Oral Solid Dosage Forms PDF

Chapter 30 Oral Solid Dosage Forms Ahmed Adel Sakr, PhD and Fars K. Alanazi, PhD Tablets  581 Capsules...

Chapter 30 Oral Solid Dosage Forms Ahmed Adel Sakr, PhD and Fars K. Alanazi, PhD Tablets  581 Capsules 604 Medicinal substances are most frequently administered orally, Compressed Tablet (CT) by means of solid dosage forms, such as tablets and capsules. Compressed tablets are formed by compression and, in their Large scale production methods used for their manufacture, as simplest form, contain no special coating. They are made from is described in this chapter, require the incorporation of other powdered, crystalline, or granular materials, alone or in combi- materials, in addition to the active ingredients. These additives nation with binders, disintegrants, controlled-release polymers, are usually included in the formulation to facilitate handling, lubricants, diluents, and, in many cases, colorants. The vast enhance the physical appearance, improve stability, and aid majority of tablets commercialized today are compressed tab- in the delivery of the medicament to the blood stream after lets, either in an uncoated or coated state. administration. These materials, as well as the employed pro- duction methods, have been shown to potentially influence the Sugar-Coated Tablets (SCT) absorption and /or bioavailability of the drugs.1 In addition, the Sugar-coated tablets are compressed tablets surrounded by a physicochemical characteristics of the drug substances may sugar coating. Such coatings may be colored and are beneficial influence the physiological bioavailability from solid dosage in covering up drug substances possessing objectionable tastes forms.2 or odors and in protecting materials sensitive to oxidation. These coatings were once quite common, but lost commercial Tablets appeal due to the high cost of process validation. Recently, they have made a comeback, due to patient popularity and technical According to the USP, tablets are solid dosage forms, contain- advances. ing medicinal substances with or without suitable diluents. They may be classed, according to the method of manufac- Film-Coated Tablets (FCT) ture, as compressed tablets or molded tablets. The vast major- Film-coated tablets are compressed tablets covered with a thin ity of all tablets manufactured today are made by compres- layer or film of a water-soluble material. A number of poly- sion, and compressed tablets are the most widely used dosage meric substances with film-forming properties may be used. form. Compressed tablets are prepared by the application of Film coating imparts the same general characteristics as sugar high pressures, utilizing steel punches and dies, to powders coating with the added advantage of the greatly reduced time or granulations. Recently, punching of laminated sheets, elec- required for the coating operation. Advances in material sci- tronic deposition methods, and three-dimensional printing ence and polymer chemistry have made these coatings the first- methods have been used to make tablets. Tablets have been choice of formulators. in widespread use, since the latter part of the 19th century, and their popularity continues. The term “compressed tab- Enteric-Coated Tablets (ECT) let” is believed to have been first used by John Wyeth and Brother, Inc. of Philadelphia. During this same period, molded Enteric-coated tablets are compressed tablets coated with sub- tablets were introduced for use as hypodermic tablets, for the stances that resist solution in gastric fluid but disintegrate in extemporaneous preparation of solutions for injection. Tablets the intestine. Enteric coatings can be used for tablets contain- remain popular as a dosage form, due to the advantages af- ing drug substances inactivated or destroyed in the stomach, forded both to the manufacturer (e.g., simplicity and economy for those that irritate the mucosa, or as a means of delayed of preparation, stability, and convenience in packaging, ship- release of the medication. ping, and dispensing) and to the patient (e.g., accuracy of dos- Multiple Compressed Tablets (MCT) age, compactness, portability, blandness of taste, and ease of administration). Although the basic mechanical approach for Multi-compressed tablets are compressed tablets made by more most tablet manufacture has remained the same, tablet tech- than one compression cycle. This process is best used when nology has undergone great improvement and experimenta- separation of active ingredients is needed for stability purposes tion. Efforts are continually made to understand more clearly or if the mixing process is inadequate to guarantee uniform dis- the physical characteristics of powder compaction and the tribution of two or more active ingredients. factors affecting the availability of the drug substance from the dosage form after oral administration. Tableting equip- Layered Tablets ment continues to improve in both production speed and the Layered tablets are prepared by compressing additional tablet uniformity of tablets. Recent advances in tablet technology granulation on a previously compressed granulation. The op- have been reviewed.3,4 eration may be repeated to produce multilayered tablets of two Although tablets are frequently discoid in shape, they also or more layers. may be round, oval, oblong, cylindrical, or triangular. Other geometric shapes, such as diamonds and pentagons, and hexa- Press-Coated Tablets gons have also been used. They may differ greatly in size and Press coated tablets, also referred to as dry-coated tablets, weight, depending on the amount of drug substance present are prepared by feeding previously compressed tablets into a and the intended method of administration. Most commercial special tableting machine and compressing another granula- tablets can be divided into two general classes: whether they tion layer around the preformed tablets. They have all the ad- are made by compression or molding. Compressed tablets are vantages of compressed tablets (i.e., slotting, monogramming, prepared by large-scale production methods, whereas molded speed of disintegration), while retaining the attributes of sugar- tablets involve small-scale operations. The various tablet types coated tablets in masking the taste of the drug substance in and abbreviations used in referring to them are listed here. the core tablets. An example of a press-coated tablet press is 581 582 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding the ­Manesty Drycota. Press-coated tablets can also be used to Dispensing Tablets (DT) separate incompatible drug substances; in addition, they can Dispensing tablets provide a convenient quantity of potent drug provide a means of giving an enteric coating to the core tablets. that can be incorporated readily into powders and liquids, thus, Both types of multiple-compressed tablets have been widely circumventing the necessity to weigh small quantities. These used in the design of prolonged-action dosage forms. tablets are supplied primarily as a convenience for extempora- neous compounding and should never be dispensed as a dosage Controlled-Release Tablets (CRT) form. Compressed tablets can be formulated to release the drug slow- ly over a prolonged period of time. Hence, these dosage forms Hypodermic Tablets (BT) have been referred to as “prolonged-release” or “sustained- ­release” dosage forms as well. These tablets, as well as capsule Hypodermic tablets are soft, readily soluble tablets and were versions, can be categorized into three types: 1) those that re- originally used for the preparation of solutions to be injected. spond to some physiological condition to release the drug, such Since stable parenteral solutions are now available for most as enteric coatings; 2) those that release the drug in a relatively drug substances, there is no justification for the use of hypo- steady, controlled manner; and 3) those that combine combina- dermic tablets for injection. Their use in this manner should be tions of mechanisms to release pulses of drug, such as repeat- discouraged, since the resulting solutions are not sterile. Large action tablets. Chapter 32 describes the performance of these quantities of these tablets continue to be made, but for oral ad- systems in more detail. Other names for these types of tablets ministration. No hypodermic tablets have ever been recognized are; Extended Release, Sustained Release, Prolonged Release, by the official compendia. Delayed Release, and, in the case of pulsatile tablets, Repeat Compressed Tablets (CT) Action, Pulsatile Release, or Pulse Release. For medicinal substances, with or without diluents, to be made Tablets for Solution (CTS) into solid dosage forms with pressure, using available equip- Compressed tablets used for preparing solutions or imparting ment, it is necessary that the material, either in crystalline or given characteristics to solutions must be labeled to indicate powdered form, possess a number of physical characteristics. they are not to be swallowed. Examples of these tablets are Hal- These characteristics include the ability to flow freely, cohesive- azone Tablets for Solution and Potassium Permanganate Tablets ness, and lubrication. The ingredients, such as disintegrants for Solution. designed to break the tablet up in gastrointestinal (GI) fluids and controlled-release polymers designed to slow drug release, Effervescent Tablets ideally, should possess these characteristics or not interfere with the desirable performance traits of the other excipients. Since In addition to the drug substance, effervescent tablets contain most materials have none or only some of these properties, sodium bicarbonate and an organic acid, such as tartaric or methods of tablet formulation and preparation have been de- citric. In the presence of water, these additives react, liberat- veloped to impart