TABLETS
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet’s appearance.
The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions. Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called “caplets”. Other products are manufactured in the form of tablets which are designed to dissolve or disintegrate; e.g. cleaning and deodorizing products.
Medicinal tablets and capsules are often called “pills”, though originally, “pill” referred specifically to a soft mass rolled into a ball shape, rather than a compressed powder.
Tabletting formulations
In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet.
Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).
Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.
Advantages and disadvantages
Variations on a common tablet design, which can be distinguished by both color and shape
Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties, for example, sustained release or fast dissolving formulations.
Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the “first pass effect”), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosae, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example salbutamol, used to treat problems in the pulmonary system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action. A proportion of the population have difficulties swallowing tablets either because they just don’t like taking them or because their medical condition makes it difficult for them (dysphagia, vomiting). In such instances it may be better to consider alternative dosage form or administration route.[1]
Tablet properties
Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.
Tablet diameter and shape are determined by the machine tooling used to produce them – a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don’t break up in the bottle, yet friable enough that they disintegrate in the gastric tract.
Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (i) simple failure and erosion tests, and (ii) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.). The hardness of tablets is the principle measure of mechanical strength. Hardness is tested using a tablet hardness tester. The units for hardness have evolved since the 1930s, but are commonly measured in kilograms per square centimeter. Models of tester include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.
Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die.
Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules.[
Manufacturing
Manufacture of the tableting blend
In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.
Wet granulation
Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.
- Procedure
- The active ingredient and excipients are weighed and mixed.
- The wet granulate is prepared by adding the liquid binder–adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone.
- Screening the damp mass through a mesh to form pellets or granules.
- Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.
- After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.
Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.
Dry granulation[
Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a ‘dry binder’ may need to be added to the formulation to facilitate the formation of granules.
Granule lubrication
After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate or stearic acid.
Manufacture of the tablets
Tablets that failed due to capping and lamination compared to a normal tablet
Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500–50 ms per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is repeated for each tablet.
Common problems encountered during tablet manufacturing operations include:
- Fluctuations in tablet weight, usually caused by uneven powder flow into the die due to poor powder flow properties.
- Fluctuations in dosage of the Active Pharmaceutical Ingredient, caused by uneven distribution of the API in the tableting blend (either due to poor mixing or separation in process.
- Sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, or a sticky powder formulation
- Capping, lamination or chipping. This is caused by air being compressed with the tablet formulation and then expanding when the punch is released: if this breaks the tablet apart, it can be due to incorrect machine settings, or due to incorrect formulation: either because the tablet formulation is too brittle or not adhesive enough, or because the powder being fed to the tablet press contains too much air (has too low bulk density).
- Capping can also occur due to high moisture content.
Tablet compaction simulator
Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.
Tablet presses
The tablet pressing operation (click image to enlarge)
An old Cadmach rotary tablet press
Tablet presses, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Common manufacturers of tablet presses include Stokes, Fette Compacting, Korsch, Kikusui, Manesty, B&D, IMA and Courtoy. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density can each be controlled. This is achieved using a series of cams, rollers, and/or tracks that act on the tablet tooling (punches). Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression. Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products. There are 2 main standards of tablet tooling used in pharmaceutical industry: American standard ‘TSM’ and European standard ‘EU’. TSM and EU configurations are similar to each other but cannot be interchanged.[2]
Tablet coating
Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings are polymer and polysaccharide based, with plasticizers and pigments included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition.
If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an enteric coating can be used, which is resistant tostomach acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the small intestine, where they are absorbed. Coatings are often chosen to control the rate of dissolution of the drug in the gastrointestinal tract. Some drugs will be absorbed better at different points in the digestive system. If the highest percentage of absorption of a drug takes place in the stomach, a coating that dissolves quickly and easily in acid will be selected. If the rate of absorption is best in the large intestine or colon, then a coating that is acid resistant and dissolves slowly would be used to ensure it reached that point before dispersing.
There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters.[3] Coating pans are used mostly for sugar coating of pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with remote control panel, dehumidifier, dust collectors. The explosion-proof design is required for alcohol containing coatings.
