MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION

GENERAL MONOGRAPH

Tablets GPM.1.4.1.0015.15

Supersedes the XI Monograph of the State Pharmacopoeia

Tablet is a solid dosage form, often produced by pressing powders or granules containing one or more active ingredients with or without excipients.

Tablets are usually even round cylinders with flat or biconvex upper and lower surfaces, unbroken edges. Tablets may be of different shapes, for example, oval, polygonal, etc. They may have bevelled edges.

The presence of coats, the speed and nature of active ingredient release, the method of production, the method of tablets use and the route of administration determine the classification of tablets into groups.

There are uncoated tablets (tablets) and coated tablets.

Coated tablets are tablets for oral administration coated with one or more layers of mixtures of various substances. Depending on the composition and method of application, drained, film and pressed coats are distinguished.

If a coat is a thin polymer coating with a weight of up to 10%, the term “film-coated tablets” is used.

Tablets are divided into immediate release tablets and modified release tablets according to the speed and nature of the release.

The coat may be protective, or destroy the tablet

in a specific part of the gastrointestinal tract, or regulate the release time of the active substances.

Enteric coated tablets are tablets that are resistant to the effects of the gastric acid and release active ingredient(s) in the intestinal acid. It is produced by coating the tablets with an enteric coat (in this case, tablets are termed “enteric coated”) or by compressing granules or particles previously coated with a gastric-resistant coat.

Modified release tablets are coated and uncoated tablets containing special excipients and/or produced by a specific technology that allow the speed and/or time and/or release location of the active ingredient to be controlled.

Modified (non-standard) release may be sustained, continuous, pulsatile, delayed and rapid.

Prolonged-release tablets are coated or uncoated tablets containing special excipients and/or produced by a specific technology, which allows the sustained continuous release of active ingredients. Prolonged release can be achieved by using:

• special coating of tablets;
• technology of producing multi-layer tablets;
• technology of producing tablets with an insoluble carcass;
• other methods of immobilization of active ingredients on an inert carrier.

Pulsatile release tablets are tablets with periodic release of an active ingredient. The term “pulsatile release tablets” is used in the name of a dosage form.

Rapid release tablets are tablets containing special excipients and/or produced by special technology, which allows to increase the release rate of an active ingredient.

By the route of administration, tablets are divided into:

• tablets that are swallowed whole;
• chewable tablets;
• tablets used after preliminary preparation of liquid dosage forms based on them. In this case, the tablets are divided into soluble, dispersible and effervescent;
• tablets for oral administration (sublingual tablets, buccal tablets, lozenges);
• orodispersible tablets;
• vaginal tablets.

Chewable tablets are tablets without coats which should be chewed.

Soluble tablets are uncoated or film-coated tablets, which are dissolved in a suitable solvent before use; the resulting solution may be slightly opalescent.

Effervescent tablets are uncoated tablets containing substances of acidic and basic nature (carbonates or hydrogen carbonates), which react quickly in water with the release of carbon dioxide; they are designed for dissolution or dispersion in water immediately before use.

Dispersible tablets are uncoated or film-coated tablets, dispersible in an appropriate solvent before use to form a suspension.

There are also tablets for solutions, suspensions and pastes for parenteral/topical/external administration.

Tablets for oral administration are usually uncoated tablets produced by a special technology to release the active ingredient(s) in the oral cavity and to provide local or systemic effect (sublingual tablets, buccal tablets, lozenges).

Sublingual tablets are tablets placed under the tongue in order to obtain a systemic effect.

Buccal tablets are tablets placed in the buccal pocket in order to obtain a systemic effect.

Lozenges are tablets placed in the oral cavity for subsequent dissolving, usually to obtain local effect. The composition of tablets provides a sustained release of active ingredients.

Orodispersible tablets are tablets that are placed in the oral cavity where they are quickly dispersed before swallowing.

Vaginal tablets are uncoated or film-coated tablets for vaginal administration, usually for local effect.

TECHNOLOGY CHARACTERISTICS

The most common method of tablet manufacture is the pressing method (direct pressing or using wet or dry granulation), less often molding and lyophilization is used. Molded tablets are manufactured under low pressure from the moistened powder mass by rubbing it into special molds or molding the molten mass. Lyophilized tablets (referred to as “lyophilizates” dosage form) are manufactured by lyophilizing liquids or gels containing active ingredients. Tablets, manufactured by the lyophilization process, dissolve rapidly when they are placed in the oral cavity or dissolved in water before administration.

Depending on the manufacturing technology, the way in which tablets are used, physical and chemical properties of active ingredients, their dosage, the speed and nature of release, various excipients are used in accordance with their purpose.

Diluents are used to provide the required tablet weight if a small amount of active ingredient(s) is included in the formulation. This group includes glucose (dextrose), starch, calcium hydrogen phosphate, calcium carbonate, lactose monohydrate, magnesium carbonate, sorbitol, microcrystalline cellulose, mannitol, etc.