these desirable characteristics to the material ing carbon dioxide that acts as a disintegrator and produces that is to be compressed into tablets. The basic mechanical unit effervescence. Except for small quantities of lubricants present, in all tablet-compression equipment includes a lower punch that effervescent tablets are soluble. fits into a die from the bottom and an upper punch, with a head of the same shape and dimensions, which enters the die cav- Compressed Suppositories or Inserts ity from the top, after the tableting material fills the die cavity Occasionally, vaginal suppositories, such as Metronidazole tab- (Fig. 30-1). The tablet is formed by pressure applied on the lets, are prepared by compression. Tablets for this use usually punches and, subsequently, is ejected from the die. The weight contain lactose as the diluent. In this case, as well as for any of the tablet is determined by the volume of the material that tablet intended for administration by means other than swal- fills the die cavity. Therefore, the ability of the granulation to lowing, the label must indicate the manner in which it is to be flow freely into the die is important in ensuring a uniform fill, used. as well as the continuous movement of the granulation from the source of supply or feed hopper. If the tablet granulation does not Buccal and Sublingual Tablets possess cohesive properties, the tablet, after compression, will Buccal and sublingual tablets are small, flat, oval tablets. Tablets crumble and fall apart on handling. As the punches must move intended for buccal administration by inserting into the buccal pouch (the space between the lip and gum in the mouth) may dissolve or erode slowly; therefore, they are formulated and compressed with sufficient pressure to give a hard tablet. Pro- gesterone tablets may be administered in this way. Some newer approaches have employed materials that act as bioadhesives to increase absorption of the drug. Other approaches use tab- lets that melt at body temperatures. The matrix of the tablet is solidified, while the drug is in solution. After melting, the drug is automatically in solution and available for absorption, thus, eliminating dissolution as a rate-limiting step in the absorp- tion of poorly soluble compounds. Sublingual tablets, such as those containing nitroglycerin, isoproterenol hydrochloride, or erythrityl tetranitrate, are placed under the tongue. Sublingual tablets dissolve rapidly, and the drug substances are absorbed readily by this form of administration. Molded Tablets or Tablet Triturates (TT) Tablet triturates are usually made from moist material, using a triturate mold that gives them the shape of cut sections of a cyl- inder. 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 completely water-soluble. Figure 30-1. Multi-tip punches and die. (Courtesy of Natoli.)  Oral Solid Dosage Forms 583 freely within the die and the tablet must be ejected readily from Upon chewing, properly prepared tablets disintegrate smoothly the punch faces, the material must have a degree of lubrication at a satisfactory rate, have a pleasant taste and feel, and leave to minimize friction and allow the removal of the compressed no unpleasant aftertaste in the mouth. Diluents used as excipi- tablets. There are three general methods typically used for com- ents for direct compression formulas have been subjected to mercial tablet preparation: the wet-granulation method, the dry prior processing to give them flow ability and compressibility. granulation method, and direct compression. The method of These are discussed in the section Direct Compression. Most preparation and the added ingredients are selected to give the formulators of immediate-release tablets tend to consistently tablet formulation the desirable physical characteristics, allow- use only one or two diluents selected from the listed group in ing the rapid compression of tablets. After compression, the tab- their tablet formulations. Usually, these are selected on the lets must have a number of additional attributes, such as appear- basis of experience and cost factors. However, in the formula- ance, hardness, disintegration ability, appropriate dissolution tion of new therapeutic agents, the compatibility of the diluents characteristics, and uniformity, which are also influenced by with the drug must be considered (e.g., calcium salts used as both the method of preparation and the added materials present diluents for the broad-spectrum antibiotic tetracycline) have in the formulation. In the preparation of compressed tablets, the been shown to interfere with the drug’s absorption from the GI formulator must also be cognizant of the effect that the ingredi- tract. When drug substances have low water solubility, it is rec- ents and methods of preparation may have on the availability of ommended that water-soluble diluents be used to avoid possi- the active ingredients and, hence, the therapeutic efficacy of the ble bioavailability problems. Highly adsorbent substances (e.g., dosage form. In response to a request by physicians to change a bentonite and kaolin) are avoided in making tablets of drugs dicumarol tablet, so it might be broken more easily, a Canadian used clinically in small dosage, such as the cardiac glycosides, company reformulated to make a large tablet with a score. Sub- alkaloids, and synthetic estrogens. These drug substances may sequent use of the tablet, containing the same amount of drug be adsorbed after administration. The combination of amine substance as the previous tablet, resulted in complaints that bases with lactose or alkaline salts with lactose in the presence larger-than-usual doses were needed to produce the same thera- of alkaline lubricant results in tablets that discolor on aging. peutic response. Conversely, literature reports indicate that the Microcrystalline cellulose (Avicel) is usually used as an ex- reformulation of a commercial digoxin tablet resulted in a tablet cipient in direct-compression formulas. However, its presence in that, although containing the same quantity of drug substance, 5–15% concentrations in wet granulations has been shown bene- gave the desired clinical response at half its original dose. Meth- ficial in the granulation and drying processes in minimizing case- ods and principles that can be used to assess the effects of ex- hardening of the tablets and in reducing tablet mottling. Many cipients and additives on drug absorption have been reviewed.5–7 ingredients are used for several different purposes, even with- in the same formulation (e.g., cornstarch can be used in paste Tablet Ingredients form as a binder). When added in drug or suspension form, it is In addition to the active or therapeutic ingredient, tablets con- a good disintegrant. Even though these uses are to achieve op- tain a number of inert materials. The latter are known as ad- posite goals, some tablet formulas use cornstarch in both ways. ditives or excipients. They may be classified according to the In some controlled-release formulas, the polymer hydroxypropyl part they play in the finished tablet. The first group contains methylcellulose (HPMC) is used both as an aid to prolong the those that help to impart satisfactory processing and compres- release from the tablet, as well as a film-former in the tablet coat- sion characteristics to the formulation. These include diluents, ing. Therefore, most excipients used in formulating tablets and binders, glidants, and lubricants. The second group of added capsules have many uses, and a thorough understanding of their substances helps to give additional desirable physical character- properties and limitations is necessary to use them rationally. istics to the finished tablet. Included in this group are disinte- grants, surfactants, colors, and, in the case of chewable tablets, Binders flavors and sweetening agents, and, in the case of controlled- Agents used to impart cohesive qualities to the powdered mate- release tablets, polymers or hydrophobic materials, such as rial are referred to as binders or granulators. They impart cohe- waxes or other solubility-retarding materials. In some cases, siveness to the tablet formulation that ensures the tablet remain antioxidants or other materials can be added to improve stabil- intact after compression, as well as improve the free-flowing qual- ity and shelf-life. Although the term “inert” has been applied to ities by the formulation of granules of desired hardness and size. these added materials, it has become apparent that there is an Materials commonly used as binders include starch, gelatin, and important relationship between the properties of the excipients sugars, such as sucrose, glucose, dextrose, molasses, and lactose. and the dosage forms containing them.8 Preformulation studies Natural and synthetic gums that have been used include acacia, demonstrate their influence on stability, bioavailability, and the sodium alginate, extract of Irish moss, panwar gum, ghatti gum, processes by which the dosage forms are prepared. The need mucilage of isapol husks, carboxymethylcellulose, methylcel- for acquiring more information and use standards for excipi- lulose, polyvinylpyrrolidone, Veegum, and larch arabogalactan. ents has been recognized in a joint venture of the Academy of Other agents considered binders under certain circumstances Pharmaceutical Sciences and the Council of the Pharmaceuti- are polyethylene glycol, ethylcellulose, waxes, water, and alco- cal Society of Great Britain. The result is called the Handbook hol. Synthetic binders, such as polyvinylpyrrolidone and HPMC of Pharmaceutical Excipients. This reference work is now dis- are becoming more popular. The quantity of binder used has tributed widely throughout the world.9 considerable influence on the characteristics of the compressed tablets. The use of too much binder or too