage form
`because of the advantages afforded both to the manufacturer
`(e.g., simplicity and economy of 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
`
`both as to production speed and the uniformity of tablets
`compressed. Recent advances in tablet technology have been
`reviewed.2'6
`-
`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
`amount of 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 are listed 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 many cases, colorants.
`Sugar-Coated Tablets (SCT)—-These are compressed tablets con-
`taining a sugar coating. Such coatings may be colored and are beneficial
`in covering up drug substances possessing objectionable tastes or odors,
`and in protecting materials sensitive to oxidation.
`
`1553
`
`WCK1041
`Page 1
`
`
`
`it
`
`
`
`_..~,.,«..-.::2,-,-2..
`
`WCK1041
`Page 1
`
`

`
`1554
`
`CHAPTER 89
`
`Film-Coated Tablets (FCT)—These are compressed tablets which
`are covered with a thin layer or 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 advantage of a greatly reduced time period required for the coating
`operation.
`Enteric-Coated Tablets (ECT)—These are compressed tablets coated
`with substances that resist solution in gastric fluid but disintegrate in the
`intestine. Enteric coatings can be used for tablets containing drug sub-
`stances which are inactivated or destroyed in the stomach, for those which
`irritate the mucosa, or as a means of delayed release of the medication.
`Multiple Compressed Tablets (MCT)——These are compressed tablets
`made by more than one compression cycle.
`Layered Tablet3—Such tablets 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 make layered tablets.
`Press-Coated Tablets—Such tablets, also referred to as dry—coated, are
`prepared by feeding previously compressed tablets into a special tableting
`machine and compressing another granulation layer around the preformed
`tablets. They have all the advantages of compressed tablets, i.e., slotting,
`monogramming, speed of disintegration, etc., while retaining the attributes
`of sugar-coated tablets in masking the taste of the drug substance in 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 means to 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—Compressed tablets can be formulated
`to release the drug substance in a manner to provide medication over a
`period of time. There are a number of types which include delayed—action
`tablets in which the release of the drug substance is prevented for 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 substance to 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
`Chapter. 91.
`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——In addition to the drug substance, these con—
`tain sodium bicarbonate and an organic acid such as tartaric or citric.
`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 which it is to be
`used.
`
`Buccal and Sublingual Tablets——’I‘hese are 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 containing nitro-
`glycerin, isoproterenol hydrochloride, or erythrityl tetranitrate, are placed
`under the tongue. Sublingual tablets dissolve rapidly and the drug sub-
`stances are readily absorbed by this form of administration.
`
`Molded Tablets or Tablet Triturates (TT)
`Tablet triturates are usually made from moist material using a triturate
`mold which gives them the shape of cut sections of a cylinder. Such tablets
`must be completely and rapidly soluble. The problem arising from
`compression of 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 (H'I‘)--Hypodermic tablets are soft, readily
`soluble tablets and were originally used for the preparation of solutions
`to be injected. Since stable parenteral solutions are now available for most
`drug substances, there is no justification for the use of hypodermic tablets
`for injection. Their use in this manner should be discouraged since the
`resulting solutions are not sterile. Large quantities of these tablets con-
`tinue to be made but for oral administration. No hypodermic tablets have
`ever been recognized by the official compendia.
`
`Compressed Tablets (CT)
`
`In order for medicinal substances, with or without cliluents,
`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 number of 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 compressed into tablets.
`tablet-compression
`in all
`The basic mechanical unit
`equipment includes a lower punch which fits into a die from
`the bottom and an upper punch, having a head of the same
`shape and dimensions, which enters the die cavity from the
`top after the tableting material fills 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 weight of 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 movement of the granulation from
`the source of supply or feed hopper.
`If the tablet granulation
`does not possess cohesive properties, the tablet after com-
`pression will crumble and fall apart on handling. As the
`punches must move freely within the die and the tablet must
`be readily ejected from the punch faces, the material must
`have a degree of lubrication to minimize friction and to allow
`for the removal of the compressed tablets.
`(1)
`There are three general methods of tablet preparation:
`the wet-granulation method; (2) the dry-granulation method;
`and (3) direct compression. The method of preparation and
`the added ingredients are selected in order to give the tablet
`formulation the desirable physical characteristics allowing
`
`the rapid compression of tablets. After compression the
`tablets must have a number of additional attributes such as
`appearance, hardness, disintegration ability, and uniformity
`which are also influenced both by the method of preparation
`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 dicumarol tablet in order that it might be more easily bro-
`ken, a Canadian company reformulated to make a large tablet
`with a score. Subsequent use of the tablet containing the
`same amount of drug substance as the previous tablet, resulted
`in complaints that larger—than-usual doses were needed to
`produce the same therapeutic response. On the other hand,
`literature reports indicate that the reformulation of a com-
`
`
`
`Fig. 89-2. Basic mechanical unit for tablet compression:
`punch, die, and upper punch (courtesy, Vector/Colton).
