Tablet design and formulation a. Characteristics of ideal tablets

(1) Free of defects (e.g., chips, cracks, discoloration, contamination) (2) Strong enough to withstand the mechanical stresses of production (3) Chemically and physically stable over time

(4) Capable of releasing medicinal agents in a predictable and reproducible manner

b. Tablet excipients. Tablets are manufactured by wet granulation, dry granulation, or direct com-pression. Regardless of the method of manufacture, tablets for oral ingestion usually contain excip-ients, which are components added to the active ingredients that have special functions (Table 2-9).

(1) Diluents are fi llers designed to make up the required bulk of the tablet when the drug dosage amount is inadequate. Diluents may also improve cohesion, permit direct com-pression, or promote fl ow.

(a) Common diluents include kaolin, lactose, mannitol, starch, microcrystalline cellu-lose, powdered sugar, and calcium phosphate.

(b) Selection of the diluent is based on the experience of the manufacturer as well as on the cost of the diluent and its compatibility with the other tablet ingredients.

For example, calcium salts cannot be used as fi llers for tetracycline products because calcium interferes with the absorption of tetracycline from the gastrointestinal tract.

(2) Binders and adhesives are added in either dry or liquid form to promote granulation or to promote cohesive compacts during direct compression.

(a) Common binding agents include a 10% to 20% aqueous preparation of cornstarch, a 25% to 50% solution of glucose, molasses, various natural gums (e.g., acacia), cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, microcrystalline cellulose), gelatins, and povidone. Th e natural gums are variable in composition and are usually contaminated with bacteria.

(b) If the drug substance is adversely aff ected by an aqueous binder, a nonaqueous binder can be used or the binder can be added dry. Th e binding action is usually more eff ective when the binder is mixed in liquid form.

(c) Th e amount of binder or adhesive used depends on the experience of the manu-facturer as well as on the other tablet ingredients. Overwetting usually produces granules that are too hard to allow proper tableting. Underwetting usually produces tablets that are too soft and tend to crumble.

(3) Disintegrants are added to tablet formulations to facilitate disintegration when the tablet contacts water in the gastrointestinal tract. Disintegrants function by drawing water into the tablet, swelling, and causing the tablet to burst.

(a) Tablet disintegration may be critical to the subsequent dissolution of the drug and to satisfactory drug bioavailability. FD&C and D&C dyes and lakes

Flavors available in two forms (spray dried, oil) Artifi cial sweeteners

Natural sweetener

D&C, drugs and cosmetics; FD&C, food, drugs, and cosmetics; NF, National Formulary; PEG, polyethylene glycol; PVP, polyvinylpyrrolidone (more commonly, povidone); USP, United States Pharmacopeia.

Table 2-9 SOME COMMON TABLET EXCIPIENTS

54

(b) Common disintegrants include cornstarch and potato starch, starch derivatives (e.g., sodium starch glycolate), cellulose derivatives (e.g., sodium carboxymethyl-cellulose, croscarmellose sodium), clays (e.g., Veegum, bentonite), and cation ex-change resins.

(c) Th e total amount of disintegrant is not always added to the drug–diluent mixture.

A portion can be added, with the lubricant, to the prepared granulation of the drug.

Th is approach causes double disintegration of the tablet. Th e portion of disintegrant that is added last causes the tablet to break into small pieces or chunks. Th e portion that is added fi rst breaks the pieces of tablet into fi ne particles.

(4) Lubricants, antiadherents, and glidants have overlapping function.

(a) Lubricants reduce the friction that occurs between the walls of the tablet and the walls of the die cavity when the tablet is ejected. Talc, magnesium stearate, and cal-cium stearate are commonly used.

(b) Antiadherents reduce sticking, or adhesion, of the tablet granulation or powder to the faces of the punches or the die walls.

(c) Glidants promote the fl ow of the tablet granulation or powder by reducing friction among particles.

(5) Colors and dyes disguise off -color drugs, provide product identifi cation, and produce a more aesthetically appealing product. Food, drug, and cosmetic dyes are applied as solu-tions. Lakes are dyes that have been absorbed on a hydrous oxide. Lakes are typically used as dry powders.

(6) Flavoring agents are usually limited to chewable tablets or tablets that are intended to dissolve in the mouth.

(a) Water-soluble fl avors usually have poor stability. For this reason, fl avor oils or dry powders are typically used.

(b) Flavor oils may be added to tablet granulations in solvents, dispersed on clays and other adsorbents, or emulsifi ed in aqueous granulating agents. Usually, the maxi-mum amount of oil that can be added to a granulation without aff ecting its tablet characteristics is 0.5% to 0.75%.

(7) Artifi cial sweeteners, like fl avors, are typically used only with chewable tablets or tablets that are intended to dissolve in the mouth.

(a) Some sweetness may come from the diluent (e.g., mannitol, lactose). Other agents (e.g., saccharin, aspartame) may also be added.

(b) Saccharin has an unpleasant aft ertaste.

(c) Aspartame is not stable in the presence of moisture and heat.

(8) Adsorbents (e.g., magnesium oxide, magnesium carbonate, bentonite, silicon dioxide) hold quantities of fl uid in an apparently dry state.

3. Tablet types and classes. Tablets are classifi ed according to their route of administration, drug delivery system, and form and method of manufacture (Table 2-10).

a. Tablets for oral ingestion are designed to be swallowed intact, with the exception of chewable tablets. Tablets may be coated for a number of reasons: to mask the taste, color, or odor of the drug; to control drug release; to protect the drug from the acid environment of the stomach;

to incorporate another drug and provide sequential release or avoid incompatibility; or to improve appearance.