strong a binder will Diluents make a hard tablet that will not disintegrate easily and will cause Frequently, the single dose of the active ingredient is small, and excessive wear of punches and dies. Differences in binders used an inert substance is added to increase the bulk to make the for CT Tolbutamide resulted in differences in hypoglycemic ef- tablet a practical size for compression. Compressed tablets of fects observed clinically. Materials that have no cohesive quali- dexamethasone contain 0.75 mg steroid per tablet; hence, it is ties of their own require a stronger binder than those with these obvious that another material must be added to make tableting qualities. Alcohol and water are not binders in the true sense of possible. Diluents used for this purpose include dicalcium phos- the word, but, due to their solvent action on some ingredients, phate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodi- such as lactose, starch, and celluloses, they change the powdered um chloride, dry starch, and powdered sugar. Certain diluents, material to granules, and the residual moisture retained enables such as mannitol, lactose, sorbitol, sucrose, and inositol, when the materials to adhere together when compressed. Binders are present in sufficient quantity, can impart properties to some used both as a solution and in a dry form, depending on the other compressed tablets that permit disintegration in the mouth by ingredients in the formulation and the method of preparation. chewing. Such tablets are commonly called chewable tablets. However, several pregelatinized starches available are intended 584 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding to be added in the dry form, so water alone can be used as the Lubricants granulating solution. The same amount of binder in solution Lubricants have a number of functions in tablet manufacture. will be more effective than if it were dispersed in a dry form and They prevent adhesion of the tablet material to the surface moistened with the solvent. By the latter procedure, the bind- of the dies and punches, reduce interparticle friction, facilitate ing agent is not as effective in reaching and wetting each of the the ejection of the tablets from the die cavity, and may improve particles within the mass of powders. Each of the particles in a the rate of flow of the tablet granulation. Commonly used lubri- powder blend has a coating of adsorbed air on its surface, and it cants include talc, magnesium stearate, calcium stearate, stea- is this film that must be penetrated before the powders can be ric acid, glyceryl behanate, hydrogenated vegetable oils, and wetted by the binder solution. After wetting, a certain period of polyethylene glycol (PEG). Most lubricants, with the exception time is necessary to dissolve the binder completely and make it of talc, are used in concentrations below 1%. When used alone, completely available for use. Since powders differ with respect to talc may require concentrations as high as 5%. Lubricants are, the ease with which they can be wetted and their rate of solubi- in most cases, hydrophobic materials. Poor selection or exces- lization, it is preferable to incorporate the binding agent in solu- sive amounts can result in waterproofing the tablets, resulting tion. By this technique, it is often possible to gain effective bind- in poor tablet disintegration and/or delayed dissolution of the ing with a lower concentration of binder. The direct-compression drug substance. The addition of the proper lubricant is highly method for preparing tablets requires a material that is not only desirable, if the material to be tableted tends to stick to the free-flowing but also sufficiently cohesive to act as a binder. This punches and dies. Immediately after compression, most tablets use has been described for a number of materials, including mi- have the tendency to expand and will bind and stick to the side crocrystalline cellulose, microcrystalline dextrose, amylose, and of the die. The choice of the proper lubricant will overcome polyvinylpyrrolidone. It has been postulated that microcrystal- this effectively. The method of adding a lubricant to a granu- line cellulose is a special form of cellulose fibril in which the indi- lation is important, if the material is to perform its function vidual crystallites are held together largely by hydrogen bonding. satisfactorily. The lubricant should be divided finely by passing The disintegration of tablets containing the cellulose occurs by it through a 60- to 100-mesh nylon cloth onto the granulation. breaking the intercrystallite bonds by the disintegrating medium. In production, this is called “bolting” the lubricant. After add- Starch Paste—Cornstarch is used widely as a binder. The ing the lubricant, the granulation is tumbled or mixed gently to concentration may vary from 10% to 20%. It is usually prepared distribute the lubricant without coating the particles too well as it is to be used, by dispersing cornstarch in sufficient cold pu- or breaking them down to finer particles. Some research has rified water to make a 5–10% w/w suspension and warming in concluded that the order of mixing of lubricants and other ex- a water bath with continuous stirring until a translucent paste cipients can have a profound effect on the performance of the forms. It has been observed that, during paste formation, not all final dosage form. Thus, attention to the mixing process itself is of the starch is hydrolyzed. Starch paste then is not only useful just as important as the selection of lubricant materials. These as a binder, but also as a method to incorporate some disinte- process variables can be seen in the prolonged blending of a lu- grant inside the granules. bricant in a granulation. Overblending materially can affect the Gelatin Solution—Gelatin is used as a 10–20% solution; gela- hardness, disintegration time, and dissolution performance of tin solutions should be prepared freshly as needed and used the resultant tablets. The quantity of lubricant varies, being as while warm, or they will solidify. The gelatin is added to cold low as 0.1% and, in some cases, as high as 5%. Lubricants have purified water and allowed to stand, until it is hydrated. It is been added to the granulating agents in the form of suspensions then warmed in a water bath to dissolve the gelatin, and the or emulsions. This technique serves to reduce the number of solution is made up to the final volume on a weight basis to give operational procedures and, thus, reduce the processing time. the concentration desired. In selecting a lubricant, proper attention must be given to its Cellulosic Solutions—Various cellulosics have been used compatibility with the drug agent. Perhaps the most widely in- as binders in solution form. Hydroxypropyl methylcellulose vestigated drug is acetylsalicylic acid. Different talcs varied the (HPMC) has been used widely in this regard. Typical of a num- stability of aspirin significantly. Talc, with a high calcium con- ber of cellulosics, HPMC is more soluble in cold water than hot. tent and a high loss on ignition, was associated with increased It is also more dispersible in hot water than cold. Hence, to ob- aspirin decomposition. From a stability standpoint, the relative tain a good, smooth gel that is free from lumps or “fisheyes,” it acceptability of tablet lubricants for combination with aspirin is necessary to add the HPMC in hot, almost boiling, water and, was found to decrease in the following order: hydrogenated under agitation, cool the mixture down as quickly as possible, vegetable oil, stearic acid, talc, and aluminum stearate. The as low as possible. Other water-soluble cellulosics, such as hy- primary problem in the preparation of a water-soluble tablet droxyethylcellulose (HEC) and hydroxypropylcellulose (HPC), is the selection of a satisfactory lubricant. Soluble lubricants have been used successfully in solution as binders. reported to be effective include sodium benzoate, a mixture Not all cellulosics are soluble in water. Ethylcellulose can be of sodium benzoate and sodium acetate, sodium chloride, leu- used effectively, when dissolved in alcohol or as a dry binder cine, and polyethylene glycol/Carbowax 4000. However, it has that then is wetted with alcohol. It is used as a binder for mate- been suggested that formulations used to prepare water soluble rials that are moisture-sensitive. tablets may represent a number of compromises between com- Polyvinylpyrrolidone–(PVP) can be used as an aqueous or pression efficiency and water solubility. Although magnesium alcoholic solution, and this versatility has increased its popu- stearate is one of the most widely used lubricants, its hydro- larity. Concentrations range from 2% and vary considerably. It phobic properties can retard disintegration and dissolution. To should be noted that binder solutions are usually made up to overcome these waterproofing characteristics, sodium lauryl Weight, rather than volume. This is to enable the formulator sulfate is sometimes included. One compound found to have to determine the weight of the solids that have been added to the lubricating properties of magnesium stearate, without their the tablet granulation in the binding solution. This becomes disadvantage, is magnesium lauryl sulfate. Its safety for use in part of the total weight of the granulation and must be taken pharmaceuticals has not been established. into consideration in determining the weight of the compressed tablet, which will contain the stated amount of the therapeutic agent. As can be seen by the list of binders in this chapter, most Glidants modern binders used in solution are polymeric. Because of this, A glidant is a substance that improves the flow characteristics the flow or spreadability of these solutions becomes important, of a powder mixture. These materials always are