tablet

from Wikipedia, the free encyclopedia
Tablets as a dosage form

Tablets (from the Latin tabuletta "small tablets") are powder, granules or substrates that are portioned and compressed under pressure. They are made on tablet presses.

Tablets as a drug form consist of individually dosed powders or granules and are in part fed to further procedures using pharmaceutical technology in order to influence their dissolving properties. Tablets for medicinal use are classified as pharmaceuticals , in other health-related uses they are classified as medical products or dietary supplements . With a share of almost 50%, tablets occupy a special position among the drug forms.

A large number of active ingredients can be tabletted - some directly, i.e. without further processing of the powder or powder mixture (direct tabletting), but most of them via the intermediate stage of granules. As a rule, in addition to the actual active ingredient, additional auxiliaries are required.

Tablets can be of different shapes. In the case of tablets to be taken, the biconvex shape (round, curved above and below) is particularly common.

Similar solid preparation forms with mixed carriers and excipients such as tablets are compacts , pellets , drug capsules , jelly capsules and caplets .

Tablets outside of medical and other health-related use

There are also numerous uses for tablets outside of medicine:

  • Fuel tablets (both in camping equipment and in nuclear technology)
  • Effervescent tablets (without active ingredient, only with coloring, flavoring and sweeteners)
  • Chlorine tablets (for swimming pools)
  • Charcoal tablets or charcoal Compretten (with activated charcoal for cleaning liquids and gases; for odor binding)
  • Cleaning tablets (for dentures, dishwashers and washing machines, coffee machines, descaling tablets; with cleaning agents)
  • Food tablets (with feed )
  • Fertilizer tablets / sticks
  • Oxygen tablets (for pond water maintenance and for aquariums)

In terms of process technology, all these different tablets are produced by compression in tablet presses (tableting).

History of the tablet as a dosage form

Sculpture “Milestones in Medicine” on the Berlin Walk of Ideas , on the left the Marie-Elisabeth-Lüders-Haus

The tablet was introduced at the end of the 19th century. It is considered to be "one of the most tremendous upheavals that the pharmacy industry has ever experienced". In 1843 the Englishman William Brockedon (1787-1854) applied for a patent for this and is therefore considered the inventor. He initially named them “shaping pills”. The first preparations made consisted of baking soda , sodium chloride and potassium chloride and were soon called "compress pills". In 1862 the term "tablet" was introduced, which was used for compressed products of the Brockedon type, pastilles having been named in this way before . In 1883, Burroughs Wellcome & Company marketed the term tablet for commercial purposes. This term was a protected trade name for drugs with a round, biconcave surface. The company then registered the name "tabloid". This was an amalgamation of tablet and alkaloid and refers to compressed products with highly effective medicinal substances in concentrated form. Brockedon copied the technology for making the tablet from briquette preparation in brick and clay factories.

In Germany, however, Isidor Rosenthal introduced tablet production in 1874. For the first time, only tablets for organ therapeutics were produced. With the so-called tablet regulation of 1898 one tried to simplify the production in the pharmacy. However, large-scale industrial production began in the early 1890s.

Later in the second half of the 20th century, the development of drugs with protracted effects increased; H. Retard or depot drug forms. As a result of the research, multi-layer and coated tablets as well as duplex tablets were then introduced into therapy.

Benefits of tablets

  • cheap and mass production possible on suitable machines
  • easy to pack and transport
  • high stability of the active ingredient in the dosage form
  • precisely metered
  • easy ingestion

Disadvantages of the tablets

  • If taken incorrectly, without sufficient amount of liquid, the tablets will not reach the stomach, but will “stick” in the esophagus for a while. This is why it is recommended to take the medication in powder form or as completely dissolved tablets, especially for bedridden patients.
  • The compliance with the medication in the form of oversized tablets is reduced because some patients have trouble swallowing such a large tablet.
  • In some people, the tablets stick to the throat area while swallowing , which causes uncomfortable foreign body sensations.

Direct compression

Direct tabletting is the compression of the powder or powder mixtures with or without the addition of auxiliaries without further pretreatment. It thus appears simple and cheap. The disadvantage is that only a few substances have the properties necessary for direct tableting, in particular the flowability of the piles and the binding forces between the particles.

Coarsely crystalline powders with cubic crystals are best processed. A grain size of 0.5 to 1 mm is optimal. The powders should be dry, i.e. a residual moisture of max. 10% and are pressed in rooms with a maximum relative humidity of 50%.

Suitable for direct compression

Auxiliary materials

The addition of auxiliaries in the powder mixture improves the properties required for tableting and modifies the properties of the finished tablet.

