Lozenges, Troches, Sublingual Tablets, Buccal tablets, and Mouth Dissolved Tablets

Tablets used in the oral cavity

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.

Sublingual Tablets

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.

Buccal Tablets

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.

Dental Cones

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

Effervescent 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.

Effervescent Tablets

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.

Soluble Tablets

Figure.15. Soluble Tablets

IGNORE REFERENCES

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Types of tablets

Pharmaceutical Tablets Types

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

ORAL TABLETS FOR INGESTION

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

TABLETS USED IN THE ORAL CAVITY

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

TABLETS ADMINISTERED BY OTHER ROUTES

1.4.3.1 Vaginal tablet1.4.3.2 Implants

1.4.4

TABLETS USED TO PREPARE SOLUTION

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

Vaginal 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

Tablets Colorants

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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