added in the when selecting the appropriate granulating equipment. The dry state just prior to compression (i.e., during the lubrication rheology of polymeric solutions is a fascinating subject in and of step). Colloidal silicon dioxide Cab-o-sil (Cabot) is the most itself and should be considered for these materials. commonly used glidant and is used in low concentrations of  Oral Solid Dosage Forms 585 1% or less. Talc (asbestos-free) is also used and may serve the They are much less effective as disintegrants, when incorpo- dual purpose of lubricant glidant. It is especially important to rated within the granules. optimize the order of addition and the mixing process for these Factors other than the presence of disintegrants can affect materials, to maximize their effect and to make sure their influ- the disintegration time of compressed tablets significantly. The ence on the lubricant(s) is minimized. binder, tablet hardness, and the lubricant have been shown to influence the disintegration time. Thus, when the formula- Disintegrants tor is faced with a problem concerning the disintegration of a A disintegrant is a substance or a mixture of substances added compressed tablet, the answer may not lie in the selection and to a tablet to facilitate its breakup or disintegration after admin- quantity of the disintegrating agent alone. The evolution of car- istration. The active ingredient must be released from the tablet bon dioxide is also an effective way to cause the disintegration matrix as efficiently as possible to allow rapid dissolution. Ma- of compressed tablets. Tablets containing a mixture of sodium terials serving as disintegrants have been classified chemically bicarbonate and an acidulant, such as tartaric or citric acid, will as starches, clays, celluloses, algins, gums, and cross-linked effervesce when added to water. Sufficient acid is added to pro- polymers. The oldest and still the most popular disintegrants duce a neutral or slightly acidic reaction when disintegration in are corn and potato starches that have been well dried and pow- water is rapid and complete. dered. One drawback to the use of the effervescent type of disinte- Starch has a great affinity for water and swells when moist- grator is that such tablets must be kept in a dry atmosphere at ened, thus, facilitating the rupture of the tablet matrix. Howev- all times during manufacture, storage, and packaging. Soluble, er, others have suggested that its disintegrating action in tablets effervescent tablets provide a popular form for dispensing aspi- is due to capillary action, rather than swelling; the spherical rin and noncaloric sweetening agents. shape of the starch grains increases the porosity of the tablet, thus, promoting capillary action. Starch, 5%, is suggested, but, Coloring Agents if more rapid disintegration is desired, this amount may be Colors in compressed tablets serve functions other than mak- increased to 10% or 15%. Although it might be expected that ing the dosage form more esthetic in appearance. Color helps disintegration time would decrease as the percentage of starch the manufacturer control the product during its preparation, in the tablet increased, this does not appear to be the case for as well as serves as a means of identification to the user. The tolbutamide tablets. In this instance, there appears to be a criti- wide diversity in the use of colors in solid dosage forms makes it cal starch concentration for different granulations of the chem- possible to use color as an important category in the identifica- ical. When their disintegration effect is desired, starches are tion code developed by the AMA to establish the identity of an added to the powder blends in the dry state. A group of materi- unknown, compressed tablet in situations arising from poison- als known as “super disintegrants” have gained in popularity ing. All colorants used in pharmaceuticals must be approved as disintegrating agents. The name comes from the low levels and certified by the FDA. For several decades, colorants have (1–4%) at which they are completely effective. Croscarmellose, been subjected to rigid toxicity standards, and, as a result, a crospovidone, and sodium starch glycolate represent examples number of colorants have been removed from an approved list of a cross-linked cellulose, a cross-linked polymer, and a cross- of Food, Drug and Cosmetic Act (FD&C) colors, or “delisted.” linked starch, respectively. The development of these disinte- Several have been listed as well. Table 30-1 lists the colorants grants fostered new theories about the various mechanisms currently approved in the United States. Each country has its by which disintegrants work. Sodium starch glycolate swells own list of approved colorants, and formulators must consider 7- to 12-fold in less than 30 seconds. Croscarmellose swells 4- this in designing products for the international market. Any of to 8-fold in less than 10 seconds. The starch swells equally in the approved, certified, water-soluble FD&C dyes, mixtures of all three dimensions, whereas the cellulose swells only in two the same, or their corresponding lakes may be used to color dimensions, leaving fiber length essentially the same. It is pos- tablets. A color lake is the combination by adsorption of a tulated that the rate, force, and extent of swelling play an im- ­water-soluble dye to a hydrous oxide of a heavy metal, result- portant role in those disintegrants that work by swelling. Cross- ing in an insoluble form of the dye. In some instances, multiple linked PVP swells little but returns to its original boundaries dyes are used to give a purposefully heterogeneous coloring in quickly after compression. Wicking, or capillary action, is also the form of speckling to compressed tablets. The dyes available postulated to be a major factor in the ability of cross-linked PVP do not meet all the criteria required for the ideal pharmaceuti- to function.10–13 In addition to the starches, large varieties of cal colorants. The photosensitivity of several of the commonly materials have been used and are reported to be effective as used colorants and their lakes has been investigated, as well as disintegrants. This group includes Veegum HV, methylcellulose, the protection afforded by a number of glasses used in packag- agar, bentonite, cellulose and wood products, natural sponge, ing tablets. Another approach for improving the ­photostability cation-exchange resins, alginic acid, guar gum, citrus pulp, and of dyes has been in the use of ultraviolet-absorbing chemi- carboxymethylcellulose. Sodium lauryl sulfate, in combina- cals in the tablet formulations with the dyes. The Di-Pac line tion with starch, has also been demonstrated to be an effective (Amstar) is a series of commercially available colored, direct-­ disintegrant. In some cases, the apparent effectiveness of sur- compression sugars. The most common method of adding col- factants in improving tablet disintegration is postulated as due or to a tablet formulation is to dissolve the dye in the binding to an increase in the rate of wetting. The disintegrating agent solution prior to the granulating process. Another approach is is usually mixed with the active ingredients and diluents after to adsorb the dye on starch or calcium sulfate from its aque- granulation. In some cases, it may be advantageous to divide ous solution; the resultant powder is dried and blended with the disintegrant into two portions: one part is added to the pow- the other ingredients. If the insoluble lakes are used, they may dered formula prior to granulation, and the remainder is mixed be blended with the other dry ingredients. Frequently, during with the lubricant and added prior to compression. Incorpo- drying, colors in wet granulations migrate, resulting in an un- rated in this manner, the disintegrant serves a double purpose: even distribution of the color in the granulation. After compres- the portion added to the lubricant rapidly breaks down the sion, the tablets have a mottled appearance, due to the uneven tablet to granules, and the disintegrant mixed with the active distribution of the color. Migration of colors may be reduced ingredients disintegrates the granules into smaller particles.12 by drying the granulation slowly at low temperatures and stir- Veegum has been shown more effective as a disintegrator in ring the granulation, while it is drying. The affinity of several sulfathiazole tablets, when most of the quantity is added after water-soluble, anionic, certified dyes for natural starches has granulation and only a small amount before granulation. Like- been demonstrated; in these cases, this affinity should aid in wise, the montmorillonite clays were found to be good tablet preventing color migration. Other additives have been shown to disintegrants, when added to prepared granulations as powder. act as dye-migration inhibitors. Tragacanth (1%), acacia (3%), 586 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding Table 30-1. Color Additives Approved for Use in Drugs Part 74, Subpart B: Color additives subject to batch certification 21 CFR Section Straight Color Year (2)Approved Uses and Restrictions §74.1101 FD&C Blue No. 1 1969 Ingested drugs generally (5) §74.1102 FD&C Blue No. 2 1987 Ingested drugs §74.1203 FD&C Green No. 3 1982 Drugs generally (5) §74.1205 D&C Green No. 5 1982 Drugs generally (5) §74.1303 FD&C Red No. 3 1969 Ingested drugs §74.1306 D&C Red No. 6 1983 Drugs such that total with D&C Red No. 7 NTE (7) 5 mg/daily dose of drug §74.1307 D&C Red No. 7 1983 Drugs such that total with D&C Red No. 6 NTE (7) 5 mg/daily dose of drug §74.1321 D&C Red No. 21 1983 Drugs generally (5) §74.1322 D&C Red No. 22 1983 Drugs generally (5) §74.1327 D&C Red No. 27 1982 Drugs generally (5) §74.1328 D&C Red No. 28 1982 Drugs generally (5) §74.1330 D&C Red No. 30 1982 Drugs generally (5) §74.1333 D&C Red No. 33 1988 Ingested drugs, other than mouthwashes and dentifrices (NTE (7) 0.75 mg/daily dose of drug) §74.1336 D&C Red No. 36 1989 Ingested drugs, other than mouthwashes and dentifrices, NTE (7) 1.7 mg/daily dose for drugs taken less than 1 yr; NTE (7) 1.0 mg/daily dose for drugs taken more than 1 yr §74.1340 FD&C Red No. 40(3) 1971 Drugs generally (5) §74.1705 FD&C Yellow No. 5 1969 Ingested drugs generally (5) §74.1706 FD&C Yellow No. 6 1986 Drugs generally (5) §74.1710 D&C Yellow No. 10 1983 Drugs generally (5) 1984. Modification of uses and restrictions 2 The year approved is based on the date listed in the “Confirmation of Effective Date” notice for the action as published in the Federal Register. 