Formulation, Manufacture and Evaluation of Chewable tablets

Chewable tablets are tablets intended to be chewed in the mouth prior to swallowing. They represent the largest market segment of the chewable dosage forms, with chewing gums and chewy squares accounting for a much smaller percentage. When chewed, chewable tablets produce pleasant tasting residue in the oral cavity that when swallowed does not leave a bitter or unpleasant aftertaste.

Chewable tablets are prepared in such a way that they can easily be crushed by chewing. They are usually formulated for patients who have difficulty in swallowing tablets. These categories of patients may be adults with pathologically compromised throats or infants and children who have not learnt how to properly swallow tablets with liquid.

As soon as chewing starts in the mouth, the tablet is broken down into smaller particles from where dissolution and subsequent absorption occurs to effect the desired pharmacologic action. The increased bioavailability from chewable tablets resulting from increased absorption rate due to its dissolution or being chewed in the mouth into the gastrointestinal tract in solution or granule form is the major advantage over conventional solid tablets or capsules which are absorbed mainly after disintegration and dissolution.

Ideal characteristics of chewable tablets

An ideal chewable tablet should be:

1. Easy to chew
2. Palatable (taste-masked or of acceptable taste)
3. Of appropriate size and shape
4. Able to disintegrate readily to facilitate dissolution

Excipients used in the formulation of chewable tablets

The subject of tablet excipients, in general, has been covered in the article “Excipients Used in the Manufacture of Tablets”. Special consideration, however, needs to be given to those materials that form the basis for chewable tablet formulation.

The acceptability in the marketplace of chewable tablets will be primarily determined by taste and, to a lesser degree, appearance. Therefore, appropriate selection and use of components that impact on these properties are of extreme importance. Of course, the formulation scientist must not become so concerned with these properties as to lose sight of other pharmaceutical and biomedical considerations; the resultant product must be as pure, safe, efficacious, and stable as any other.

a. Diluents

These are added to chewable tablet formulations to increase the bulk volume of the tablet. When mixed with the drug substance, the final product is given adequate weight and size to assist in production and handling. Diluents commonly used in chewable tablets include:

i. Mannitol

Mannitol is a desirable filler in tablets when taste is a factor as in chewable tablets. It is a white, odourless, crystalline powder, or free-flowing granules that is essentially inert and nonhygroscopic. It is commonly used as diluent in the manufacture of chewable tablet formulation because of its negative heat of solution, sweetness, and ‘mouth feel’. The popularity of mannitol as a suitable base in chewable tablet formulations is also attributed to its hygroscopic property. Mannitol also acts as sweetening agent, and is said to be about 70% as sweet as sucrose.

In powder form, it is suitable only for wet granulation in combination with an auxiliary binder. For direct-compression applications, a granular form (“tablet grade”) is available (ICI Americas). Mannitol has low moisture content and the equilibrium moisture content remains at approximately 0.5 % up to a relative humidity of approximately 85 %. This property, combined with those related to sweetness, mouth-feel and nonhygroscopic nature of the powder, represent significant advantages for the formulation of chewable tablets.

ii. Sorbitol

Sorbitol is a polyol that occurs as an odourless, white or almost colourless, crystalline, hygroscopic powder. It is used as a diluent in tablet formulations prepared by either wet granulation or direct compression. For direct compression, it is available commercially as SorbTab (ICI Americas) and Crystalline Tablet Type (Pfizer Chemical).

Sorbitol is particularly useful in chewable tablets owing to its pleasant, sweet taste and cooling sensation. It is a slightly sweeter and considerably more hygroscopic isomer of mannitol.

iii. Dextrose

This is an odourless, sweet-tasting, colourless or white crystalline or granular powder obtained through acid or enzymatic hydrolysis of starch (usually maize/corn starch). Dextrose is used as a wet granulation diluent and binder, and as a direct-compression tablet diluent and binder, primarily in chewable tablets. Its sweetness level is approximately 70% that of sucrose, and it is available in both anhydrous (but more hygroscopic) and a monohydrated form.

Although dextrose is comparable as a tablet diluent to lactose, tablets produced with dextrose monohydrate require more lubrication, are less friable, and have a tendency to harden markedly during the first few hours after compression.

iv. Lactose

Lactose, also known as milk sugar is a disaccharide commercially produced from the whey of cows’ milk; whey being the residual liquid of the milk following cheese and casein production. Although generally acknowledged as the oldest and most widely used pharmaceutical excipient in the history of tablet making, its applicability to chewable tablets is minor at best, due to its extremely low sweetness level (20 % of sucrose).

