Granulate (pharmacy)

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The granulate is a medicinal form that consists of dry and solid grains. Each grain represents an agglomerate of powder particles. Granules are mostly used for tableting or for filling capsules . Furthermore, they can be dissolved or dispersed in water or another suitable liquid before being taken orally. They are also suitable for direct oral application. The properties of granulates can be further modified by further processing steps such as the application of various functional coatings, the addition of flavor corrections or colorings. Further requirements for granulates (for tabletting) are a uniform size, high lubricity and strength, low residual moisture of 3 to 5% and a maximum powder content of 10%.

Types of granules

According to the European Pharmacopoeia 8.0

According to the European Pharmacopoeia, a distinction is made between the following granulates:

  • Effervescent granules : are not coated and contain acidic substances such as carbonates or hydrogen carbonates. Acid reacting substances include, for example, citric acid and tartaric acid , although these must be used in solid form. The acidic substances react with the carbonates and form carbonic acid , which quickly breaks down into water and CO 2 . HCO 3 - + H + → H 2 CO 3 → H 2 O + CO 2
  • Coated granules : The coating can affect the release. Reasons for coating include the protection of the drug and improved patient compliance (taste and odor masking).
  • Modified-release granules : They can be coated or uncoated. Based on the formulation, the location of the release, the speed and the point in time can be modified in a targeted manner. This is divided into extended and delayed release of active ingredients.
  • Gastric juice-resistant granules : Are granules with a modified release of active ingredients, which are stable in gastric juice and only release their active ingredient in the intestine.

Subdivision based on physicochemical properties

For a classification based on the physicochemical properties of a granulate, the interparticle bridges within the granulate that lead to cohesion are best suited. A distinction is made here between: cohesive interparticle bonds , liquid bridges and solid bridges .

The cohesive interparticle bonds are based in part on Coulomb interactions between charged powder particles. In addition, the form-fitting interlocking of individual, non-spherical particles can generate a very good bond. Furthermore, cohesive interparticle bonds can be formed by water sorption sheaths between individual particles. These water sorption envelopes and the resulting forces can be explained by the surface tension of the water.

The liquid bridges are formed by capillary liquids in particle pores. The particle strength is based on the capillary adhesive forces of the capillary liquids mentioned. Liquid bridges also occur as a preliminary stage in wet granulation. Solid bridges are created by the penetration of the adhesive-containing binder, such as polyvinylpyrrolidone or HPMC , into the superficial capillary pores and subsequent drying out. So-called adhesive bridges are thus formed between the individual powder particles. Another possibility is to dissolve the topmost particle layer with a suitable solvent, such as water or aqueous-organic mixtures. The subsequent evaporation of the solvent by means of drying creates crystalline bridges between individual particles. Such granules, which are created by partially dissolving the particle surface, are also called crust granules.

Pellets

Pellets represent a special form of granules. Compared to conventional granules, pellets are approximately spherical and therefore have relatively better flow properties. This is due, among other things, to the lower static friction due to the reduced surface area in relation to the particle volume.

Pellets are mainly produced in a fluidized bed or with the help of a Spheronizer®. Production with a pelletizing plate is also carried out in rare cases.

Pellets can be filled into capsules. It is not uncommon for one capsule to contain differently processed pellets, which can be used to achieve the desired release of the active ingredient. For example, untreated pellets disintegrate immediately in the stomach, pellets provided with sustained-release coatings in the same capsule release their active ingredient at a constant rate over a longer period of time. Pellets are now increasingly being pressed into so-called MUPS tablets (Multiple Unit Pellet System).

Production of granules

The production of granules can be roughly divided into two processes. Build-up and breakdown granulation. In addition, the degradation granulation can be divided into wet and dry granulation.

Degradation granulation

During degradation granulation, the powder is aggregated by moisture or pressure. When they are broken down, they are then broken down to a specific grain size.