5 Color additives permitted for general use may not be used in the area of the eye, in injections or in surgical sutures, unless such use is specified in the color additive listing regulation. Currently, no color additives are listed for use in injected products, such as tattoos or permanent makeup. 7 NTE—not to exceed attapulgite (5%), and talc (7%) were effective in inhibiting the ingly, improvements have been made only with regards to speed migration of FD&C Blue Nolin lactose. In using dye lakes, the of manufacture and quality control. The process of compaction problem of color migration is avoided, since the lakes are in- has several identifiable phases. As can be seen in Figure 30-2, soluble. Prevention of mottling can also be helped, by the use of when powders undergo compression (a reduction in volume), lubricants and other additives that have been colored similarly the first process to occur is a consolidation of the powders. to the granulation prior to their use. The problem of mottling During this consolidation phase, the powder particles adopt a becomes more pronounced as the concentration of colorants more efficient packing order. The second phase of the compac- increases. Color mottling is an undesirable characteristic com- tion process is elastic, or reversible deformation. If the force mon to many commercial tablets. were removed during this phase, the powder would completely recover to the efficiently packed state. For most pharmaceuti- Flavoring Agents cal powders, this phase is very short in duration and very dif- In addition to the sweetness that may be afforded by the dilu- ficult to identify on most instrumented tablet presses. The third ent of the chewable tablet (e.g., mannitol or lactose) artificial phase of compaction is plastic, or irreversible, ­deformation of sweetening agents may be included. Formerly, the cyclamates, the powder bed. It is this phase that is the most critical in tablet either alone or in combination with saccharin, were used wide- ly. With the banning of the cyclamates and the indefinite status Filling (Apparent Density) of saccharin, new natural sweeteners are being sought. Aspar- tame (Pfizer), has found applications in pharmaceutical formu- Close Packing (Tapped Density) lations. Sweeteners, other than the sugars, have the advantage of reducing the bulk volume, considering the quantity of su- Deformation crose required to produce the same degree of sweetness. Pres- ent in small quantities, they do not markedly affect the physical Fracture/Plastic Flow Volume characteristics of the tablet granulation. Fusion Powder Compaction Compressed tablets became a commercially viable and efficient dosage form with the invention of tablet machines. In 1843, Wil- liam Brockendon, a British inventor, author, artist, and watch- maker, received British Patent #9977 for Shaping Pills, Loz- Pressure enges, and Black Lead by Pressure in Dies. In over 150 years of tablet manufacture, the basic process has not changed. Surpris- Figure 30-2. The stages of powder compaction.  Oral Solid Dosage Forms 587 formation. If too much force is applied to the powder, brittle Changes in Surface Area During Compression fracture occurs. If the force is applied too quickly, fracture and Bulk powders change their state of packing during compac- de-bonding during stress relaxation can occur. In 1950, Stewart tion, and individual particles fracture and/or plastically deform. reported on the importance of plastic flow and suggested that, During this process, the surface area of the powders and the if a material has significant plastic flow under compression, it compact, in whole change. Conventional nitrogen absorption will be more likely to form a compact. Stress-relaxation data, techniques can estimate these changes. Although this can be using the Maxwell model of viscoelastic behavior, were evalu- tedious, these measurements can give a means of examining ated, in an attempt to quantify the rate of plastic deformation of lamination tendency. some direct compression excipients. The term “contact time” was used to describe the total time for which a moving punch Stress Relaxation applies a detectable force to the die contents during the com- Stress relaxation, an experimental technique, consists of hold- pression and decompression event, excluding ejection. ing the compression process at a point of maximum compres- sion and observing the compression force over various periods Tablet Strength-Compression Pressure Profile of time. By increasing the duration of this period (or dwell Most formulators use tablet hardness, or tensile strength, as time), plastic flow is maximized, and tablet strength increases. a measure of the cohesiveness and/or the crushing strength/ breaking strength of the tablet. With even the simplest of in- Stress Transmissions during Compression strumented tablet presses, it is possible to plot tensile strength If the stresses in the upper punch, lower punch, and die wall versus the force applied to the tablet. These plots can be useful are monitored, a general plot can be constructed, showing the in identifying forces that can cause fracture and can lead to a relationship between these forces. quick, tangible assessment of the compatibility of the formula- tion. However, there are many limitations to this method, as Granulation Methods these plots cannot predict lamination or capping. In addition, Wet Granulation the cohesiveness of a tablet can change upon storage, in either The most widely used and most general method of tablet prepa- a positive or negative direction. ration is the wet-granulation method. Its popularity is due to the greater probability that the granulation will meet all the Tablet Friability physical requirements for the compression of good tablets. Its There have been many suggestions about how tablet friability chief disadvantages are the number of separate steps involved, tests should be performed. Many formulators believe this is an as well as the time and labor necessary to carry out the proce- important indicator of cohesiveness but is of limited value in dure, especially on a large scale. The steps in the wet method predicting failure in the field. are weighing, mixing, wet massing, screening the damp mass, drying, dry screening, lubrication, and compression. The equip- Changes in Bed Density During Compression ment involved depends on the quantity or size of the batch and the percent active ingredient per total weight of the tablets. Wet As applied stress (force) increases, elastic and plastic deforma- massing can be performed by: tion of the particles occurs, which results in plastic flow and a reduction in inter- and intraparticulate void spaces. This low- 1. Low Shear mixers/granulators, ers the overall compact density. For highly cohesive systems, 2. High Shear mixers/granulators, the reduction in void space may yield a compact of sufficient 3. Fluid-Bed granulators/dryers, strength for insertion into a capsules shell. However, the in- 4. Spray Dryers, or herent cohesiveness for most drugs and excipients is not suit- 5. Extruders and Spheronizers. able alone for tablet manufacture. The Heckel equation is sub- sequently given; K can be considered equal to the reciprocal Low shear mixers include the barrel, cube, twin shell, double of the mean yield pressure, and A is a function of the original cone, slated double cone, ribbon, sigma blade, planetary ­mixers, compact volume and is related to the densification and particle etc. (Fig. 30-3). Although these mixers continue to be used in rearrangement prior to bonding: some older pharmaceutical factories, they are replaced, now, Log [1/(1 − D)] = KP + A, by the high shear mixers/granulators. High shear mixers are stationary shell mixers with a large mixer scraper blade, which where D is the relative density at pressure P, and K and A are mixes the ingredients, eliminates dead spots, and presents the constants. ingredients with a high speed chopper blade, which intimately Figure 30-3. Twin Shell Blender with Intensifier Bars. (Courtesy of Patterson Kelly Buflovak LLC.) 588 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding mixes the ingredients and breaks the lumps. The advantages of the high shear mixers/granulators are: simple, robust tech- nology, production of high density granules, rapid and efficient mixing, low liquid requirements, and equipped for drying. There are many models/trade names of high shear mixers in the pharmaceutical market, such as the Loedige, Littleford MGT, Diosna, Fiedler, Vector, Glatt, GEA, and Hüttlin Gentlew- ing. Figure 30-4 shows a typical high shear mixer granulator from Vector, and Figure 30-5 shows a typical Glatt high shear mixer. A relatively new high shear mixer from Hüttlin is the Gentlewing High Shear Mixer, which is available in laboratory and large scale sizes, either top driven or bottom driven. The Gentlewing technology applies the principle of a positive dis- placement impeller for blending a non-Newtonian medium. The impeller shape matches the contour of the mixing container, and its angled impeller plate ensures a forced mixing of the product. Rather than using the impulse of an impeller for