This deficiency requires the addition of an artificial sweetener of sufficient potency to overcome lactose’s blandness. Lactose based chewable tablets are unsuitable for those who are lactose intolerant.

v. Sucrose

Sucrose has been extensively used in tablets both as a filler, usually in the form of confectioners sugar, and as a binder in wet granulations. Attempts to directly compress sucrose crystals have never been successful but various modified sucroses have been introduced into the direct-compression formulation. These include Di-Pac^® (97% sucrose plus 3% modified dextrins), Sugartab (90 to 93% sucrose plus 7 to 10% invert sugar) and NuTab (95% sucrose, 4% invert sugar, and 0.1 to 0.2% each of corn starch and magnesium stearate).

All of the above sucrose-based diluent-binders find application in direct compaction tablet formulas for chewable tablets, particularly where artificial sweeteners are to be avoided. Sucrose has several disadvantages as a filler.

Tablets made with a major portion of it in the formulation tend to harden with time. It is not a reducing sugar but with alkaline materials, it turns brown with time. It is somewhat hygroscopic and tends to cake on standing.

Read Also:  Direct Compressible Excipients, Properties and Uses

b. Flavouring agent

Flavourants are commonly used to impart pleasant flavour and often odour to chewable tablets. They are incorporated as solids in the form of spray-dried beadlets and oils, usually at the lubrication step, because of the sensitivity of these materials to moisture and their tendency to volatilize when heated (e.g., during drying of moist granules in wet granulation). Aqueous (water-soluble) flavours have found little acceptance due to their lesser stability upon ageing.

Since oxidation destroys the quality of a flavour, oils are usually emulsified with acacia and spray-dried. Dry flavours are easier to handle and are generally more stable than oils. Oils are usually diluted in alcohol and sprayed onto the granulation as it tumbles in a lubrication tub. Various group of flavours for general baseline taste types are shown below.

Flavour groups for general baseline taste types

c. Sweetening agents

Sweeteners are added primarily to chewable tablets when the commonly used carriers such as mannitol, lactose, sucrose, and dextrose do not sufficiently mask the taste of the active substance or components. In these cases, the formulation scientist must often use artificial enhancers to increase the overall sweetness impact. Because of the possible carcinogenicity of the artificial sweeteners (e.g., cyclamates and saccharin), pharmaceutical formulators are increasingly attempting to design their tablet products without such agents.

Common sweeteners used in pharmaceutical products, their relative sweetness levels, and pertinent comments

Common sweeteners used in pharmaceutical products include:

i. Aspartame

Aspartame (NutraSweet) is a nondrug approved artificial sweetener. It is approximately 200 times sweeter than sucrose and its duration is greater than that of natural sweeteners. Aspartame is also approved for use in beverages, desserts, and instant coffee and tea. It enhances and extends citrus flavours. Its dry stability is said to be excellent at room temperature and relative humidity of 50 %, while in solution it is most stable at pH 4.

Aspartame exhibits discolouration in the presence of ascorbic acid and tartaric acid, thus greatly limiting its use. Its typical usage level in chewable tablets is 3 to 8 mg per tablet.

ii. Glycyrrhizin (Magnasweet)

Glycyrrhizin is a liquorice derivative with an intense, late, long-lasting sweetness. These properties permit its use as an auxiliary sweetener to boost sweetness level while overcoming aftertaste. Typical use levels are 0.005 to 0.1 %, with higher concentrations tending to lend a slight liquorice flavour.

iii. Saccharin

Saccharin, which is FDA-approved, is 500 times sweeter than sucrose. The major disadvantage of saccharin is its bitter aftertaste, which can sometimes be minimized by incorporating a small quantity (1 %) of sodium chloride.

The saccharin aftertaste is highly discernible to about 20 % of the population. The relative sweetness of saccharin decreases as the sweetener level is increased. Furthermore, as the saccharin concentration is increased, the level of unpleasant aftertaste increases.

d. Colourants

Colourants are used in the manufacture of chewable tablets for the following reasons:

1. To increase aesthetic appeal to the consumer
2. To aid in product identification and differentiation
3. To mask unappealing or non-uniform colour of raw materials
4. To complement and match the flavour used in the formulation

The Food Drug and Cosmetic Act of 1938 created three categories of coal tar dyes, of which only FD & C colours and D & C colours are used in the manufacture of chewable tablets. The third category (External D & C) are not certifiable for use in products intended for ingestion due to their oral toxicity but are considered safe for use in products applied externally.