(1) Compressed tablets are formed by compression and have no special coating. Th ey are made from powdered, crystalline, or granular materials, alone or in combination with excipients such as binders, disintegrants, diluents, and colorants.

(2) Multiple compressed tablets are layered or compression coated.

(a) Layered tablets are prepared by compressing a tablet granulation around a pre-viously compressed granulation. Th e operation is repeated to produce multiple layers.

(b) Compression-coated, or dry-coated, tablets are prepared by feeding previously compressed tablets into a special tableting machine. Th is machine compresses an outer shell around the tablets. Th is process applies a thinner, more uniform coating than sugar coating, and it can be used safely with drugs that are sensitive to moisture.

Th is process can be used to separate incompatible materials, to produce repeat-action or prolonged-action products, or to produce tablets with a multilayered appearance.

(3) Repeat-action tablets are layered or compression-coated tablets in which the outer layer or shell rapidly disintegrates in the stomach (e.g., Repetabs, Schering, Extentabs, Wyeth).

Th e components of the inner layer or inner tablet are insoluble in gastric media but solu-ble in intestinal media.

(4) Delayed-action and enteric-coated tablets delay the release of a drug from a dosage form. Th is delay is intended to prevent destruction of the drug by gastric juices, to prevent irritation of the stomach lining by the drug, or to promote absorption, which is better in the intestine than in the stomach.

(a) Enteric-coated tablets are coated and remain intact in the stomach, but yield their ingredients in the intestines (e.g., Ecotrin, GlaxoSmithKline). Enteric-coated tablets are a form of delayed-action tablet. However, not all delayed-action tablets are en-teric or are intended to produce an enen-teric eff ect.

(b) Agents used to coat these tablets include fats, fatty acids, waxes, shellac, and cellulose acetate phthalate.

(5) Sugar-coated and chocolate-coated tablets are compressed tablets that are coated for various reasons. Th e coating may be added to protect the drug from air and humidity, to provide a barrier to a drug’s objectionable taste or smell, or to improve the appearance of the tablet.

(a) Tablets may be coated with a colored or an uncolored sugar. Th e process includes seal coating (waterproofi ng), subcoating, syrup coating (for smoothing and coloring), and polishing. Th ese steps take place in a series of mechanically operated coating pans.

(b) Disadvantages of sugar-coated tablets include the time and expertise required for the process and the increase in tablet size and weight. Sugar-coated tablets may be 50% larger and heavier than the original tablets.

(c) Chocolate-coated tablets are rare today.

(6) Film-coated tablets are compressed tablets that are coated with a thin layer of a water-insoluble or water-soluble polymer (e.g., hydroxypropyl methylcellulose [hypromellose], ethylcellulose, povidone, PEG).

(a) Th e fi lm is usually colored. It is more durable, less bulky, and less time consuming to apply than sugar coating. Although the fi lm typically increases tablet weight by only 2% to 3%, it increases formulation effi ciency, resistance to chipping, and output.

(b) Film-coating solutions usually contain a fi lm former, an alloying substance, a plas-ticizer, a surfactant, opacifi ers, sweeteners, fl avors, colors, glossants, and a volatile solvent.

(c) Th e volatile solvents used in these solutions are expensive and potentially toxic when released into the atmosphere. Specifi cally formulated aqueous dispersions of Tablets for oral ingestion

Compressed Multiple compressed Layered

Compression coated Repeat-action

Delayed action and enteric coated Sugar coated and chocolate coated Film coated

Air suspension coated Chewable

Tablets used in the oral cavity Buccal

Sublingual

Troches, lozenges, and dental cones

Tablets used to prove solutions Effervescent

Dispensing Hypodermic Triturates

Table 2-10 TABLET TYPES AND CLASSES

56

polymers (e.g., ethylcellulose) are now available as alternatives to organic solvent-based coating solutions.

(7) Air suspension–coated tablets are fed into a vertical cylinder and supported by a column of air that enters from the bottom of the cylinder. As the coating solution enters the sys-tem, it is rapidly applied to the suspended, rotating solids (Wurster process). Rounding coats can be applied in  1 hr when blasts of warm air are released in the chamber.

(8) Chewable tablets disintegrate smoothly and rapidly when chewed or allowed to dissolve in the mouth. Th ese tablets contain specially colored and fl avored mannitol and yield a creamy base.

(a) Chewable tablets are especially useful in formulations for children.

(b) Th ey are commonly used for multivitamin tablets and are used for some antacids and antibiotics.

b. Tablets used in the oral cavity are allowed to dissolve in the mouth.

(1) Buccal and sublingual tablets allow absorption through the oral mucosa aft er they dis-solve in the buccal pouch (buccal tablets) or below the tongue (sublingual tablets). Th ese forms are useful for drugs that are destroyed by gastric juice or poorly absorbed from the intestinal tract. Examples include sublingual nitroglycerin tablets, which dissolve prompt-ly to give rapid drug eff ects, and buccal progesterone tablets, which dissolve slowprompt-ly.

(2) Troches, lozenges, and dental cones dissolve slowly in the mouth and provide primarily local eff ects.

c. Tablets used to prepare solutions are dissolved in water before administration.

(1) Eff ervescent tablets are prepared by compressing granular eff ervescent salts or other ma-terials (e.g., citric acid, tartaric acid, sodium bicarbonate) that release carbon dioxide gas when they come into contact with water. Commercial alkalinizing analgesic tablets are oft en made to eff ervesce to encourage rapid dissolution and absorption (e.g., Alka-Seltzer, Bayer).

(2) Other tablets used to prepare solutions include dispensing tablets, hypodermic tablets, and tablet triturates.