mix- ing, the Gentlewing’s uniform presence throughout the product container distributes the mixing energy, at lower speeds but higher torque, evenly throughout the product, reducing segre- gation issues typically caused by high dynamic forces (Fig. 30-6 and Fig. 30-7). The active ingredient, diluent, and part of the disintegrant are mixed or blended well. Solutions of the binding agent are added or sprayed to the mixed powders with stirring. The pow- der mass is wetted with the binding solution, until the mass has the consistency of damp snow or brown sugar. If the granulation is over-wetted, the granules will be hard, requiring considerable pressure to form the tablets, and the resultant tablets may have a mottled appearance. If the powder mixture is not wetted suf- ficiently, the resulting granules will be too soft, breaking down during lubrication and causing difficulty during compression. In modern high shear mixers, the end point of wet granulation is no more dependent on the experience of the operator and the Figure 30-5. High Shear Mixer. (Courtesy of GLATT.) “hand” feeling of the wet mass, but is measured accurately by a built in torque meter. This consistency and reproducibility from batch to batch are assured. The wet granulation mass is then forced through a 6- or 8-mesh screen. Small batches can be forced through by hand, using a manual screen. For larger quan- tities, one of several comminuting mills suitable for wet screen- ing can be used. These include the Stokes oscillator, Colton rotary granulator, Fitzpatrick comminuting mill, Cone Mill, or Stokes tornado mill. In comminuting mills, the granulation is forced through the sieving device by rotating hammers, knives, or oscillating bars (Fig. 30-8–30-10). Most high-speed mixers are equipped with a chopper blade that operates independently of the main mixing blades and can replace the wet milling step (i.e., can obviate the need for a separate ­operation). For tablet Figure 30-6. Gentlewing High Shear Mixer, diagram. (Courtesy of Figure 30-4. Vector High Shear Mixer. Hüttlin GmbH, A Bosch Packaging Technology Company.)  Oral Solid Dosage Forms 589 Figure 30-7. Gentlewing High Shear Mixer. (Courtesy of Hüttlin Figure 30-8. Fitzmill Comminutor. (Courtesy of Fitzpatrick Co.) GmbH, A Bosch Packaging Technology Company.) formulations in which continuous production is justified, ex- ture, as well as by comminuting the granulation to the desired truders, such as the Reitz extruder, have been adapted for the granule size after drying. Recently, many machine manufactur- wet-granulation process. Moist material from the wet milling ers, such as Hüttlin, GEA, and Glatt, introduced the single pot step, traditionally, was placed on large sheets of paper on shal- technology in which the drying process can also take place in a low wire trays and placed in drying cabinets with a circulating vertical granulator specially equipped for this purpose. The dry- air current and thermostatic heat control. Although tray drying ing is assisted by suitable measures, according to the product was the most widely used method of drying tablet granulations and the process, such as heated wall surfaces, gas stripping, and in the past, fluid-bed drying is now considered the standard. In vacuum (Fig. 30-12). drying tablet granulation by fluidization, the material is sus- In drying granulations, it is desirable to maintain a residual pended and agitated in a warm air stream, while the granulation amount of moisture in the granulation. This is necessary to is maintained in motion. Drying tests comparing the fluidized maintain the various granulation ingredients, such as gums, bed and a tray dryer for a number of tablet granulations indi- in a hydrated state. Also, the residual moisture contributes to cated that the former was 15 times faster than the conventional the reduction of the static electric charges on the particles. In method of tray drying. In addition to the decreased drying time, the selection of any drying process, an effort is made to ob- the fluidization method is claimed to have other advantages, tain uniform moisture content. In addition to the importance such as better control of drying temperatures, decreased han- of moisture content of the granulation in its handling, during dling costs, and the opportunity to blend lubricants and other the manufacturing steps, the stability of the products contain- materials into the dry granulation directly in the fluidized bed ing moisture-sensitive active ingredients may be related to the (Fig. 30-11). The application of microwave drying and infra- moisture content of the products. Previously, it was indicated red drying to tablet granulations has been reported as success- that water-soluble colorants can migrate toward the surface of ful for most granulations tried. These methods readily lend the granulation during the drying process, resulting in mottled themselves to continuous granulation operations. The study tablets after compression. This is also true for water-soluble of drying methods for tablet granulations led to the develop- drug substances, resulting in tablets unsatisfactory as to content ment of the Rovac dryer system by Ciba Novartis pharmacists uniformity. Migration can be reduced by drying the granulation and engineers. The dryer is similar in appearance to the cone slowly at low temperatures or using a granulation in which the blender, except for the heating jacket and vacuum connections. major diluent is present as granules of large particle size. The By excluding oxygen and using the lower drying temperatures presence of microcrystalline cellulose in wet granulations also made possible by drying in a vacuum, opportunities for degra- reduces migration tendencies. After drying, the granulation is dation of the ingredients during the drying cycle are minimized. reduced in particle size, by passing it through a smaller-mesh A greater uniformity of residual moisture content is achieved, screen. Following dry screening, the granule size tends to be due to the moving bed, controlled temperature, and controlled more uniform. For dry granulations, the screen size selected time period of the drying cycle. Particle-size distribution can be depends on the diameter of the punch. The following sizes are controlled by varying the speed of rotation and drying tempera- suggested: 590 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding Figure 30-9. Hammers. (Courtesy of Fitzpatrick Co.) 1. Tablets up to 3/16 inch diameter, use 20-mesh 2. Tablets 7/32 to 5/16 inch, use 16-mesh 3. Tablets 11/32 to 13/32 inch, use 14-mesh 4. Tablets7/16 inch and larger, use 12-mesh For small amounts of granulation, hand screens may be used and the material passed through with the aid of a stainless steel Figure 30-11. Schematic Fluid bed Dryer. (Courtesy of Glatt.) spatula. With larger quantities, any of the comminuting mills with screens corresponding to those just mentioned may be It is screened onto the granulation through 60- or 100-mesh used. Note that the smaller the tablet, the finer the dry granula- nylon cloth to eliminate small lumps, as well as to increase the tion to enable more uniform filling of the die cavity; large gran- covering power of the lubricant. As it is desirable for each gran- ules give an irregular fill to a comparatively small die cavity. ule to be covered with the lubricant, the lubricant is blended With compressed tablets of sodium bicarbonate, lactose, and with the granulation very gently, preferably in a blender using a magnesium trisilicate, a relationship has been demonstrated tumbling action, such as the Patterson Kelly Twin Shell Blender between the particle size of the granulated material and the (Fig. 30-3). Gentle action is desired to maintain the uniform disintegration time and capping of the resultant tablets. For a granule size, resulting from the granulation step. It has been sulfathiazole granulation, however, the particle-size distribu- claimed that too much fine powder is not desirable, because tion did not appear to influence hardness or disintegration. fine powder may not feed into the die evenly; consequently, After dry granulation, the lubricant is added as a fine powder. variations in weight and density result. Fine powders, common- ly designated as “fines,” also blowout around the upper punch and down past the lower punch, making it necessary to clean the machine frequently. Fines, however, at a level of 10–20%, are, traditionally, sought by the tablet formulator. The presence of some fines is necessary for the proper filling of the die cavity. Now, even higher concentrations of fines are used successfully in tablet manufacture. Most investigators agree that no general limits exist for the amount of fines that can be present in a granulation; it must be determined for each specific formula. Many formulators once believed (and some still believe) that over blending resulted in an increased amount of fines and, hence, caused air entrapment in the formula. The capping and laminating of tablets associated with over blending lubricants was thought to be caused by these air pockets. Most scientists now recognize that a more plausible explanation has to do with the function of the lubricants themselves. Since the very nature of a lubricant tends to make surfaces less susceptible to ad- hesion, over blending prevents the intergranular bonding that takes place during compaction. Fluid-Bed Granulation A relatively new method for granulating evolved from the fluid- bed drying technology previously described. The concept was Figure 30-10. Screens. (Courtesy of Fitzpatrick Co.) to spray a granulating solution onto the suspended particles,  Oral Solid Dosage Forms 591 Figure 30-12. Single Pot Vertical Granulator. (Courtesy of Glatt.) which then would be dried rapidly in the suspending air. The main benefit from this system is the rapid granulation