1.4 Tablet Types

What will you gain? 1.4.1 Oral tablets for ingestion 1.4.2 Tablets used in the oral cavity 1.4.3 Tablets administered by other routes 1.4.4 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	ORAL TABLETS FOR INGESTION	1.4.1.1 Standard compressed tablets 1.4.1.2 Multiple compressed tablets I. Compression coated tablet II. Layered tablet III. Inlay tablet 1.4.1.3 Modified Release tablet 1.4.1.4 Delayed action tablet 1.4.1.5 Targeted tablet I. Floating tablet II. Colon targeting tablet 1.4.1.6 Chewable tablet 1.4.1.7 Dispersible tablet
1.4.2	TABLETS USED IN THE ORAL CAVITY	1.4.2.1 Lozenges and troches 1.4.2.2 Sublingual tablet 1.4.2.3 Buccal tablet 1.4.2.4 Dental cones 1.4.2.5 Mouth dissolved tablet
1.4.3	TABLETS ADMINISTERED BY OTHER ROUTES	1.4.3.1 Vaginal tablet 1.4.3.2 Implants
1.4.4	TABLETS USED TO PREPARE SOLUTION	1.4.4.1 Effervescent tablet 1.4.4.2 Hypodermic tablet 1.4.4.3 Soluble tablet

1.4.1 Oral tablets for ingestion ^(1-3)

These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulation is the most popular world wide and the major attention of the researcher is towards this direction.

1.4.1.1 Standard compressed tablets

These are the standard uncoated tablets made by either direct compression or wet granulation or dry granulation or double compaction.

1) Figure.1. Standard Compressed Tablet

They may be used for local action in gastro-intestinal tract or systemic action. When the tablet exert local action, they are formulated as more water insoluble by means of selecting slow dissolving excipients and thus provides local action for long time period. e.g., antacids and adsorbents. The drugs that produce systemic action have some aqueous solubility and designed to disintegrate and dissolve quickly so that the drug can be quickly absorbed and produce systemic action. Generally, an API exhibits bioavailability depending upon Biopharmaceutical Class, which is based on water solubility and gastro-intestinal membrane permeability criteria. But, it can be altered by appropriate selection of excipients and processing technology.

1.4.1.2 Multiple compressed tablets

The tablets in this category are prepared for two reasons: to separate physically or chemically incompatible ingredients and to produce repeat action/ prolonged action tablet.

The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression tablet. There are three categories under this class:

I.Layered tablets - two to three component system.

II.Compression coated tablets - tablet within a tablet.

III.Inlay tablet - coat partially surrounding the core.

The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid.

I. Multilayered tablets

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. It consists of several different granulations that are compressed to form a single tablet composed of two or more layers and usually each layer is of different colour to produce a distinctive looking tablet. Each layer is fed from separate feed frame with individual weight control. Dust extraction is essential during compression to avoid contamination. Therefore, each layer undergoes light compression as each component is laid down. This avoids granules intermixing if the machine vibrates.

For example, admixture containing Phenylephedrin HCL and Ascorbic Acid with Paracetamol.

Paracetamol + phenylephedrine Hydrochloride - one layer

Paracetamol + ascorbic acid - another layer.

Figure.2. Multilayered Tablet

2) II. Compression coated tablets

This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret. For preparing final tablet, a bigger die cavity in another turret is used in which first the coat material is filled to half and then core tablet is mechanically transferred, again the remaining space is filled with coat material and finally compression force is applied. This tablet readily lend itself in to a repeat action tablet as the outer layer provides the initial dose while the inner core release the drug later on. But, when the core quickly releases the drug, entirely different blood level is achieved with the risk of over dose toxicity. To avoid immediate release of both the layers, the core tablet is coated with enteric polymer so that it will not release the drug in stomach while, the first dose is added in outer sugar coating. Even so, coating operation requires interpretation while manufacturing and dawdling the manufacturing process. Sometimes, inner core may be of liquid formulation to provide immediate release of core after the coat gets dissolved.

Figure.3. Compression Coated Tablet

III. Inlay tablets ⁽⁴⁾

A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets:

i)Less coating material is required.

ii)Core is visible, so coreless tablets can be easily detected.

iii)Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.

Figure.4. Inlay Tablets

1.4.1.3 Modified Release tablets

The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet.

Figure.5. Graphical Comparison Of Blood Concentration V/S Time

A widespread use of this type of tablet is seen in present scenario, as well as many researchers have concentrated their attention in this direction. This is mainly because of improvement in patient's compliance as the dosage frequency is reduced, patient can take an undisturbed sleep at night, it's also beneficial for psychiatric patients who forget to take their tablets regularly and the dose related side effects and toxicities are reduced. Any adjuvant that can alter water uptake rate, swelling and gelling characteristics of Matrixing agents can alter the release rate of API e.g., electrolytes in HPMC matrix tablet. It's also possible to achieve pulsed drug release. Weakly basic drugs exhibit good solubility at low pH while less soluble at high pH conditions, which can result in incomplete drug release for sustained release formulations. The drug release can be modified by providing suitable micro environmental pH in the tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline polymers results in desirable drug release of acidic drugs. On the other hand, formulation of this type of dosage form presents challenge for the formulator: increases the cost of manufacturing, chances of burst drug release and drop in drug release rate in terminal phase and thus incomplete release on API. In case of accidental poisoning, the doctor has to deal with special treatment problems. Due to large size, patient may feel difficulties in swallowing as the matrixing agent to drug ratio is high. Classic approaches are usually based on adaptation of either film coated or multiparticulate technologies or those involving slow release matrices.