`WCK1041
`Page 2
`
`lower
`
`WCK1041
`Page 2
`
`

`
`
`
`mercial digoxin tablet resulted in a tablet, although containing
`the same quantity of drug substance, that gave the desired
`clinical response at half its original dose. Methods and
`principles that can be used to assess the effects of excipients
`and additives on drug absorption have been reviewed.” See
`Chapters 37,75 and 76.
`
`Tablet Ingredients
`
`In addition to the active or therapeutic ingredient, tablets
`contain a number of inert materials. The latter are known
`as additives or “adds.” They may be classified 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 (8) lubricants. The second group of added
`substances helps to give additional desirable physical char-
`acteristics to the finished tablet.
`Included in 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 there is
`an important relationship 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 forms are
`prepared. The need for acquiring more information and use
`standards for excipients has been recognized in a joint venture
`of the Academy of 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.
`
`TABLETS, CAPSULES, AND PILLS
`
`1555
`
`to the point where they are not completely available after
`administration. The combination of amine bases with lactose,
`or amine salts with lactose in the presence of an alkaline lu-
`bricant, results in tablets which discolor on aging.
`Microcrystalline cellulose (Avicel) is usually used as an
`excipient
`in direct compression formulas. However,
`its
`presence in 5—l5% concentrations in wet granulations has been
`shown to be beneficial in the granulation and drying processes
`in minimizing case-hardening of 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 ini-
`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 include starch, gelatin, and sugars as sucrose,
`glucose, dextrose, molasses, and lactose. Natural and syn-
`thetic gums which have been used include acacia, sodium al-
`ginate, extract of Irish moss, panwar gum, ghatti gum, muci-
`lage of isapol husks, carboxymethylcellulose, methylcellulose,
`polyvinylpyrrolidone, Veegum, and larch arabogalactan.
`Other agents which may be considered binders under certain
`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
`much binder or too strong a binder will make a hard tablet
`which will 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 on the other ingredients in the formulation and the
`method of preparation. The same amount of binder in so-
`lution will be more effective than if it were dispersed in a dry
`form and moistened with the solvent. By the latter procedure
`the binding agent is 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
`powders differ with respect to the ease with which they can
`be wetted, it is preferable to incorporate the binding agent in
`solution. By this technique it 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 only is free-flowing but
`also sufficiently cohesive to act as a binder. This use has been
`described for a number of materials including microcrystalline
`cellulose, microcrystalline dextrose, amylose, and polyvinyl-
`pyrrolidone.
`It has been postulated that microcrystalline
`cellulose is a special form of cellulose 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 the dis-
`integrating medium.
`Starch Paste~Corn starch is widely used as a binder. The
`concentration may vary from 10 to 20%.
`It is usually prepared
`as it is to be used by dispersing corn starch in sufficient cold
`
`WCK1041
`Page 3
`
`Diluents
`
`Frequently the single dose of the active ingredient is small
`and an inert substance is added to increase the bulk in order
`to make the tablet a practical size for compression. Com-
`pressed tablets of dexamethasone contain 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 present in 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 unpleasant aftertaste
`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 group in 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. Foriexample, 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
`
`WCK1041
`Page 3
`
`

`
`1556
`
`CHAPTER 89
`
`purified water to make a 10% w/w solution and warming in a
`water bath with continuous stirring 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 made up 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
`where the 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 which is then wetted with alcohol. As
`a binder in solution it 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 made up to 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
`added to the tablet granulation in the binding solution. This
`becomes part of the total weight of the granulation and must
`be taken into consideration in determining the weight of the
`compressed tablet which will contain the stated amount of the
`therapeutic agent.
`
`Lubricants
`
`Lubricants have a number of functions in tablet manufac-
`ture. They improve the rate of flow of the tablet granulation,
`prevent adhesion of 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, talc 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 tends to stick to the punches and
`dies.
`Immediately after compression most tablets have the
`tendency to expand and will bind and stick to the side of the
`die. The choice of the proper lubricant will effectively over-
`come this.
`The method of 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 passing it 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 to finer
`particles. Prolonged blending of lubricant with a granulation
`can materially affect the hardness and disintegration 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 number of operational procedures and thus reduce the
`processing time.