Wet granulation

During the degrading wet granulation, a dough-like, homogeneous mass is first produced, which is then broken up into the granules. This consists of various active ingredients and auxiliaries, such as flavor corrections, fillers, colorings, disintegration accelerators and the granulating liquid. The granulating liquids consist either of dissolved adhesives or an aqueous-organic solvent mixture. Adhesive granules are usually more stable than crust granules.

Adhesives for the production of adhesive granules should not be toxic and should not develop any pharmacological effects of their own. In addition, incompatibility with the ingredients used must be excluded.

Common adhesives for the production of adhesive granules are:

  • Polyvinylpyrrolidone - a fully synthetic binder that can be processed cold.
  • Cellulose ethers - semi-synthetic binders, such as hypromellose
  • Gelatine - as a natural binding agent, it is rarely used nowadays. On the one hand, gelatine has to be heated to produce the adhesive solution, which makes its use more complex. In addition, because of various ethical and religious backgrounds, gelatin is used less often these days.

The so-called adhesive granules are created in this way. The granules produced with the use of solvents are called crust granules.

The base mass produced is then crushed into granules with the help of suitable equipment and various techniques. A distinction can be made between perforated disc , pressed and shaken granulates. Another possibility is the subsequent processing into pellets with the help of a Spheronizer®.

The solvents in the granulating liquids are then removed using tray dryers, vacuum drying ovens or microwaves.

Dry granulation

In degrading dry granulation, granulates are produced by compacting the powder by applying pressure. For this purpose either roller compactors or in rare cases tablet presses are used. The material to be pressed is then further reduced to the desired size.

Build-up granulation

With build-up granulation, the granulates are produced directly from powder particles. A fluidized bed can be used for this purpose, for example. Powder particles are swirled in a stream of air and sprayed with a granulating liquid. The powder particles collect to form agglomerates, which are dried by the continuous air flow. Furthermore, granulates can be produced with "high-shear mixers". These work according to the rotor-stator principle at a low speed. The design results in high shear forces that lead to small particles. The "high-shear mixer "is also equipped with a side-mounted chopper, which ensures that large agglomerates are broken up. The powder is introduced into a "high-shear mixer" at the beginning of processing. The granulating liquid is fed in with an interval pump (peristaltic pump) for the duration of the process. The high shear forces and the friction on the wall of the device result in uniform granulate agglomerates.

A pelletizing plate can be used to produce pellets, the material being conveyed upwards by the rotating movement of the plate and being sprayed with granulating liquid in parallel. The rolling movement and simultaneous spraying with the granulating liquid produce even and round pellets. The size of the pellets can be varied by tilting the plate.

Advantages and disadvantages of granules

Granules have better flow properties than powders, which is particularly advantageous for subsequent tableting. The reason for this is the lower adhesive forces between the individual granules due to the smaller surface area in relation to the volume compared to powders. Due to their spherical shape, pellets have even better flow properties.

Granules have a higher dosing accuracy due to the improved flow properties. A high level of dosing accuracy is of great relevance in the tableting process, for example, in order to ensure uniform and reproducible filling of the die of the tablet press. The mold is the shape of the tablet press into which the tablet is filled and then pressed.

Granulating results in fewer segregation processes and thus fewer dosing inaccuracies, since the granules consist of a homogeneous powder mixture. The tablets resulting from granules usually have a higher mechanical strength than tablets which are generally pressed directly from powders. This can be explained by the rough, uneven surfaces of the granules and the resulting interlocking of the grains with one another. Another advantage is the reduced dust contamination, which reduces "cross-contamination". The high workload and the associated higher production costs compared to direct tableting are to be regarded as disadvantageous. In addition, moisture- and heat-sensitive medicinal substances can only be used to a limited extent for the granulation process.

literature

  • Alfred Fahr : Voigt Pharmazeutische Technologie, 12th edition, Deutscher Apotheker Verlag, ISBN 978-3-7692-6194-3 .
  • Bauer / Frömming / Führer: Pharmazeutische Technologie, 10th edition, Wissenschaftliche Verlagsgesellschaft Stuttgart, ISBN 978-3-8047-3268-1 .
  • European Pharmacopoeia 8.0