Filler

When processing very small amounts of active ingredients (e.g. alkaloids, hormones, vitamins, etc.), fillers are required. Fillers ensure that the tablet has the necessary size / mass. Starches (corn, potato and wheat starch) and lactose are used. Other fillers are: glucose, mannitol, sorbitol. Fructose is rarely used due to its high price. Sucrose is mainly used for lozenges. Direct tableting is also possible after adding lubricants and lubricants.

binder

Binding agents ensure the cohesion of granules and, in addition to the compression pressure, ensure the strength of tablets. They are divided into dry binders such as B. MCC (microcrystalline cellulose) or starch and in wet binders / adhesives for granulation such. B. starch paste, cellulose ether, Kollidon and gelatin .

Disintegrant (disintegrant)

They improve the compression into durable tablets (= improvement of the particle adhesion) and the later disintegration of the tablets in the gastrointestinal tract.

Disintegrants (disintegrants) work in three ways:

  • Substances that absorb moisture, increase capillarity and swell
  • Compounds that develop gases and flare up under the influence of moisture
  • Substances that increase the wettability of the tablets (hydrophilizing agents)

Important disintegrants are potato and corn starch, PVP, Carbopol and magnesium peroxide.

The group of disintegrants or disintegrating agents is v. a. determined by the cross-linked PVP brands (Kollidon CL).

lubricant

Lubricants are divided into three subgroups:

Superplasticizers improve the flow properties of the pile. This allows it to flow better into the die during tableting, which means that superplasticizers also improve dosing accuracy. They reduce interparticle friction. They reduce the moisture on the surface. They reduce friction and adhesive forces between the bulk material particles.

Lubricants have the function of facilitating the ejection of the tablet from the die in that the friction between the inner wall of the die bore and the tablet side surface is reduced. In addition, the friction between the die bore and the lower punch is reduced in order to prevent the lower punch from seizing.

Mold release agents are intended to prevent the tablet compound from sticking to the punches and the inner wall of the die. Excessive moisture must also be excluded here. Hygroscopic substances can be problematic for gluing. Compounds with a melting range below 75 ° C stick very strongly and cannot easily be tabletted.

Coated tablets (dragees and film-coated tablets)

Dragee worker, VEB Arzneimittelwerk Dresden , 1976

Coated tablets consist of a core and an even, gapless layer. The core usually consists of a tablet or a granulate or pellet. The applied layer consists either of sugar (classic sugar dragée ) or of another film-forming agent ( film- coated tablet ). The layer can be colored and optionally contain other substances in order to change or cover the properties of the finished dosage form in the desired manner, e.g. B. Smell and Taste.

The sugar coating is the production step in which the core is coated with sugar layers. Other coating materials are now also used, e.g. B. Hydroxypropyl methyl cellulose (HPMC) and polyacrylate methacrylate (PAMA). If the layer consists of a single thin film, one speaks of film-coated tablets.

History of coating

Anis de Flavigny in the individual production steps from the aniseed to the finished dragee

In ancient Greece, tragemata (sweets) were made, which consisted of nuts glazed with honey and resins. Around the year 1000 AD the Persian scholar Ibn Sina described in his work Canon of Medicine the coating of pills with sugar and wax; he also observed that the color of a pill had a psychological effect. Around the same time, the Benedictines in Flavigny-sur-Ozerain began coating parts of plants, including anise seeds. The Anis de Flavigny coated tablets are still available.

From 1608, Jean de Renoult, a Parisian pharmacist, produced flattened tablets coated with sugar and gold. Pharmacists copied the production method used by French confectioners who were already making candy dragees: saccharified pills were placed in round basins, coated with a gum arabic solution, sprinkled with sugar powder and moved the basin, which was attached to the ceiling with a cord, to and fro so that the pills rolled. They were then dried on a hair sieve at 25 ° C. This entire process was then repeated two more times. In French aristocratic circles the consumption of such dragees became fashionable, so that production to meet demand was increasingly mechanized, up to and including industrial production in coating pans. In the middle of the 19th century, industrial production in the USA developed through the pharmacist Warner, who later founded Warner-Lambert (since 2000 Pfizer ).

The film dragee, which was described as early as 1930, was commercialized in the 1950s. The company Abbott Laboratories is film coated tablets since 1953 in the US ago.

Reasons for coating tablets

  • Cover up unpleasant taste
  • Improved processing during assembly (better sliding)
  • Covering up an uncomfortable or inconsistent appearance
  • Protection of medicinal substances from external influences
  • Achieving resistance to gastric juice
  • In general, control / modification of the drug release
  • Make swallowing easier
  • Facilitating identification (drug safety)

Sugar coating

This is the classic panning, i.e. H. coating the kernels with sugar solutions. The high production costs, the difficulties in standardizing (automating) the process and the long production time of up to one week per batch mean that this process is increasingly receding in favor of the film-coated tablet.