Coating technology ⁽⁶⁾

It combines semi permeable coatings and osmotic tablet cores to produce "zero order release" technology. Attention is also focused to trigger drug release at critical time point e.g., to achieve drug release 1 -2 hours before the patient awakens. Alza's prolific research activities have yielded a technology called "Ringcap" which is based on a tablet, preferentially film coated, partially coated with a series of rings whose respective thickness provides the means of moderating the rate at which the drug is released from final dosage form.

Figure.6. Ringcap (Coated) Tablet

Matrix technology

Classically matrix products exhibit first order (or perhaps square-root-of-time) drug release characteristics. In order to achieve zero order release characteristics, it's necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.

Figure.7. Matrix Tablet

Release of medicament can follow various mechanisms ⁽²⁾

i) Diffusion is rate limiting

Diffusion is driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.

Figure.8. Diffusion Release Pattern

In practice, we can follow either of the two methods,

1.The drug is formulated in an insoluble matrix; the gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion.

2.The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood.

ii) Dissolution is rate limiting

The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for water soluble drugs, it's possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release.

iii) Osmotic pressure is rate limiting

Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But, it declines to zero once the concentration drops below saturation.

Figure.9. Osmotic Release Pattern

iv) Release is controlled by ion exchange

Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.

1.4.1.4 Delayed action tablets

Enteric coated tablet is such an example of delayed action tablet. This formulation is preferred when,

i)The API irritates gastric mucosa e.g., aspirin or strong electrolytes

ii)Drugs that produce nausea and vomiting.

iii)API is sensitive to low pH e.g., erythromycin

iv)When it's necessary to release the drug undiluted. e.g., intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.

The commonly used coating agents are: Cellulose acetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetate phthalate, Eudragit^(r), etc. This dosage form is intended to hydrate and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH increases to 7 to 8. The presence of esterases or bile salts like surface active agents plays a role in drug release.

1.4.1.5 Targeted tablets

When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Depending upon the composition and release mechanism of a tablet, the drug is delivered to a particular region. Under this category, we have two types of tablet:

I. Gastro retentive Tablet

This type of dosage form is to be opted when API release is desired in stomach (Antacids, APIs used against H.pylori infection) or site of absorption is either stomach or upper part of small intestine.

Figure.10. Floating Tablet

To retain the drug for longer time period in stomach, following approaches can be used:

i) Low density tablet (effervescent or non effervescent)

ii) Tablets that can expand in gastric environment (swelling or by unfolding) and thus increasing the size so that it cannot cross the pyloric sphincter.

iii) Using mucoadhesive polymers that stick to mucosa of stomach and provide slow drug release.

Supine position is to be avoided and also high level of fluid is necessary or if the swelling formulation leaves stomach before it swells it's ineffective. Drugs like Diazepam, Levodopa, Benserazide, and Ciprofloxacin are successfully marketed in this formulation.

II. Colonic tablets ^(7,8)

When the aim is to deliver the drug into colon without dilution in other regions of gastrointestinal tract or the drug has poor absorption in stomach or small intestine, colonic drug delivery is an answer of choice. The pH in this region varies from 6.4 - 7 and presence of microbial flora plays as important role in drug release especially in this region. Various mechanisms are adopted for drug release in this area are coating with pH sensitive polymer e.g., Eudragit^(r)S100, Eudragit^(r) L100, biodegradable polymer like polymers which are sensitive to colonic bacteria, bioadhesive polymers which selectively sticks to colonic mucosa e.g., polycarbophils or polyethans, redox sensitive polymers that respond to redox potential in colon which expresses the total metabolic and bacterial action.

1.4.1.6 Chewable tablets

The patients who have difficulty in swallowing tablets whole or for children who have not yet learnt to swallow a tablet, chewable tablet serves as an attractive alternative. The added advantage of this medication is that it can be taken at any time or when water is not available. Mannitol is normally used as a base due to low hygroscopy and more importantly, it gives pleasant, cooling sensation. Antacid tablets are invariably prepared as chewable to obtain quick ingestion relief as well as the antacid dose is too large to swallow and the activity is related to particle size. Another example is multivitamin tablet which a patient can take as a daily dose.

1.4.1.7 Dispersible tablet ⁽⁹⁾

These tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water. So, it's preferred for pediatric patients who cannot swallow a solid dosage form and the API is unstable if formulated in liquid formulation. Also helpful for patients having prolonged illness who are prone to nauseatic sensations if they have to swallow a tablet. The added advantage of this formulation is faster onset of action as compared to standard compressed tablet. The properties of the water dispersible tablet, such as porosity, hardness, disintegration time and increase in viscosity after dispersion are necessary to investigate during manufacturing which decides the product performance. The common examples of API formulated in this dosage form are analgesics e.g., aspirin, ibuprofen, etc.

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.

1.4.3 Tablets administered by other routes ^(1-3)

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.

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

Key Phrases O 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 water O 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.