Upon completion of this exercise, you should be able to:
- Describe the advantages and limitations of tablets as dosage forms.
- Describe the official USP tests required of tablets.
- Describe three methods of tablet preparation.
- Evaluate tablets as a unit dosage form by performing and analyzing data from official USP tests.
Without question, the compressed tablet is one of the most popular dosage forms today. About one-half of all prescriptions dispensed are for tablets. Usually one considers a compressed tablet as an oral medication; however, tablets have many other uses. The sublingual tablet, the pellet, the wafer, the troche, and the vaginal insert are manufactured by the same procedure as an oral tablet.
There are three methods of commercially making compressed tablets:
- The direct compression method
A compressible vehicle is blended with the medicinal agent, and if necessary, with a lubricant and a disintegrant, and then the blend is compressed. Substances that are commonly used as directly compressible vehicles are: anhydrous lactose, dicalcium phosphate (Emcompress), granulated mannitol, microcrystalline cellulose (Avicel), compressible sugar (Di-Pac), starch (Sta-Rx 1500), hydrolyzed starch (Celutab), and a blend of sugar, invert sugar, starch and magnesium stearate (Nutab).
- The dry granulation method (slugging method)
The ingredients in the formulation are intimately mixed and precompressed on heavy duty tablet machines. The slug which is formed is ground to a uniform size and compressed into the finished tablet.
- The wet granulation method
This method has more operational manipulations, and is more time-consuming than the other methods. The wet granulation method is not suitable for drugs which are thermolabile or hydrolyzable by the presence of water in the liquid binder. The general steps involved in a wet granulation process are:
- The powdered ingredients are weighed and mixed intimately by geometric dilution.
- The granulating solution or binder is prepared.
- The powders and the granulation solution are kneaded to proper consistency.
- The wet mass is forced through a screen or wet granulator.
- The granules are dried in an oven or a fluidized bed dryer.
- The dried granules are screened to a suitable size for compression.
- A lubricant and a disintegrating agent are mixed with the granulation.
- The granulation is compressed into the finished tablet.
The only limitation of commercially manufactured tablets is that they are available only in fixed dosage strengths and combinations. To provide the flexibility of compounded formulations, pharmacists can extemporaneously prepare molded and compressed tablets for their patients. Molded tablets are compounded using a tablet triturate mold. Compressed tablets can be made using a pellet press or a single-punch tableting machine.
One of the advantages of molded tablets is that they quickly disintegrate in the presence of moisture. And since the tablets are actually compressed powder mixtures, the pharmacist can easily adjust the composition for any number of dosages. Their chief disadvantage is their small size which will limit their use to substances effective in small doses.
Molded tablets are generally prepared by mixing the active drug with lactose, dextrose, sucrose, mannitol, or some other appropriate diluent that can serve as the base. This base must be readily water soluble and should not degrade during the tablet’s preparation. Lactose is the preferred base but mannitol adds a pleasant, cooling sensation and additional sweetness in the mouth.
The base ordinarily used for molded tablet triturates is lactose containing 10% – 20% sucrose, the latter being added to make a firmer tablet. Drugs that react chemically with sugars require special bases such as precipitate calcium carbonate, precipitated calcium phosphate, kaolin, or bentonite. A liquid is added to moisten the powder mixture so it will adhere while being pressed into the mold cavities. Mixtures of alcohol and water in varying proportions (typically about 50 – 80% alcohol) are employed; the alcohol will speed up the drying of the liquid and the water will cause the sugars to dissolve and bind the tablet. If the tablet contains ingredients that are very soluble in water, water can be omitted altogether and alcohol alone can be used.
Tablet triturate molds are made of metal. There are two plates, the cavity plate is the plate that has only holes and the peg plate that has pegs. The mold will indicate the capacity of one cavity in the cavity plate but that indication is only an approximation. Typical die plate cavity sizes are 60 mg and 100 mg.
The volume of the cavities always remains constant, but the weight of the tablet made will depend nature of the material. Different bases will have different densities and so the cavity capacity must be determined for each base, e.g., the mold must be calibrated. (This is the same reason why all molds must be calibrated for each base.)
Calibration of the mold:
- Tablets that contain only the powder base are made first. The tablets produced are weighed as a batch and the average weight per tablet for that base is calculated.
- The average weight per tablet of the active drug is determined. Generally, just a few cavities are used in this determination. Tablets containing only the active drug are made and the average weight per tablet for the drug is calculated.
- The quantity of drug that will be required in the prescription per tablet is divided by the average weight per tablet of the active drug. This will give a percentage of the cavity volume that will be occupied by the active drug
- Subtracting the percentage in step 3 from 100% will give the percentage of the cavity volume that will be occupied by the tablet base.
- The percentage of active drug in the cavity volume and the percentage of base in the cavity volume are used to calculate the appropriate amounts of base and drug to weigh. For example, if the mold contains 50 cavities and each will hold approximately 100 mg, then 5000 mg of mixture will be needed to fill the mold. The amount of base and drug to weigh can be determined by multiplying 5000 mg by the two different percentages determined in the preceding steps.