Pill-splitters
It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill-splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this will expose the tablet core to the digestive juices, circumventing the intended delayed-release effect.
References
- Kibbe, A.H., ed. Handbook of Pharmaceutical Excipients. 3rd Edition ed. 2000, American Pharmaceutical Association & Pharmaceutical Press: Washington, DC & London, UK.
- Hiestand, E.N., 2003. Mechanics and physical principles for powders and compacts, SSCI Inc., West Lafayette, In, USA.
- United States Pharmacopeia, United States Pharmacopeia / National Formulary (USP25/NF20). 2002, Rockville, MD: United States Pharmacopeia Convention Inc.
ADDITIONAL INFO FOR READERS
According to IP “tablets are solid dosage forms each containing a unit dose of one or more ingredients”.(1) 90%of the drugs thar are administered to produce systemic effect are through oral dosage forms. The advantage of the tablets and the capsules over liquid dosage forms includes elixirs, syrups,solutions is that the exact dose of the drug can be given to the patient.(2) William Brockedon got the first patent for tablet press and showed a route for the future development.(3)The main aim in using a tablet is to provide required amount and to dispense a unit dose of drug to patient. By the time it reaches the target action organ, the drug should not change chemically.(2) And the amount of active ingredient varies a lot. E.g. L-thyroxine has 25ug of active ingredient whereas amoxicillin has about 1g of active ingredient. The weight of the active ingredient ranges from 0.1 to 90% of the total weight of the drug.(3) Tablets should be both physically and chemically stable. They should have capability to withstand the stress during packaging and transport. Physical stability is more important as its effects the bioavailability of the tablet. In the tablet the drug should not undergo any chemical change and the effect of dug on the body must be an expected one.(2) And the drugs have different physical and chemical properties like water solubility, crystalline nature etc
.(3) INGREDIENTS: Diluents: whenever the dose of the drug is less then in order to increase the bulk of the tablet, diluents are used. The diluents also increase the flow properties, the cohesive forces. E.g. lactose USP, Dibasic calcium phosphate, mannitol (used in chewable tablets) Using Calcium phosphate to increase the bulk of the drug tetracycline decreases the bioavailabilty.(2) Binders: These are used in the wet granulation process to give compactness to the powder. It can be added in two ways whch will be described later.(2) e.g. acacia, tragacanth, gelatin Gelatin is better than the former two as making of gelatin solution is easy.(2) Disintegrants: These are the substances that absorb the water in the body, swell and cause the breakup of the particles into individual particles.(2) e.g. Veegum HV and bentonite Matrix forming agents: These are agents that are intended to raise the compactness. If the materials are elastic, when ever the forces are removed reduces the compactness and these agents are intended to prevent this. (3) e.g. Methyl cellulose, mannitol, gelatine Agents used to reduce friction include -Lubricant which will decrese the friction between walls of tablet and die cavity. -Glidant are added to increase the flow properties e.g. talc -Antiadherants which will increase the friction between the punch face and tablet i.e. they reduce the friction during the compression. .(2) Coloring agents, flavoring agents and sweetening agents are used to improve organoleptic properties of a tablet. Coprocessed excipient products: diluents+binders (They may also contain disintegrating agent)(3) CLASSIFICATION Basic classification includes 1) Tablets ingested orally 2) Tablets used in the oral cavity 3) Tablets administered by other routes A) Tablets ingested orally a) Standard compressedtablets: These tablets are prepared by either direct compression or wet granulation or double compaction. The disintegration should be fast in case of these tablets. Antacids and adsorbent which produce local effects comes into this category. Tablets intended for the systemic circulation are soluble in water to some extent and are absorbed into the body. And dissolution is directly proportional to surface area.