With cold coating, the sugar solution is applied at normal room temperature, with warm coating (hot coating) the heated sugar syrup is used (approx. 50–60 ° C).

The process takes place in coating pans, in which the cores are made to roll by rotating the drum. The coating liquid is added and gradually coats the cores. At the same time it is carefully dried (warm air or IR heater). The process is repeated until a sufficiently thick and stable layer has formed around the core. This can take up to 50 panning processes. The cores experience an increase in weight and volume.

The coating process in detail

  • Impregnate
    • to protect against penetration of the coating liquid into the core; z. B. with shellac solutions or polymers.
  • Cover
    • for mechanical protection and preparation for application. In addition to sugar, cover syrup also contains binding agents ( PVP , cellulose, etc.)
  • Application (up to 50 times)
    • The application is the actual coating process. Repeated until the desired thickness is reached.
  • To dye
    • For coloring, dye is added to the last layer of application (1–3%).
  • Smooth
    • The smoothing syrup is applied to remove imperfections. Drying slowly is important, so do not add heat.
  • polishing
    • To improve the appearance, the dragees are processed in special drums lined with felt using oil or polishing wax.

Fast coating

In its essential operations, rapid coating corresponds to the coating described above. The time saving is realized by being satisfied with a 70-90% lower layer thickness. In addition, coating emulsions are used for rapid coating. In this way, coated tablets can be produced in a few hours.

Filmtabletten (film dragees) / film coated tablets

The difference to sugar-coating is that the cores are covered with a single, continuous, colored layer made of special coating materials. Neither the volume nor the shape of the core is changed. Engravings remain visible. Although this layer is only very thin, it should still have all the essential advantages of the properties mentioned under “ Reasons for coating ”.

The decisive advantage of the film covers is time savings.

Covering materials

Coating materials are usually classified according to chemical or functional criteria.

Chemical division

  • Cellulose and cellulose derivatives
  • Methacrylic acid copolymers
  • Polyvinylpyrrolidone (PVP) and derivatives

Functional classification

Fast dissolving film formers
Film formers soluble in gastric juice and small intestine
Insoluble film formers

Other auxiliaries such as plasticizers (citric acid esters , phthalic acid esters , polyalcohols, polyoxyethylene derivatives) increase the flexibility of the film and reduce its brittleness. The usual food colors are used as colorants (with restrictions) . The use of dyes in medicinal products is regulated in the Medicinal Dyes Ordinance (AMFarbV).

Changed drug release

Modified-release tablets can be either coated or uncoated. They are manufactured using special processes (e.g. hydroxpropylmethyl cellulose as a matrix) or with the use of certain auxiliary materials (e.g. coatings). Combinations of these can also be made. The aim of this type of tablet production is to change the location, the time or the rate of active ingredient release in a targeted manner. The European Pharmacopoeia includes different active ingredient release profiles for tablets with modified release, such as delayed, prolonged or pulsed release.

Delayed drug release

Delayed-release tablets are mostly tablets that only release their active ingredient in the intestinal lumen . This means that they are resistant to the acidic environment in the gastric juice . They can either be coated as a whole tablet with one or more layers or they can be produced from already coated granules .

Prolonged drug release

Extended-release tablets are long-term drug forms. These are modified in such a way that they either release their active ingredient bit by bit (e.g. slow active ingredient dissolution or establishment of a diffusion barrier) or the biotransformation and elimination are delayed in order to achieve a long biological half-life. A general distinction is made between sustained-release and depot pharmaceutical forms, with the sustained-release type (sustained release of active ingredients), prolonged-release type ( prolonged release of active ingredient), repeat-release type (staggered release of active ingredient) and delayed-release type (delayed release of active ingredient) ) can be divided.

Pulsating drug release

With this staggered type of active ingredient release, an initial dose is released first and, after a certain time, further single doses. In the outer part they contain a dose for the initial effect and in the core a dose for the long-term effect. This creates a structure of a tablet in a tablet.

This type of drug release is the principle of z. B. OROS ® ( osmotic release oral system ). Here the active ingredient is mixed with a strongly osmotic auxiliary (e.g. mannitol or NaCl) and pressed together. The finished tablet is then coated with a semipermeable membrane, which prevents the active ingredient from passing through. A laser drills a hole in the tablet through which the active ingredient can be released. The prevailing osmotic pressure causes water to flow into the tablet, in which the active ingredient dissolves and can be released through the drilled hole.

Methods of manufacture

Modified-release tablets can be made in a number of ways. On the one hand, they can be coated, which either “only” guarantee gastric juice resistance, have a retarding effect or, on the other hand, lead to an oral osmotic system with the help of other auxiliaries. Furthermore, the active ingredient can be embedded in a matrix, which dissolves in pieces and thus leads to a prolonged release of the active ingredient.