The form of colourant used in the manufacture of chewable tablets depends on the process of manufacture. Dyes are generally used in chewable tablets manufactured by wet granulation method. The powders are first dissolved in water or appropriate solvent and used in the granulation process. The granulation and drying operations must be optimized to prevent or minimize dye migration.

Lakes are used in chewable tablets made by direct compression in a concentration range of 0.1 to 0.3%. They possess a higher light and heat stability than dyes, are quite inert, and are compatible with most ingredients used in chewable tablets.

For effective use in direct-compression formulation of chewable tablets, lakes should preferably be deagglomerated to their original particle size ranges by premixing them with some of the inert ingredients in a formulation using high-shear mixers and finally incorporating the rest of the ingredients. Some unique cases of wet granulation (such as dye migration) may also call for the use of lakes.

Equipment used in the manufacture of chewable tablets

The equipment used in the manufacture of chewable tablets include:

1. Weighing balance
2. Mixer (such as mortar and pestle, mechanical blenders)
3. Sieves/screens (e.g., granulating sieve)
4. Oven
5. Tabletting machine

Equipment for quality control and/or performance tests are also necessary e.g., equipment for testing the content and release rate of active ingredient (dissolution test), friability, hardness, stability, etc.

Production techniques in chewable tablet Formulation

The manufacture of chewable tablets basically follows the design/ pattern for conventional tablets. The wet granulation method is usually employed. However, other methods such as direct compression, and dry granulation or slugging/pre-compression may be employed depending on the nature of the excipients being used.

The formulation of chewable tablets is designed to include substances that impart or improve palatability and pleasant, cooling sensation. Palatability is usually provided by the addition of suitable flavouring agents. These are added to the other usual tablet excipient excepts disintegrant. Disintegrants are not usually included in chewable tablets since they are meant to be broken down by chewing.

Steps involved in the manufacture of chewable antacid tablets

Typical formula for a chewable antacid tablet formulation

To prepare Aluminum hydroxide and Magnesium hydroxide chewable tablets using the formula above follow the following steps:

1. Mix the first four ingredients in a suitable blender
2. Add items 5 and 6, us this to moisten the mix of the first four ingredients
3. Granulate by passing through a l4-mesh screen
4. Dry at 140 to 150 °F (60.00 to 65.56 °C)
5. Size through a 20-mesh screen
6. Add and thoroughly mix items 7, 8 and 9
7. Compress using 0.5-inch, flat-face, bevelled-edge punches.

Methods of improving flow properties of powders during manufacture of chewable tablets

In order to obtain a suitable solid chewable tablet formulation, two critical properties of the ingredients, namely, ability to flow well and compressibility are generally taken into consideration. Good flow properties of the material (ingredients mixture) are necessary for easy passage from the hopper of the tablet machine to, and adequate filling of, the dies.

To enhance powder (or granule) flow, the following may be done:

1. Addition of glidant (e.g., fumed silicon dioxide) to the formulation
2. Formation of spherical particle may be made to be spherical by either by spray drying or spheronization
3. Particle size enlargement by granulation
4. Mechanical agitation using vibrators. This is no longer recommended due to the problems of particle segregation and stratification.

Granulation is the most popular method of improving flow properties since most powdered ingredients can be granulated. In most cases, granulation also improves compressibility of powders, that is, the ability of the granules to form a stable, intact mass on application or pressure.

Taste masking/ Overcoming the bitter taste of some active ingredients

Taste masking is defined as a reduction of undesirable taste that would otherwise exist. It will be beneficial when the taste and palatability of a drug substance is likely to be unpleasant to patients or when the dosage form has a high degree of interaction with patients’ taste buds as is common with chewing and orally disintegrating tablets, gums and gummies.