(2) b) Multiple compressed tablets: these are of two types 1) Layered tablets: they may be two or three laters 2) Compression coated tablets: they may tablets within a tablet(two component) or tablet within a tablet within a tablet (three component) In two layered tablets, the two layers are separated and so the contents that can interact whereas in case of three layered system, a physical barrier is present between the two layers. In case of compression coated tablets the layer present in the outer side disintegrated in the stomach and the inner layer is made to disintegrate in the intestine region. (2) c) Repeat action tablets: compression coated tablets will also come into this category. Other method is use of sugar coated tablet. Here the tablet part containing the drug is covered with shellac and then the drug is added to the sugar solution and coated on the outer layer. Drug if present as solution or suspension in the sugar solution results in the formation of uniform outer dose. (2) d) Delayed action tablets: As the name specifies there will be some late in the action of the drug present in the tablet. (2) e.g. Enteric coated tablet. In this case, the tablets remain in contact with the stomach, but the drug release occurs in the intestine. Materials of enteric coating polyvinyl acetate and phthalate & hydroxyl propyl methyl cellulose and phthalate. The materials generally consists ester group. This prevents the drug to get solubilized in stomach. They will pass to small intestine where these agents disintegrate at alkaline conditions. Advantages: -To prevent irritation -To safe guard the drug harmful acidic stomach environment -To release the drug more at the intestine region(2) e) Sugar coated tablets: The patience will feel comfortable while taking the tablet and also acts as a barrier between the core and other ingredients. it is used excessively in the preparation of multivitamin and multimineral tablets.
(2) f) Film-coated tablets: The drug is not essential in this coating and this process completes within less time. The film consists of plasticizer(acts as polymer) and surfactant(which enhances the spreading) Adv: there will be a slight raise in weight of the tablet. Sugar is avoided which is not suitable for some patients. Film coated Tablets are stronger than sugar coated tablet (2) g) Chewable tablets: These tablets should be chewed in the mouth. This has an advantage that children and old people as they feel tough to swallow the whole tablet. They will give unit dosage. This is mainly used in antacid preparations, which are very bulky and so its tough to swallow. (2) B) Tablets used in the oral cavity: a) Buccal and sublingual tablets: Buccal tablets will be placed in between cheeks and teeth whereas sublingual tablets will be placed below the tongue. In these the drug will be absorbed directly from oral mucosa and then into blood circulation and gives systemic effect. This helps the drug to escape the first pass metabolism. (2) b) Troches and lozens: Lozens are prepared by compression or fusion or candy molding process whereas Lozens are prepared by compression. Both will produce local effect in mouth and throat. These tablets should not break in the mouth but they should get dissolved slowly. (2) c) Dental cones: These are placed wherever there is empty socket in the mouth. They usually contain a coagulant (prevents bleeding) or antibacterial agent. Sodium chloride and sodium bicarbonate re the common vehicles used. (2) C) Tablets administered by other route a) Implantation tablets: These tablets will be placed below the skin. Limitation includes the need of surgery to remove the tablet and these type of tablets causes tissue irritation. (2) b) Vaginal tablets: These will be inserted in the vagina. Dissolution in slow and hence the drug release. They are mainly intended to release steroids or may contain antibacterial agent. (2) D) Tablets administered by other route: a) Effervescent tablets: they release carbon dioxide gas when they are dissolved in water. They contain: drug + acid (citric acid/tartaric acid) + sodium bicarbonate When they are dissolved in water, carbon dioxide will be released due to reaction between acid and sodium bicarbonate. (2) b) Hypodermic tablets: these tablets are readily dissolved in sterile water and can be used for IV purpose. (2) MANUFACTURE: There are three well known methods for the preparation of granules. I) Direct compression method: It is useful for the moderate dosage drugs. The diluents used should be inert. It should be compressed easily and it should loose this quality when drug and other excepients are added. Some of the materials for which this method is used are KCl, NaCl, NaBr But this is not used for most of the drugs because, the drug do not attain attraction forces on compression or the molecules will be covered by a layer of air Advantages: Very less number of steps are involved Disadvantages: -The variations in particle size and density when compared to diluents leads to