and dry- ing of a batch. The main firms that developed this technology are Glatt, Aeromatic (now GEA), Vector, and Hüttlin. The gen- eral design of these systems is the same with most companies (Fig. 30-13–30-16). In this method, particles of an inert ma- terial or the active drug are suspended in a vertical column with a rising air stream; while the particles are suspended, the common granulating materials in solution are sprayed into the column. There is a gradual particle buildup under a con- trolled set of conditions, resulting in a tablet granulation ready for compression after the addition of the lubricant. An obvious advantage exists, since granulating and drying can take place in a single piece of equipment. It should be noted, however, that many of the mixers discussed previously can be supplied with a steam jacket and vacuum and can provide the same ad- vantage. In these systems, a granulating solution or solvent is sprayed into or onto the bed of suspended particles. The rate Figure 30-14. Bottom Spray Fluid Bed. (Courtesy of Glatt.) of addition of the binder, temperature in the bed of particles, temperature of the air, volume, and moisture of the air all play an important role in the quality and performance of the final a fluid-bed system knows that the many operating parameters product. Many scientists feel that this method is an extension involved make it somewhat more complex. In addition to its of the wet-granulation method, as it incorporates many of its use for the preparation of tablet granulations, this technique concepts. However, anyone who has developed a formulation in has also been proposed for the coating of solid particles, as a means of improving the flow properties of small particles. Re- searchers have observed that, in general, fluid-bed granulation yields a less dense particle than conventional methods, and this can affect subsequent compression behavior. The Merck facility at Elkton, VA, was the first completely automated tablet pro- duction facility in the world. The entire tablet-manufacturing process, based on a wet-granulation method, was computer- controlled. The system weighed the ingredients, blended, granulated, dried, and lubricated to prepare a uniform granu- lation of specified particle size and particle-size distribution. The computer directed the compression of the material into tablets with exacting specifications for thickness, weight, and hardness. After compression, the tablets were coated with a water-based film coating. The computer controlled and moni- tored all flow of material. The plant represented the first totally automated pharmaceutical manufacturing facility. However, due to shifting market trends, the burdens of process valida- tion, and changes to processes, totally automated processes are, generally, not used today. Instead, many production ­operations focus on computer-controlled and monitored unit operations, such as seen in various tableting machines and granulators. Equipment suppliers work closely with individual pharma- ceutical companies in designing specialized and unique sys- tems. Newer developments from the machine manufacturing industries improved the process efficiency by modifying the air ­distribution plate and introducing the new Diskjet with a tangential air exit, which ensures optimum exchange of mate- rials and energy, as well as reduced process time for drying, granulating, and coating (Fig. 30-17). Total containment sys- Figure 30-13. Fluid Bed Top Spray Granulator. (Courtesy of Glatt.) tems are available from Glatt, GEA, and Hüttlin. Thus, a high 592 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding Figure 30-15. Tangential Spray Fluid Bed. (Courtesy of Glatt.) Figure 30-17. Disk Jet. (Courtesy of Hüttlin GmbH, A Bosch Pack- aging Technology Company.) shear mixer is connected to a cone mill and then a fluid bed dryer. Charging and discharging take place under totally dust minuted through the desirable mesh screen either by hand or, and contamination free conditions (Fig. 30-18). for larger quantities, through the Fitzpatrick or similar commi- nuting mill. The lubricant remaining is added to the granulation Dry Granulation and blended gently, and the material is compressed into tab- lets. Aspirin is a good example of where slugging is satisfactory. When tablet ingredients are sensitive to moisture or are unable Other materials, such as aspirin combinations, acetaminophen, to withstand elevated temperatures during drying and when the thiamine hydrochloride, ascorbic acid, magnesium hydroxide, tablet ingredients have sufficient inherent binding or cohesive and other antacid compounds, may be treated similarly. Results properties, slugging may be used to form granules. This method comparable to those accomplished by the slugging process are is referred to as dry granulation, precompression, or double- also obtained with compacting mills. In the compaction method, compression. It eliminates a number of steps but still includes the powder densified passes between high-pressure rollers that weighing, mixing, slugging, dry screening, lubrication, and com- compress the powder and remove the air. The densified material pression. The active ingredient, diluent (if required), and part is reduced to a uniform granule size and compressed into tablets of the lubricant are blended. One of the constituents, either the after the addition of a lubricant. Excessive pressures that may active ingredient or the diluent, must have cohesive proper- be required to obtain cohesion of certain materials may result in ties. Powdered material contains a considerable amount of air; a prolonged dissolution rate. Compaction mills available include under pressure, this air is expelled, and a fairly dense piece is the Chilsonator (Fitzpatrick), Roller Compactor (Vector), and formed. The more time allowed for this air to escape, the bet- the Compactor Mill (Allis-Chalmers; Fig. 30-19). ter the tablet or slug. When slugging is used, large tablets are made as slugs, because fine powders flow better into large cavi- Direct Compression ties. Also, producing large slugs decreases production time: 7/8- As its name implies, direct compression consists of compress- 1 in are the most practical sizes for slugs. Sometimes, to obtain ing tablets directly from component materials, without modify- the pressure desired, the slug sizes are reduced to 3/4 in. The ing the physical nature of the materials themselves. Formerly, punches should be flat-faced. The compressed slugs are com- direct compression, as a method of tablet manufacture, was re- served for a small group of crystalline chemicals having all the physical characteristics required for the formation of a good tablet. This group includes chemicals, such as potassium salts (chlorate, chloride, bromide, iodide, nitrate, and permanga- nate), ammonium chloride, and methenamine. These materials possess cohesive and flow properties that make direct compres- sion possible. Since the pharmaceutical industry is constantly making efforts to increase the efficiency of tableting operations and reducing costs by using the smallest amount of floor space and labor as possible for a given operation, increasing attention is given to this method of tablet preparation. Approaches used to make this method more universally applicable include the introduction of formulation additives capable of imparting the characteristics required for compression and the use of force- feeding devices to improve the flow of powder blends. For tablets in which the drug itself constitutes a major por- tion of the total tablet weight, it is necessary that the drug pos- sess those physical characteristics required for the formulation to be compressed directly. Direct compression for tablets con- Figure 30-16. Fluid-Bed. (Courtesy of Hüttlin GmbH, A Bosch taining 25% or less of drug substances can frequently be used Packaging Technology Company.) by formulating with a suitable diluent that acts as a carrier or  Oral Solid Dosage Forms 593 Figure 30-18. Horizontal granulation line consisting of a Top Driven Granulator and a Fluid bed Dryer. (Courtesy of Glatt.) vehicle for the drug. Direct-compression vehicles or carriers to have properties suitable for direct compression. It also may must have good flow and compressible characteristics. These contain small quantities of dextrin, starch, or invert sugar. It properties are imparted to them by a preprocessing step, such is a white crystalline powder with a sweet taste and complete as wet granulation, slugging, spray-drying, spheronization, or water solubility. It requires the incorporation of a suitable lu- crystallization. These vehicles include processed forms of most bricant at normal levels for lubricity. The sugar is used widely of the common diluents, including dicalcium phosphate dihy- for chewable vitamin tablets because of its natural sweetness. drate, tricalcium phosphate, calcium sulfate, anhydrous lac- One commercial source is Di-Pac (Amstar), prepared by the tose, spray-dried lactose, pregelatinized starch, compressible co crystallization of 97% sucrose and 3% dextrins. Some forms sugar, mannitol, and microcrystalline cellulose. These com- of lactose meet the requirements for a direct-compression ve- mercially available, direct compression vehicles may contain hicle. Hydrous lactose does not flow, and its use is limited to small quantities of other ingredients (e.g., starch) as processing tablet formulations prepared by the wet-granulation method. aids. Dicalcium phosphate dihydrate (Di-Tab, JRS), in its un- Both anhydrous lactose and spray-dried lactose have good flow- milled form, has good flow properties and compressibility. It is ability and compressibility and can be used in direct compres- a white, crystalline agglomerate insoluble in water and alcohol. sion, provided a suitable disintegrant and lubricant are present. The chemical is