Disintegrants are included in the formulation of tablets in order to ensure their disintegration. They include swelling disintegrants: cross-linked povidone, alginic acid and its sodium and potassium salts, starch (including chemically modified starch), methylcellulose, sodium carboxymethylcellulose (carmellose sodium), croscarmellose, crospovidone, maltose, microcrystalline cellulose; gas-producing disintegrants: Solid organic acids in combination with carbonates or hydrocarbonates and wetting – surface active substances.

Binders are introduced to achieve hardness of granules and tablets. Starch paste, gelatin, sucrose, sodium alginate, alginic acid gels, natural gums, macrogol, cellulose derivatives, povidone, povidone-vinyl acetate (copovidone), etc. are used for this purpose.

Glidants prevent adhesion to the press tool, have a lubricating effect, improve flowability of tableting mixtures. These include starch, talc, aerosil (silicon dioxide colloid), kaolin, skim milk powder, macrogol, polysorbate, stearic acid and its calcium and magnesium salts, polysorbate-80, sodium lauryl sulfate, etc. They slow down the disintegration rate of a tablet and dissolve active ingredient, therefore it is not recommended to exceed the content of polysorbate-80, stearic acid, calcium and magnesium stearate by more than 1%, talcum by 3%, aerosil by 10% of tablet weight.

The formulation of chewable tablets generally includes mannitol, sorbitol, sucrose, etc., as excipients.

Various excipients, conventionally divided into the following groups, can be used for coating: Adhesive substances that ensure the adhesion of coating materials to the tablet core – sugar syrup, magnesium oxide; substances that create carcasses – sucrose, talc, magnesium carbonate basic (magnesium hydroxycarbonate), ethylcellulose; plasticizers that impart plasticity properties to coatings – herbal oils, methylcellulose, carboxymethylcellulose (carmellose), polysorbate, etc.; substances that impart moisture-resistance properties to the coatings – aerosil (silicon dioxide colloidal), shellac, polyacrylic resins, etc.; coloring agents and flavoring and odorant agents.

Flavoring and coloring agents are used to improve the appearance of tablets and give them the desired taste and smell, dose labelling as well as drug identification.

When coating is applied by the building up method, gum arabic (gum acacia), gelatin, sugar syrup, magnesium carbonate basic (magnesium hydroxycarbonate), starch, methylcellulose, wheat flour, calcium stearate, calcium carbonate, sodium alginate, talc, magnesium oxide, etc. are used.

The composition of film coats includes such substances as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose (hyprolose), carboxymethylcellulose sodium (carmellose), acetylphthalylcellulose (cellulose acetate), methylcellulose, ethylcellulose, sodium carboxymethylcellulose (carmellose sodium), copolymers of methacrylic acid and its esters, macrogol, povidone, gelatin and others.

For pressed coatings, sucrose, lactose, starch, wheat flour, stearic acid, etc. are used.

The tablet manufacturing technology should provide the necessary resistance of tablets to abrasion and mechanical hardness.

In the manufacturing, packaging and storage of tablets, measures should be taken to ensure the necessary microbiological purity in accordance with the requirements of the GM “Microbiological purity”.

TESTING

Description

Evaluation of tablet appearance is performed when examining 20 tablets with the naked eye.

The description of tablet shape and color is given. The surface of a tablet should be smooth, homogeneous, unless otherwise justified. There can be breakline, lettering and other marks on the surface of a tablet. For tablets with a diameter of 9 mm or more, the presence of scorelines is recommended.

Uniformity of weigh

For suppositories, the uniformity of weight is determined in accordance with the requirements of the GM “Uniformity of weight of dosage forms”. If a test for uniformity of dosage units is provided, no weight uniformity control is required.

Resistance to abrasion

The determination is carried out in accordance with the requirements of the GM “Tablet resistance to abrasion” in terms of control of the tablet manufacturing process.

Disintegration

Uncoated tablets should withstand the disintegration test in accordance with the GM “Disintegration of tablets and capsules”. Water is used as a liquid medium, unless otherwise specified in the monograph or regulatory documentation. Tablets should disintegrate within 15 minutes, unless otherwise specified in the monograph or regulatory documentation.

Coated tablets should withstand the disintegration test in accordance with the GM “Disintegration of tablets and capsules”. Water is used as a liquid medium, unless otherwise specified in the monograph or regulatory documentation. Tablets should disintegrate within 30 minutes, unless otherwise specified in the monograph or regulatory documentation.

For enteric coated tablets, unless otherwise specified in the monograph or regulatory documentation, the disintegration test is carried out in accordance with the GM “Disintegration of tablets and capsules” with the following changes. The test is carried out in two stages. As a liquid medium at the first stage, a solution of 0.1 M hydrochloric acid is used. The tablet stability time in an acid medium may depend on their composition, but it should not be less than 1 hour and more than 3 hours. Tablets should not disintegrate and show evidence of cracking and softening. At the second stage the acid is replaced with a phosphate buffer solution with a pH of 6.8. Tablets should disintegrate in the buffer solution within 1 hour, unless otherwise specified in the monograph or regulatory documentation.