the formation of layers. This is problematic especially in case of low potet drugs. Most of the large dosage form drugs are need large quantities of binder which increase both bulk and cost of the tablet. -Drug may react with diluents in some cases. e.g. Amine drugs with spray dried lactose(2) II) Compression granulation: In compression granulation the powder is compressed in dies having large capacity. This will form ‘slug’ and the process s known as slugging. Then these masses are passed through the screen and again compressed to form tablets. This greatly increases the strength of bonds between the particle within a tablet. Advantages: -There is no wetting and drying -Less space and equipment is enough E.g. Aspirin tablets. (2) III) Wet granulation: here binders in the formof solution or suspension are added. It is of two methods. (2) Method 1: When only small amount of solvent is allowed in formulation, then powder +binder+solvent Method 2: If large amount of solvent is allowed, then powder +binder solution and then mixing is performed. After mixing, wet screening should be done. In this process, the powder mass is passed into the hammer mill and then through the large perforated screens. This increases the surface area of the powdered mass and so the rate of drying increases. In the drying process, the damp mass is dried in order to remove excess solvent. Now screening is performed and then finally compressed(2) Advantages of tablets: (2) -Through tablets, the exact dose of the drug can be administered to the patient. -Transportation is cheap and easy -Microbial contamination chances will be less -Large scale production can be easily achieved.
1) Indian Pharmacopoeia, volume2, Published by controller of Publications, page no.735
2) The theory and practice of Industrial Pharmacy by Leon Lachman, Herbert A. Liberman, Joseph L. Kaing, and Joseph L. Kaing, Third edition, Varghese Publishing House, page no. 293 to 336 3) Modern Pharmaceutics basic principles and systems, edited by Florence and Siepmann, volume 1, informa healthcare publishers, page no 481 to 487 “This blog does not contain any plagiarized material”
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NEW SET
1.1 Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form?
1.2 What is a tablet?
1.3 Advantages and disadvantages of tablet as a dosage form
1.1 Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form? (1-5)
Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug excipients mixture is as important as API itself.
Patient acceptability can be improved by controlling the organoleptic properties. Dosage form provides desired therapeutic level of a drug.
1.2 What is a pharmaceutical tablet? (1-5)
It is a solid dosage form each containing a unit dose of one or more medicament/s. Tablets are solid, flat or biconvex discs prepared by compressing a drug or a mixture of drugs with or without suitable excipients.
Tablets may be swallowed whole or being chewed. Some are dissolved or dispersed in water before administration. Some are put in oral cavity, where the active ingredient is liberated at a predetermined rate. Implants or passeries may also be presented in form of tablet.
Tablet may vary in shape and differ greatly in size and weight depending on the amount of medicinal substance and the intended mode of administration.
1.3 Advantages and disadvantages of tablet as a dosage form. (1-5)
The advantages are listed below:
I.Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved.
II.Accuracy of dose is maintained since tablet is a solid unit dosage form.
III. Tailor made release profile can be achieved.
IV. Longer expiry period and minimum microbial spillage owing to lower moisture content.
V. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department.
VI. Ease of packaging (blister or strip) and easy handling over liquid dosage form.
VII. Easy to transport in bulk. Emergency supply supplies can be carried by patients.
VIII.Organoleptic properties (taste, appearance and odour) are best improved by coating of tablet.
IX. Product identification is easy and markings done with the help of grooved punches and printing with edible ink.
X. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc.
XI. In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible.
XII. In comparison to capsules, tablets are more tamperproof.
The disadvantages are listed below:
I.It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use.
II.Difficult to formulate a drug with poor wettability, slow dissolution into a tablet.
III. Slow onset of action as compared to parenterals, liquid orals and capsules.
IV. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less.