Taste masking can be achieved using taste-masking agents, specific flavours and sweeteners. Sweeteners are essential to complete the experience and produce a pleasant taste of the product. Some techniques which have been used in taste masking include:

1. Coating by wet granulation
2. Microencapsulation (especially phase separation and coacervation)
3. Solid dispersions
4. Adsorbate formulation techniques (Solvent method)
5. Ion Exchange
6. Spray congealing and spray coating
7. Formation of different salts or derivatives
8. Use of amino acids and protein hydrolysates
9. Inclusion complexes
10. Molecular complexes

For effective taste-making, certain factors have to be taken into consideration. These include:

1. Level of masking required
2. Dose size
3. Physicochemical properties of the drugs
4. Influence of substrate properties (particle size and shape)
5. Selection of flavouring and sweetening agents
6. Formulation strategies

Quality control tests for chewable tablets

The following important quality control tests are carried out on chewable tablets

1. Content of active ingredient
2. Uniformity of content of active ingredients
3. Uniformity of weight test
4. Organoleptic properties
   1. Taste
   2. Mouth feel
   3. Colour
   4. Odour
5. Chewing property
6. Stability test
7. Friability test
8. Hardness test

Other tests carried out to ensure quality of the chewable tablets include uniformity of thickness, uniformity of diameter and measurement of tablet density.

Note: Disintegration time test is usually not required for chewable tablets

Examples of Chewable Tablets

• Claritin – Loratadine 5 mg (Bayer)
• Montair – Montelukast 4 mg and 5 mg (Ascent Pharma)
• Lamictal – Lamotrigine 5 mg, 25 mg, 50 mg, 100 mg, 200 mg (GlaxoSmithKline)
• Mylanta Gas Minis- Simethicone (McNeil Consumer Pharmaceuticals Company)
• Danacid – Compound magnesium trisilicate tablet (Dana Pharmaceutical Ltd)
• Lipitor – Atovastatin 10 mg (Pfizer)
• Natecal D3 – Calcium 600 mg + Cholecalciferol 400 I.U. (Chiesi Limited)
• Imodium Advanced – Loperamide Hydrochloride 2 mg + Simethicone 125 mg (McNeil Consumer Pharmaceuticals Company)
• Alzol – Albendazole USP 400 mg (Rene Industries Ltd)
• Tylenol – Acetaminophen 160 mg (McNeil Consumer Pharmaceuticals Company)
• Epanutin Infatabs – Phenytoin 50 mg (Pfizer)

Advantages of Chewable Tablets

• Patient convenience; can be taken at any required time and place when water is not available.
• Increased bioavailability resulting from increased absorption rate, due to its dissolution or being chewed in the mouth into the gastrointestinal tract (GIT) in solution or granule form.
• Improved patient acceptance (especially pediatric) through pleasant taste
• Possible to use as a substitute for liquid dosage forms where immediate pharmacological action is desired.
• The large size of the dosage form is difficult to swallow. In such cases, chewable tablet offers advantages over it
• Effectiveness of therapeutic agent is improved by the reduction in size that occurs during mastication of tablets before swallowing

Disadvantages of Chewable Tablets

• Bitter or foul-tasting drugs are not good candidates for chewable tablet formulation.
• Chewable tablets contain sorbitol which causes diarrhoea and flatulence
• The presence use of flavouring agents in chewable tablet may cause ulcer in the oral cavity
• Prolonged chewing of chewable tablet results in pain in facial muscles
• Chewable tablets are hygroscopic in nature, so must be kept in a dry place
• They show the fragile, effervescence granules property
• Since these tablets have insufficient mechanical strength, so careful handling is required

References

• British Pharmacopoeia (2009).
• Lieberman, H., Lachman, L. and Schwartz, J. (1989). Pharmaceutical Dosage Forms: Tablets Vol 1. New York: Marcel Dekker, Inc.
• Mbah, C. (2015). Lecture on Personal Collection of Mbah, University of Nigeria, Nsukka, Enugu State.
• Niazi, S. K. (2009). Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products. New York: Informa Healthcare USA, Inc.
• Ofoefule, S. I. (2002). Textbook of Pharmaceutical Technology and Industrial Pharmacy. Nigeria: Samakin (Nig) Enterprise.
• Rowe, R., Sheskey, P. and Quinn, M. (2009). Handbook of Pharmaceutical Excipients. USA: Pharmaceutical Press and American Pharmacists Association.
• United States Pharmacopoeia (2007). The US Pharmacopoeial Convention. 35th edn. Inc.12601 Twinbrook Parkway, Rockville MD20852.
• WHO Drug Information Vol. 25, No. 3, 2011. available online at: http://www.who.int/druginformation.