`In selecting a lubricant, proper attention must be given to
`its compatibility with the drug agent. Perhaps the most
`widely investigated drug is acetylsalicylic acid. Different tales
`varied significantly the stability of aspirin. Talc with a 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 water solubility. 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 lauryl sulfate is sometimes included. One compound
`found to have the lubricating properties of magnesium stea-
`rate without its disadvantages is magnesium lauryl sulfate.
`Its safety for use in pharmaceuticals has not yet been estab-
`lished.
`
`
`
`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 must be 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 com 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 of the
`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 percentage of starch in the
`tablet increased, this does not appear to be the case for tol-
`butamide tablets.
`In this instance, there appears to be a
`critical starch concentration for different granulations of the
`chemical. When their disintegration effect is desired, starches
`are added to the powder blends in 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-exchange resins, alginic acid, guar gum, citrus pulp, and
`carboxymethylcellulose. Sodium lauryl sulfate in combina-
`tion with starch also has been demonstrated to be an effective
`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 some cases
`it may be advantageous to divide the starch into two portions;
`one part is added to the powdered formula prior to granula-
`WCK1041
`Page 4
`
`WCK1041
`Page 4
`
`

`
`tion, and the remainder is mixed with the lubricant and added
`prior to compression.
`Incorporated in this manner the starch
`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 be more
`effective as a disintegrator in sulfathiazole tablets when most
`of the quantity is added after granulation and only a small
`amount before granulation. Likewise, the montmorillonite
`clays were found to be good tablet disintegrants when added
`to prepared granulations as powder. They are much less ef-
`fective as disintegrants when incorporated within the gran-
`ules.
`'
`Factors other than the presence of disintegrators can affect
`significantly the disintegration time of compressed tablets.
`The binder, tablet hardness, and the lubricant have been
`shown to influence the disintegration time. Thus, when the
`formulator is faced with a problem concerning the disinte-
`gration of a compressed tablet, the answer may not lie in the
`selection and the quantity of the disintegrating agent
`alone.
`The evolution of carbon dioxide is also an effective way to
`cause the disintegration of compressed tablets. Tablets
`containing a mixture of sodium bicarbonate and an acidulant
`such as tartaric or citric acid will effervesce when added to
`water. Sufficient acid is added to produce a neutral or slightly
`acidic reaction when disintegration in water is rapid and
`complete. One drawback to the use of the effervescent type
`of disintegrator is that such tablets must be kept in a dry at-
`mosphere at all times during manufacture, storage, and
`packaging. Soluble, effervescent tablets provide a popular
`form for dispensing aspirin and noncaloric sweetening
`agents.
`
`TABLETS, CAPSULES. AND PILLS
`
`155?
`
`colors in wet granulations migrate, resulting in an uneven
`distribution of the color in the granulation. After compres-
`sion the tablets will have a mottled appearance due to the
`uneven distribution of the color. Migration of colors may be
`reduced by drying the granulation slowly at low temperatures
`and stirring the granulation .while it is drying. The affinity
`of several water-soluble anionic certified dyes for natural
`starches has been demonstrated; in these cases this affinity
`should aid in preventing color migration. Other additives
`have been shown to act as dye migration inhibitors. Traga-
`canth (1%), acacia (3%), attapulgite (5%), and tale ('7%) were
`effective in inhibiting the migration of FD&C Blue No. 1 in
`lactose.
`In using dye lakes the problem of color migration is
`avoided since the lakes are insoluble. Prevention of mottling
`can be helped also by the use of lubricants and other additives
`which have been colored similarly to the granulation prior to
`their use. The problem of mottling becomes more pro-
`nounced as the concentration of the colorants increases.
`Color mottling is an undesirable characteristic common to
`many commercial tablets.
`
`Flavoring Agents
`In addition to the sweetness which may be afforded by the
`diluent of the chewable tablet, e.g., mannitol or lactose, arti-
`ficial sweetening agents may be included. Formerly, the cy-
`clamates, either alone or in combination with saccharin, were
`widely used. With the banning of the cyclamates and the
`indefinite status of saccharin new natural sweeteners are being
`sought. Among the most promising are two derivatives of
`glycyrrhizin, the glycoside obtained from licorice.” These
`derivatives are ammoniated glycyrrhizin and monoammonium
`glycyrrhizinate. The former is among the sweetest com-
`pounds on the FDA listing of natural GRAS flavors, its mag-
`nitude of sweetness being 50 times that of sucrose. Chemi-
`cally, ammonium glycyrrhizin is the fully ammoniated product
`while monoammonium glycyrrhizinaté is only partially am-
`moniated. The former is water-soluble, precipitating at pH
`4.5 and lower while the latter exhibits poor solubility in water.
`Sweete