V. Difficult to swallow for kids, terminally ill and geriatric patients.
VI. Patients undergoing radiotherapy cannot swallow tablet.
Key Phrases
O Reasons to go for dosage form
i) To control organoleptic properties
ii) Achieve desired therapeutic level of drug
O The most widely used dosage form is tablet
O Advantages
i) Accurate dose
ii) Tailor made release profiles
iii) Longer expiry period
iv) Stringent environmental condition is NOT required
v) Easy handling
O Disadvantages
i) Slow onset of action
ii) Large amount of liquid cannot be incorporated
iii) Difficulty in swallowing especially for geriatric and pediatric patients
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Lozenges, Troches, Sublingual Tablets, Buccal tablets, and Mouth Dissolved Tablets
1.4.2 Tablets used in the oral cavity (1-3)
The tablets under this group are aimed release API in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity.
1.4.2.1 Lozenges and troches
The tablet is a flat faced at least about 18mm in diameter and meant to suck and dissolves in the mouth. The compressed tablet is called troches and the tablets produced by fusion or candy molding process are called lozenges. Flavours and sweeteners are added to make tablets palatable. The tablet generally contains sucrose or lactose and gelatin solution to impart smooth taste. Lozenges for local action in mouth/ throat are: antiseptics, antibiotics, demulcents, antitussive agents or astringents. To produce systemic action: multivitamin tablet.
1.4.2.2 Sublingual tablets
They are to be placed under the tongue and produce immediate systemic effect by enabling the drug absorbed directly through mucosal lining of the mouth beneath the tongue.
Figure.11. Sublingual Tablets
The drug absorbed from stomach goes to mesenteric circulation which connects to stomach via portal vein. Thus, absorption through oral cavity avoids first-pass metabolism. The tablets are usually small and flat, compressed lightly to keep them soft. The tablet must dissolve quickly allowing the API to be absorbed quickly. It’s designed to dissolve in small quantity of saliva. After the tablet is placed in the mouth below the tongue, the patient should avoid eating, drinking, smoking and possibly talking in order to keep the tablet in place. Swallowing of saliva should also be avoided since the saliva may contain dissolved drug. Bland excipients are used to avoid salivary stimulation. Due to inconvenience in administration, this dosage form is prepared only for those API(s) for which the only satisfactory nonparenteral method is this route. For example, Glyceryl trinitrate (vasodilator) and Isoprinosine sulphate (bronchodilator).
1.4.2.3 Buccal tablets
Completeness of drug absorption is desired but fast drug absorption is not intended. The tablets are designed not to disintegrate. They are flat elliptical or capsule shaped tablets as it can be easily held between gum and cheek. It’s placed near the opening of parotid duct to provide the medium to dissolve the tablet.
Figure.12. Buccal Tablets
Since this tablet is to be kept for 30-60 minutes in oral cavity, care should be taken to see that all the ingredients are finely divided to avoid gritty or irritating sensation. This tablet is most often used when replacement hormonal therapy is to be administered. Antifungal drugs are preferred to be administered by this route. e.g., Miconazole – under preclinical trial – still not in market.
1.4.2.4 Dental cones
These tables are designed to be loosely packed in the empty socket remaining following a tooth extraction.
Figure.13. Dental Cones
Main purpose behind the use of this tablet is either to prevent multiplication of bacteria in the socket by employing a slow releasing antibacterial compound or to reduce bleeding by an astringent or coagulant containing tablet. It’s formulated to dissolve or erode slowly in presence of a small volume of serum or fluid over 20-40 minutes period.