odorless, tasteless, and nonhygroscopic. Since Mannitol is a popular diluent for chewable tablets, due to its it has no inherent lubricating or disintegrating properties, other pleasant taste and mouth feel, resulting from its negative heat additives must be present to prepare a satisfactory formulation. of solution. In its granular form (lCI Americas), it has good flow Compressible sugar consists mainly of sucrose that is processed and compressible qualities. It has low moisture content and is not hygroscopic. The excipient that has been studied extensive- ly as a direct compression vehicle is microcrystalline cellulose (Avicel, FMC). This non-fibrous form of cellulose is obtained by spray-drying washed, acid-treated cellulose and is available in several grades, ranginge in average particle size from 20 to 250 um. It is water-insoluble, but the material has the ability to draw fluid into a tablet by capillary action; it swells on con- tact and, thus, acts as a disintegrating agent. The material flows well and has a degree of self-lubricating qualities, thus, requir- ing a lower level of lubricant than other excipients. Recently, FMC introduced Avicel DG, which occurs as a white, odorless powder, containing 75% of microcrystalline cellulose and 25% anhydrous dibasic calcium phosphate. The wet dispersion and spray-drying of microcrystalline cellulose and anhydrous diba- sic calcium phosphate results in an intimate physical combina- tion, which cannot be achieved by traditional dry blending. JRS PHRMA introduced PROSOLV, which is coprocessed silicified microcrystalline cellulose. JRS PHARMA also introduced to the pharmaceutical excipient market PROSOLV EASY TAB, which is composed of coprocessed microcrystalline cellulose, colloi- dal silicon dioxide, sodium starch Glycolate, and sodium stearyl fumarate, which is claimed to be the ideal direct compression complete excipient. Forced-flow feeders are mechanical de- vices, available from pharmaceutical equipment manufactur- ers, designed to deaerate light and bulky material. Mechani- cally, they maintain a steady flow of powder moving into the die cavities under moderate pressure. By increasing the density of the powder, higher uniformity in tablet weights is obtained (Fig. 30-20, 30-21). Recently, many companies have reversed their optimism for some direct-compression systems. Some for- mulations made by direct compression were not as ­forgiving as the older, wet-granulated products were. As raw material variations occurred, especially with the drug, many companies found themselves with poorly compactable formulations. Inter- Figure 30-19. Roller Compactor Granulator. (Courtesy of ­Fitzpatrick est in direct compression is also stimulating basic research on Co.) the flowability of powders with and without additives. 594 PHARMACEUTICAL DOSAGE FORMS: Manufacturing and Compounding Figure 30-21. Forced Flow Feeder. (Courtesay of Courtesy of Bosch Packaging Technology Ltd., Manesty.) The feed is sprayed into a current of warm filtered air. The air supplies the heat for evaporation and conveys the dried product to the collector; the air is then exhausted with the moisture. As the liquid droplets present a large surface area to the warm air, local heat and transfer coefficients are high. The spray-dried powder particles are homogeneous, approximately spherical in shape, nearly uniform in size, and frequently hollow. The latter characteristic results in low bulk density, with a rapid Figure 30-20. Forced Flow Feeder. (Courtesy of Fette.) rate of solution. Being uniform in size and spherical, the par- ticles possess good flowability. The design and operation of the spray-dryer can vary many characteristics of the final product, such as particle size and size distribution, bulk and particle densities, porosity, moisture content, flowability, and friability. Related Granulation Processes Among the spray-dried materials available for direct compres- Spheronization–Spheronization, a form of pelletization, refers sion formulas are lactose, mannitol, and flour. Another applica- to the formation of spherical particles from wet granulations. tion of the process in tableting is spray-drying the combination Since the particles are round, they have good flow properties of tablet additives as the diluent, disintegrant, and binder. The when dried. They can be formulated to contain sufficient binder spray-dried material is then blended with the active ingredi- to impart cohesiveness for tableting. Spheronization equipment, ent or drug, lubricated, and compressed directly into tablets. such as the Marumerizer (Luwa) and the CFGranulator (Vector), Since atomization of the feed results in a high surface area, the are commercially available for small-scale manufacture, on up moisture evaporates rapidly. The evaporation keeps the prod- to commercial sized equipment. A wet granulation containing uct cool and, as a result, the method is applicable for drying the drug substance, diluent (if required), and binder is passed, heat-sensitive materials. Among heat-sensitive pharmaceuti- first, through an extruding machine to form rod-shaped cylindri- cals successfully spray-dried are the amino acids; antibiotics, cal segments, ranging in diameter from 0.5 to 12 mm. The seg- such as aureomycin, bacitracin, penicillin, and streptomycin; ment diameter and the size of the final spherical particle depend ascorbic acid, cascara extracts, and liver extracts; pepsin and on the extruder screen size. After ­extrusion, the segments are similar enzymes; protein hydrolysates; and thiamin. Frequent- placed into the Marumerizer, where they are shaped into spheres ly, spray-drying is more economical than other processes, since by centrifugal and frictional forces on a rotating plate. The pel- it produces a dry powder directly from a liquid and eliminates lets are then dried by conventional methods, mixed with suitable other processing steps as crystallization, precipitation, filtering lubricants, and compressed into tablets or used as capsule- fill or drying, particle-size reduction, and particle classifying. By material. Microcrystalline cellulose has been shown to be an ef- the elimination of these steps, labor, equipment costs, space fective diluent and binder in granulations to be spheronized. The requirements and possible contamination of the product are re- advantages of the process include the production of granules, duced. Intrinsic factor concentrate obtained from hog mucosa regular in shape, size, and surface characteristics; low friability, was previously prepared by Lederle / American Home Products, resulting in fewer fines and less dust; and the ability to regulate using a salt-precipitation process, followed by freeze-drying. By the size of the spheres within a narrow particle-size distribution. using spray-drying, it was possible to manufacture a high-grade Spheres can also be produced by fluid-bed granulation tech- material by a continuous process. The spherical particles of the niques and other specialized equipment, such as the CFGranula- product facilitated its subsequent blending with vitamin B12. tor (Vector). These processes, however, must begin with crystals Similar efficiencies have been found in processes producing or nonpareil seeds followed by buildup. Exact results, such as magnesium trisilicate and dihydroxyaluminum sodium carbon- sphere density, are different for the various methods and could ate; both chemicals are used widely in antacid preparations. be important in product performance. These processes can be Encapsulation of chemicals can also be achieved using spray- run as batches or continuously. drying equipment. The process is useful in coating one material Spray-Drying–A number of tableting additives suitable for on another to protect the interior substance or to control the direct compression have been prepared by the drying process rate of its release. The substance to be coated can be either known as spray-drying. The method consists of bringing togeth- liquid or solid, but must be insoluble in a solution of the coating er a highly dispersed liquid and a sufficient volume of hot air material. The oil-soluble vitamins A and D can be coated with a to produce evaporation and drying of the liquid droplets. The variety of materials, such as acacia gum to prevent their dete- feed liquid may be a solution, slurry, emulsion, gel, or paste, rioration. Flavoring oils and synthetic flavors are coated to give provided it is pumpable and capable of being atomized. the so-called dry flavors.  Oral Solid Dosage Forms 595 Spray-Congealing–Also called spray-chilling, spray-congeal- ing is a technique similar to spray-drying. It consists of melting solids and reducing them to beads or powder, by spraying the molten feed into a stream of air or other gas. The same basic equipment is used as with spray-drying, although no source of heat is required. Either ambient or cooled air is used, depend- ing on the freezing point of the product. For example, mono- glycerides and similar materials are spray-congealed with air at 50°F. A closed-loop system with refrigeration cools and recycles the air. Using this process, drugs can be dissolved or suspended in a molten wax and spray-congealed; the resultant material can then be adapted for a prolonged-release form of the drug. Among the carbohydrates used in compressed tablets, manni- tol is the only one that possesses high heat stability. Mannitol melts at 167 and, either alone or in combination with other car- bohydrates, can be fused and spray-congealed. Selected drugs have been shown to be soluble in these fused mixtures, and the resultant spray-congealed material possesses excellent flow and compression characteristics. Tablet Machines As mentioned previously, the basic mechanical unit in tablet compression involves the operation of two steel punches within a steel die cavity. The tablet is formed by the pre