- It is prudent to prepare a slight excess of powder mixture (5 – 10%). This will allow for any variance in the approximate and actual capacity of the mold, and will also allow for powder loss during the compounding procedure.
To compound the molded tablets, prepare the powder mixture by proper techniques and sift the mixture through a 80-100 mesh sieve. Then moisten the powder mixture until the mass has the consistency of “Play Dough.” Press the mass into the cavities of the cavity plate. Have the plate on an ointment tile or glass plate. A hard rubber spatula should be used to press the material into the cavities; stainless steel spatulas will scratch the surface of the metal plate. Sufficient pressure should be applied to tightly pack each cavity with base.
It is important to insure that all cavities are equally filled especially the marginal cavities. Both sides of the cavity plate should be inspected to make sure that all of the space in each cavity is filled. When the cavity plate is loaded, the plate is placed on the peg plate so that the pegs are aligned with the holes. The cavity plate is then carefully pressed onto the peg plate. As the cavity plate falls, the tablets are pushed out of the cavity plate onto the tops of the pegs. The tablets are left on the pegs until they dry.
Single Punch Tablet Machines
Tableting machines are commonly used in pharmaceutical industry. They are high-speed machines that create thousands of tablets in a small period. The compounding pharmacist uses a variation of these machines. It is called a single-punch tablet press and makes one tablet at a time. A “punch” has two pieces of casted tubular metal. The bottom metal piece has a small cavity in one end of the tube; the top metal piece has one end that is tapered into a small rod that will just fit into the small cavity in the other piece. The rod does not go all the way to the bottom of the cavity, but leaves a small gap. The punch is fitted into a press so that when the handle is depressed and released, the rod goes into and then comes out of the bottom piece. To make a tablet, the powder material is placed into the bottom piece, and the handle is depressed and released. The powders are compressed and occupy the size of the gap designed in the punch.
Punches come in many sizes which allows the production of tablets of different sizes and compression strengths. But each punch is a matched set; it is not possible to interchange the top and bottom pieces of different punches.
Chewable tablets, effervescent tablets, and compressed tablets can be made using a tablet press. Chewable tablets are generally made using mannitol because it has a sweet, cooling taste and is easy to manipulate. Other ingredients may include binders (e.g., acacia), lubricants (e.g., stearic acid), colors, and flavors. The powder mixture is prepared, the desired quantity of mixture is weighed, and then pressed with a single-punch tablet machine.
Effervescent tablets generally contain ingredients such as tartaric acid, citric acid, and sodium bicarbonate. These powders would be appropriately mixed and pressed into tablets using the same procedure as chewable tablets. They will not require a disintegrant since they will effervesce when placed in water. Compressed tablet mixtures generally contain the active drug, a diluent (e.g., lactose), a disintegrant (e.g., starch), and a lubricant (e.g., 1% magnesium stearate).
Tablets are evaluated by a variety of methods.
- Analytical determination of tablet content: This probably will not be done due to the requirement of specialized equipment. However, the weight variation of the tablets can be measured by weighing each individual tablets and determining the percent difference from the intended amount. Guidelines in the USP 24/NF19 Supplement 1 indicate that each tablet “shall be not less than 90% and not more than 110% of the theoretically calculated weight for each unit.”
- Tablet hardness: The tablets must be hard enough to withstand mechanical stress during packaging, shipment, and handling by the consumer. Section <1216> of the USP 24/NF19 outlines a standard tablet friability test applicable to manufactured tablets. Most compounding pharmacies would not have the apparatus specified in Section <1216>. However, there are several hand operated tablet hardness testers that might be useful. Examples of devices are the Strong Cobb, Pfizer, and Stokes hardness testers. The principle of measurement involves subjecting the tablet to an increasing load until the tablet breaks or fractures. The load is applied along the radial axis of the tablet. Oral tablets normally have a hardness of 4 to 8 or 10 kg; however, hypodermic and chewable tablets are much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).
- Tablet disintegration: There are commercially available disintegration and dissolution apparatus. Most pharmacists will not have this equipment. However, a simple disintegration apparatus can be made. Start by supporting a 10 mesh screen about 2 inches above the bottom of a 1000 ml beaker. Fill the beaker with 1000 ml of water, add a stirring bar, and place the beaker on a magnetic stirring plate. Stir at a moderate speed. Drop the tablets onto the mesh screen and record the time needed for the tablets to disintegrate. A reasonable disintegration time should be between 15 and 30 minutes, although the time will depend on the product, the stirring speed, etc.
- Tablet dissolution: Disintegration time determination is a useful tool for production control, but disintegration of a tablet does not imply that the drug has dissolved. A tablet can have a rapid disintegration time yet be biologically unavailable. The dissolution rate of the drug from the primary particles of the tablet is the important factor in drug absorption and for many formulations is the rate-limiting step. Therefore, a dissolution time is more indicative of the availability of a drug from a tablet than the disintegration test. Even though this is an important parameter to measure, most pharmacies do not have the equipment needed to conduct these kinds of tests.