1.4.2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets (10)
Known to the FDA as orally disintegrating tablets, they are also called mouth-dissolving, fast-dissolving, rapid-melt, porous, orodispersible, quick dissolving. These kinds of tablets are preferred when fast action or relief is desired. Most commonly used drugs under this formulation are the agents active against Migraine. The tablets are designed to disintegrate as well as dissolve within one minute or some within 10 seconds of oral administration in limited quantity of saliva. They liquefy on tongue and patient swallows the liquid, without the need of water. A number of techniques are used to prepare these tablets, including lyophilization, soft direct compression. Matrices having an API and high porosity are also being prepared using sublimation process. Urea, urethane, ammonium carbonate, ammonium bicarbonate, hexamethylene, benzoic acid, naphthalene and camphor are commonly used for sublimation processing as they they volatize rapidly. After removal by sublimation, these inert volatile substances leave the matrices with a high porosity. Disintegrants and sugar based excipients, such as sodium starch glycolate, cross carmellose sodium, mannitol, xylitol, dextrose, fructose, maltose and polydextrose have been incorporated in almost all the orally disintegrating dosage forms (ODDFs). Loading of drug is made by preparing a blank and drug is post loaded. Generally the drug in solution is added after which the solvent evaporates. Taste masking poses numerous challenges since the drug product dissolves in mouth, any taste of drug must be covered, either by flavoring technique or by micro encapsulation or nanoencapsulation. A major drawback of most of these systems is that the packaging system needs a higher degree of protection due to the lower hardness and more friability of the porous nature of tablets, except the DuraSolv technology of CIMA Labs, which are suitable for rigors of bulk bottle packaging. Keep the orally disintegrating tablet in the blister pack inside the outer foil pouch until the patient is ready to take the medicine. Make sure that operator’s hands are dry and peel open the blister to remove the tablet. Place the tablet on tongue and let it dissolve. These dosage forms have become a delivery system of choice for most patients as they provide comfort for administration throughout the day. Pharmaceutical companies, on the other hand, benefit from value addition in terms of product life-cycle management in today’s market.
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Effervescent Tablets , Hypodermic Tablets , and Soluble tablets
1.4.4 Tablets used to prepare solution
The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used.
1.4.4.1 Effervescent tablets (11)
The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, effervescent tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water.
Figure.14. Effervescent Tablets
Due to liberation in CO2 gas, the dissolution of API in water as well as taste masking effect is enhanced. The advantages of effervescent tablets compared with other oral dosage forms includes an opportunity for formulator to improve taste, a more gentle action on patient’s stomach and marketing aspects. To manufacture these tablets, either wet fusion or heat fusion is adopted. The tablets are compressed soft enough to produce an effervescent reaction that is adequately rapid. Water soluble lubricants are used to prevent an insoluble scum formation on water surface. To add sweetness to the formulation, saccharin is added since sucrose is hygroscopic and add too much of bulk to the tablet. The manufacturing shall be done under controlled climatic condition to avoid effervescent reaction. The packaging is done under 25% RH at 25oC. Hands of the consumers and atmospheric moisture after opening the container can also result in loss of product quality. The most commonly used effervescent tablet today is aspirin tablet.
1.4.4.2 Hypodermic tablets
These tablets contain one or more readily water soluble ingredients and are intended to be added in water for injection of sterile water to form a clear solution which is to be injected parenterally. They were widely used by rural physician due to its portability. One bottle of sterile water was carried by the doctor to prepare many types of injectables. It can be used for medicaments whose stability in water is very poor.
1.4.4.3 Soluble tablets (12)
Tablets are pre-formed solids of uniform shape and dimensions, usually circular, with either flat or convex faces, the distance between faces being less than the diameter. Water soluble tablets are intended for application after dissolution in water and contain an active ingredient should be totally soluble in water at used concentrations. All the excipients used to formulate these tablets are required to be completely soluble in water including the glidants, binders, etc. So, manufacturing of this kind of tablets are challenge for the formulator. Companies manufacturing these tablets have patented them.
Figure.15. Soluble Tablets
IGNORE REFERENCES
Types of tablets
1.4 Tablet Types
| What will you gain?1.4.1 Oral tablets for ingestion1.4.2 Tablets used in the oral cavity1.4.3 Tablets administered by other routes1.4.4 Tablets used to prepare solution |
With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patient’s perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablets here are classified by their route of administration and by the type of drug delivery system they represent within that route.