Dispersible tablets and soluble tablets should disintegrate within 3 minutes. The test is carried out in accordance with the GM “Disintegration of tablets and capsules”. Water (15 to 25 °C) is used as a liquid medium.

Lyophilized tablets. One tablet is placed in a beaker containing 200 ml of water at a temperature of 15 to 25 °C. The disintegration time should not exceed 3 min, unless otherwise specified in the monograph or regulatory documentation. The test is repeated with 5 other tablets. Tablets meet the requirements if all 6 tablets have disintegrated.

Tablets for oral administration (sublingual tablets, buccal tablets, lozenges); A test is carried out in accordance with the requirements of the GM “Disintegration of tablets and capsules”. Disintegration time is specified in the monograph or regulatory documentation. In some cases, the time during which the tablet should not disintegrate is additionally specified.

Vaginal tablets. Except prolonged-release tablets, a test is carried out in accordance with the requirements of the GM “Disintegration of suppositories and vaginal tablets.” Unless otherwise specified in the monograph or regulatory documentation, the disintegration time should not exceed 30 min.

Effervescent tablets should disintegrate or dissolve within 5 minutes. One tablet is placed in a beaker containing 200 ml of water at a temperature of 15 to 25 °C, and gas bubbles begin to form. A tablet is considered to be disintegrated or dissolved if, after ceasing gas bubbles to form around it or its fragments, the tablet either dissolves or disperses in water, and there are no agglomerates of particles. The test is repeated with 5 other tablets.

Dissolution

This test is conducted to confirm the appropriate release of the active ingredient(s) by one of the methods described in the GM “Dissolution for solid dosage forms”. If a definition of “dissolution” is specified in the monograph or regulatory documentation, a disintegration test for tablets is not necessary.

For prolonged-release tablets, a test is performed to confirm the sustained release of the active ingredient.

For enteric coated tablets, unless otherwise specified in the monograph or regulatory documentation, a test confirming the sustained release of the required amount of the active ingredient is carried out in accordance with the GM “Dissolution for solid dosage forms”.

Dispersion

A test is carried out for dispersible tablets. Two tablets are placed in a flask containing 100 ml of water and mixed until completely dispersed. A homogeneous suspension passing through a sieve with a nominal hole size of 710 μm should be formed.

Loss on drying or Water

The section is introduced in cases where the water content can affect the properties of the active ingredient, the drug stability, etc. The test is mandatory for lyophilized tablets. The determination is carried out in accordance with the GM “Loss on drying” or the GM “Determination of water”.

Residual organic solvents

When using organic solvents in the manufacturing process of tablets, it is necessary to monitor their residual contents in accordance with the requirements of the GM “Residual organic solvents”. The normal range of the organic solvent content is given in μg/tablet, based on the maximum permissible daily dose of the solvent and the maximum daily dose of the drug.

The determination of excipients (talc, aerosil, calcium, magnesium stearate, etc.), the content of which is specified in monographs or regulatory documentation, is carried out according to the following procedure.

About 1 g (accurately weighed quantity) of powdered tablets is treated in a vessel with 200 ml of warm water, the liquid is filtered through an ash-free filter and the vessel is carefully rinsed with water. The filter cake is washed several times with warm water (10 ml each) until there is no visible residue on evaporation of a drop of wash water on the watch glass. The filter with the residue is dried, burned, calcined and weighed to the nearest 0.0001 g.

If the tablets contain non-combustible or insoluble in warm water substances, then the sample of the tablets after burning and calcination is treated by heating 30 ml of 10% diluted hydrochloric acid, the solution is filtered and the filter cake is washed with hot water until chlorides are not present in the wash water. The filter with the residue is dried, burned, calcined and weighed to the nearest 0.0001 g.

Uniformity of dosage units

Tablets should comply with the requirements of the GM “Uniformity of Dosage Units”, unless otherwise specified in the monograph or regulatory documentation.

Assay

A sample of powdered tablets (not less than 20 pieces) is taken for analysis. If grinding of a tablet can lead to the decomposition of the active ingredient or the production of a uniformly ground powder is difficult, a test is carried out with the whole tablet or tablets. In this case, it is recommended to use at least 10 tablets.

As the assay result, the average value obtained in the test for uniformity of dosage units can be taken.

PACKAGING

In accordance with the requirements of the GM “Dosage forms”.

LABELLING

In accordance with the requirements of the GM “Dosage forms”. On the packaging of soluble, effervescent and dispersible tablets, there should be a warning notice about the need for pre-dissolution of the tablets before administration.

STORAGE CONDITIONS

In accordance with the requirements of the GM “Storage of medicinal products”. In a package that provides stability during the indicated shelf life of the medicinal product, in a dark place at a temperature of 8 to 15 °C, unless otherwise specified in the monograph or regulatory documentation.