Coatings

Certain coatings on a tablet prevent it from dissolving in the stomach. Such enteric tablets (with coatings such as Eudragit L, Eudragit S and Eudragit FS) only release their active ingredient in the intestinal lumen. Pharmaceutical forms with retarding coatings release the active ingredient with a time delay, such as. B. with the coatings Eudragit RL, Eudragit RS, Eudragit NM and Eudragit NE.

Retard coatings

Some determined polymethacrylates - trade name u. a. Eudragit - due to their structure, can ensure that a tablet is not attacked by gastric juice and that its swelling property creates a delayed effect .

The Eudragite RL / RS contain quaternary ammonium compounds, the counterion of which is a chloride ion. These chloride ions are replaced by a phosphate in the gastrointestinal tract. This phosphate ion develops a hydration shell which causes the coating to swell. This swelling leads to “cracks” in the coating layer, from which the medicinal substance can now escape.

The difference between the two Eudragite is the ammonium content. Eudragit RL ( L calibrates R etardierend) has a 10% ammonium content, with Eudragit RS ( S tark R etardierend) solution of a 5%, whereby a different source effect is achieved.

Oral osmotic system

The oral osmotic system offers a further possibility of influencing the active ingredient release of a tablet . Through an osmotically active substance, water gets into the drug form. The resulting increase in pressure forces the active ingredient through a laser-drilled hole through the semi-permeable membrane into the intestinal lumen.

Sequence of tablet production

in a tablet factory (1904)
Tablet turbine

Tablets are pressed from powder mixtures. Usually - if not always - these mixtures are granulated before pressing, i.e. H. converted into coarser particles. The more important reason for this should be illustrated with an example:

If you tilt a shovel with fine flour more and more, nothing happens at first, until when you tilt it all the flour suddenly falls down in a large cloud of dust. If, on the other hand, you take a shovel with granular sugar, it starts flowing much earlier and more evenly.

Sugar is not a granulate , but its crystals flow just as well as granulates. Such a flow is very important for processing on the tablet presses, because if the mass gets stuck, tablets that are too light are formed. Another reason for granulating is that the various components in the granulate adhere to one another and cannot separate again. Inconsistent mixtures lead to fluctuations in the active ingredient content. Sometimes, however, you can do without granulating and press the tablets directly from the powder mixture. This type of production is called direct compression. Overall, the following processes are used to produce tablet masses:

  • Powder mixture (for direct compression)
  • Wet granulation
  • Fluidized bed granulation
  • Dry granulation

Direct compression is the most economical and elegant method, but it can only be used with some of the tablets, as powder mixtures are often difficult to process.

Wet granulation is the most common method for preparing molding compounds. A kind of dough is made, which is pressed through a sieve and dried. Fluidized bed granulation is a special form of wet granulation. Dry granulation is necessary if the mixture is sensitive to moisture.

The tablet production process is divided into steps

  1. Preparation of the substances and weighing,
  2. Granulation
  3. Grouting.

During compression, one or two grooves arranged at a 90 ° angle, so-called break notches, can be pressed into the tablet in order to make it easier to break up the tablet. A tablet divider can also be used to divide tablets, which can be particularly difficult for elderly people with visual impairments and manual disabilities . Decorative notches , on the other hand, are used to identify tablets.

literature

  • Annette Bauer-Brandl, Wolfgang A. Ritschel: The tablet. Manual of design, manufacture and quality assurance. 3rd edition, Editio Cantor, Aulendorf 2011, ISBN 3871934070 .

Web links

Commons : tablets  - collection of pictures, videos and audio files
Wiktionary: tablet  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ a b c d e f Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 31 ff .
  2. ↑ a b Gerhard Waßmann, Mont Kumpugdee-Vollrath, Jens-Peter Krause: Introduction and History of Coatings. In: Easy Coating: Basics and trends in coating pharmaceutical products. Vieweg + Teubner Verlag, Wiesbaden 2011, pp. 2–5
  3. ^ Warner Lambert. 2000: Pfizer joins forces with Warner-Lambert. pfizer.com, 2018; accessed on January 28, 2020
  4. ↑ European Pharmacopoeia . tape 8.0 .
  5. ^ Voigt: Pharmaceutical Technology . Ed .: Deutscher Apotheker Verlag. 2015, ISBN 978-3-7692-6194-3 .
  6. ↑ American Pharmaceutical Association (Ed.): Handbook of Pharmaceutical Exciepients . UNITED STATES.
  7. ↑ a b pharmaceutical industry - Drug discovery and development . In: Encyclopedia Britannica . ( britannica.com [accessed January 22, 2017]).
  8. ↑ a b Evonik Nutrition & Care GmbH (Ed.): Eudragit® . ( evonik.com [PDF]).