Table.1. Various Types Of Tablets
|
1.4.1 |
1.4.1.1 Standard compressed tablets1.4.1.2 Multiple compressed tabletsI. Compression coated tabletII. Layered tabletIII. Inlay tablet1.4.1.3 Modified Release tablet1.4.1.4 Delayed action tablet1.4.1.5 Targeted tabletI. Floating tabletII. Colon targeting tablet1.4.1.6 Chewable tablet
1.4.1.7 Dispersible tablet |
|
|
1.4.2 |
1.4.2.1 Lozenges and troches1.4.2.2 Sublingual tablet1.4.2.3 Buccal tablet1.4.2.4 Dental cones1.4.2.5 Mouth dissolved tablet | |
|
1.4.3 |
1.4.3.1 Vaginal tablet1.4.3.2 Implants | |
|
1.4.4 |
1.4.4.1 Effervescent tablet1.4.4.2 Hypodermic tablet1.4.4.3 Soluble tablet |
| Key PhrasesO When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet.O When we need to release the medicament slowly for long time duration after administration of a single tablet we go for modified release formulation.O When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option.O Dispersible tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of waterO Sublingual tablet is designed to dissolve in small quantity of saliva and used when immediate action within few minutes is desired.O Buccal tablet is most often used when replacement hormonal therapy is to be administered.O Implants are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year. |
Tablets administered by Vaginal Route and Implants
1.4.3 Tablets administered by other routes
These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application.
1.4.3.1 Vaginal tablets
This tablet undergoes slow dissolution and drug release in vaginal cavity of women. The shape is kept ovoid or pear shaped to facilitate retention in vagina. The tablet should be made compatible with plastic tube inserters which are designed to place the tablet in the upper region of vaginal tract. These tablets generally release antibacterial, antiseptics or astringents to treat vaginal infections or release steroids for systemic absorption.
1.4.3.2 Implants
These tablets are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year. A special injector with a hollow needle and plunger is used to administer the rod shaped tablet for other shapes, surgery is required. The tablets may be pellet, cylindrical or rosette shaped with diameter not more than 8mm. They are sterile formulation without excipients and made hard with large particle size to achieve gradual drug release. The tablets are produced by a sterile single punch hand operated machine in which the die cavity is filled with hand since the material does not normally flow well. Mainly, these tablets are prepared to deliver growth hormones to food producing animals and ear is the preferred site for administration of the drug.
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Tablet Sweeteners, Tablet Preservativies and Tablet Wetting Agents
1.5.6 Miscellaneous Excipients
| What will you gain?1.5.6.1 Wetting Agents1.5.6.2 Dissolution Retardants1.5.6.3 Dissolution Enhancers1.5.6.4 Adsorbents1.5.6.5 Buffers1.5.6.6 Antioxidants1.5.6.7 Chelating Agents1.5.6.8 Preservatives1.5.6.9 Colourants1.5.6.10 Flavours
1.5.6.11 Sweeteners |
1.5.6.1 Wetting Agents
Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been established that SLS improves permeation of drug through biological membrane since it destroys the path through which drug has to pass and thus minimizing the path length for the drug to travel. Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation.
1.5.6.2 Dissolution Retardants
Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy materials like stearic acid and their esters can be used as dissolution retardants.
1.5.6.3 Dissolution Enhancers
They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.
1.5.6.4 Adsorbents (4)
Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added can play as both glidant and an adsorbent role in the formula.
1.5.6.5 Buffers
Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate.
1.5.6.6 Antioxidants
Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid .
1.5.6.7 Chelating Agents
Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used chelators.
1.5.6.8 Preservatives
Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
1.5.6.9 Colourants(1, 4,16)
Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time .While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface.
Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic)
|
FD & C COLOUR |
COMMON NAME |
| Red 3 | Erythrosine |
| Red 40 | Allura red AC |
| Yellow 5 | Tartrazine |
| Yellow 6 | Sunset Yellow |
| Blue 1 | Brilliant Blue |
| Blue 2 | Indigotine |
| Green 3 | Fast Green |
1.5.6.10 Flavours(1,4)
Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are incorporated either as solids (spray dried flavors) or oils or aqueous (water soluble) flavors. Solids that is dry flavors are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous flavors are less used because of its instability on aging.
1.5.6.11 Sweeteners(1,4,45)
Sweeteners are added primarily to chewable tablets.
Table.21. Some Of The Sweeteners Used In Tablet Formulation
|
NATURAL SWEETENERS |
ARTIFICIAL SWEETENERS |
| MannitolLactoseSucroseDextrose | SaccharinCyclamateAspartame |
Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic .Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is available in market under the brand NutrasweetO manufactured and marketed by Nutrasweet Company.
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Tablet Compression Machine: Trends and Demands
Tablet compression: The process that is opted first if any formulation had to be developed. To meet this demand many changes in the equipment have been made.
This growing demand is due to many factors like: Whether its the case of generics or new formulation, the first trial is carried with tablet compression owing to its lowcost.
The change of pharma market from western to other developing countries like India, and the potency of the API’s demands more of protection both in terms of operator and product has led to certain equipment changes.
Advances in Technology:
Many changes have been made to reduce the cost and time and to increase the flexibility, productivity and safety.
Time required to clean the machine during change over of the process has been emphasized.The changes made included
Exchangeable turret – Fette in 1990s.
Openess of teh structure and accessiblity improved in the XL varsions of Korsch.
Centrifugal die filling and clean in place facility by IMA.
In 2002 exchangeable compression module by GEA Courtoy. This ECM technology has combined productivity, flexibility and safety.2
WOL-ECM (wash off-line)- teh latest range of ECM.2
Exchangeable Die disc and die shells- PERFORMA P.2
Stepped cabinet design to allow fast access to the turret, Novel WIP solution capability, – OYSTAR Manesty (Xpress 300, 500 and 700)3
In order to increase the output of tablet presses:
Uniform die filling was necessary to get uniform tablet weight, the prior requirement at high speeds.
Increase in number of punch stations- Die plate segments by Fette.
Exchangeable die disc with die shells by GEA courtoy.
To compensate the decreased dwell time for each tablet, air compensation, larger compression rollers and punches with special head design have been made.
Speed control by AC inverter drive (conventionally variable speed pulley)- UNIK-I FC model with RIMEK brand.4
In case of potent drugs, it would be ideal to have a wash in place tablet compression machine like that of OYSTAR Manesty (Xpress 300, 500 and 700)3 while off line washing is favourable when equipment is smaller, easier to install and operate with low cost.
Formulation Advancements:
Equipment is also altered according to the formulation like those of bilayer tablets.
For example: KORSCH XM 12 5, MODUL P rotary tablet press with Bi-layer ECM 6,Fette high speed bi-layer tablet press-3002.7
Incorporation of sensors like 8
Main compression and Pre-compression sensors: performed by replacing the pins that hold the main and precompression wheels in place.
Ejection sensors: Replacement of ejection cams.
Take off sensors: To measure the forces during tablet from the die table to the collection container.
Torque Sensors: To determine the End point conditions or to measure the amount of work required for mixing a batch of product.
Calibration kits: For calibration of tablet press sensors.
Conclusion:
Finally all these advancements of the tablet compression machine should result in tablet of high quality with desired hardness, friability, weight, disintegration and finally dissolution. but, still the quest of the best machine is not quenched suggesting that all this is just the beginning.
References:
1.Primary source: Jan Vogeleer.Tablet Compression: changing trends, more demands. Available from http://pharmtech.findpharma.com/pharmtech/Manufacturing/Tablet-compressi…
Secondary sources:
2.http://www.gea-ps.com/npsportal/cmsdoc.nsf/WebDoc/ndkw73ejku
3.http://www.oystar.manesty.com/2304.html
4.http://www.indiamart.com/karnavatiengineering/pharmaceuticalsmachines.html
5.http://docs.google.com/viewer?a=v&q=cache:lKDO8GV5KC4J:abstracts.aapspha…
6.http://www.gea-ps.com/npsportal/cmsdoc.nsf/WebDoc/ndkw73nl3c
7.http://www.equipnet.com/FETTE-HIGH-SPEED-BI-LAYER-TABLET-PRESS_listid_20…
8.http://www.sensing-systems.com/products/pharmaceutical_sensors/default.html
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