Granules Meaning in Pharmacy

What are granules?

Granules are dry granular preparations with certain particle size made of drugs or extracts of medicinal materials and appropriate excipients (carrier, adhesive, dispersant, wetting agent, stabilizer, etc.) or fine powder of medicinal materials. In order to achieve the purpose of taste correction, odor correction, stability, long-term or enteric dissolution, the granules can be coated, generally using film coating. Granulation is one of the most important processes in the pulping process, the manufacture of pharmaceutical solid oral dosage forms. The purpose of granulation is to improve the characteristics of the raw material, such as flow characteristics, surface properties and bulk density. In addition, it ensures the uniformity of the particle formulation and prevents the separation of active pharmaceutical ingredients (API) and dust from forming, thus improving operator safety. Granules are produced as pharmaceutical dosage forms themselves for oral use, but more often they are used as intermediate products in tablet production.

Types of granules

Granules can be divided into soluble granules, suspended granules, effervescent granules, enteric granules, sustained release granules and controlled release granules.

Soluble granules

In general, Chinese patent medicine is mostly used, which can maintain the characteristics of fast absorption and rapid action of the decoction, and overcome the shortcomings of inconvenient cooking, large dosage and easy deterioration of the decoction when it is used. For example: small bupleuri granules, jade screen granules, etc. This kind of Chinese patent medicine soluble granules should be taken with boiling water.

Suspended granules

It is a dry granule made of insoluble solid drug and suitable excipients. For example: azithromycin dry suspension, cefprozil dry suspension, etc. Such suspension granules need to be shaken with water or other suitable liquid before use and configured into suspension for oral consumption.

Effervescent granules

Effervescent granules definition: effervescent granules contain sodium bicarbonate and either citric acid, tartaric acid, or sodium biphosphate in addition to the active ingredients. On solution in water, carbon dioxide is released because of the acid-base reaction. The release of the water of crystallization makes the powder coherent and helps form the granules. The effervescence from the release of the carbon dioxide masks the taste of salty or bitter medications. Effervescent granules examples: compound calcium carbonate effervescent granules.

Enteric granules

It is a granule made of enteric-soluble material coated with granules or other suitable methods. Enteric granules are resistant to stomach acid, which can prevent the breakdown of drugs in the stomach and avoid irritation to the stomach. For example: omeprazole enteric granules. It should be noted that enteric-soluble granules are generally taken on an empty stomach or before meals to quickly reach the intestine.

Sustained (controlled) release granules

Granules that release drugs at a slow and non-constant rate (constant rate) in a specified release medium. For example: mesalazine sustained release granules.

Powders and granules

In drug formulations, both powders and granules are used, but understanding their differences and complementary effects can improve drug manufacturing efficiency.

Powder: Fine, dry particles formed by crushing solid matter. They are usually illiquid and prone to segregation. The powder properties are not always constant, they can change during processing, e.g. when the feeder or turret speed increases, the tableting mixture may become more resistant to flow (increasing compaction coefficient) or more free flowing (decreasing compaction coefficient), what may result in non-reproducible die filling. This behavior can be predicted by powder flow speed dependence test.

Granules: Condensed powders form large, free-flowing entities with improved handling and compaction properties. Compared with powder, granule has better fluidity, dispersibility and adhesion, and the particle size, shape and appearance are uniform. For example, granule tablets prepared from granules tend to be more uniform in dose distribution than those prepared directly from powder.

SEM images of powder mixture with diazepam - Powd-D (A), fraction of granules below 250 mm - Gran-D < 250 (B) and fraction above 250 mm - GranD > 250 (C). (Kotlowska, H., 2020)

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Development in granulation technology

Granulation technology can be broadly divided into two types: dry granulation and wet granulation. Dry grain by mechanical compression or compaction methods to promote the agglomeration of dry powder particles. Wet granulation induces the adhesion of raw materials through granulation solution (adhesive/solvent), and promotes the adhesion of wet soft materials into clumps. Of these two technologies, wet granulation is the most widely used granulation technology.

Reverse wet granulation is a new development of wet granulation technology. Dry powder is immersed in adhesive liquid and then directionally crushed to form particles. During the process of granulation, the binder as a wetting agent is evenly distributed, so that the drug is fully wetted, and the dissolution rate of the insoluble drug is improved. It also increases the chances of sufficiently uniform contact between the drug and the hydrophilic polymer, allowing the drug to dissolve better. These improved particle properties ensure uniform dissolution during tablet dissolution.

Pneumatic dry granulation (PDG) is an innovative dry granulation technology that uses rolling and gas classification to prepare particles with good fluidity and compressibility. PDG can be any prescription of raw materials mixed powder into a good flow of particles, and it is made into a tensile strength of about 0.5 MPa tablet. Compared with the conventional rolling method, PDG can still prepare particles with good fluidity under lower roll pressure (or low material amount), and PDG technology can also be applied to granulation when the drug load is as high as 70-100%.

Steam granulation is a new wet granulation technology, which uses water vapor instead of traditional liquid water as granulation solution. Vapor is a transparent gas in a single group, has a higher diffusion rate in the powder, and is more favorable for removing moisture when drying. When the steam condenses, the water forms a hot film on the surface of the powder particles, and the hot film is easier to evaporate, so only a small amount of energy is required to eliminate excess water.

Thermoplastic granulation is a very simple and convenient granulation method. In a closed space, compressible granules or excipient properties can be improved using minimal water and a binder. The resulting granules have high sphericity, good flowability, and high tensile strength.

Melt granulation is a technique that uses a fusible powder as a binder to melt or soften the powder at a lower temperature (50-90 °C) and then aggregate it. Melt granulation can replace other wet granulation methods in the application of water-sensitive drugs. Compared with the traditional wet granulation, the method does not require organic solvent or water solvent. There are no moisture wetting and drying stages, reducing granulation time and energy consumption.

Freeze granulation technology involves spraying a solution or suspension into liquid nitrogen, instantly freezing into granules, followed by removing the water from the frozen granules through sublimation drying. Freeze granulation technology can maintain the particle size and uniformity of granules when processing suspensions. This method can be used to prepare reconstitutable parenteral formulations, nano-formulations, solid self-emulsifying drug delivery systems, etc., to maintain particle size and uniformity. The uniformity of the suspension ultimately determines and reflects the granule uniformity. In the pharmaceutical industry, low-temperature freeze-drying granulation offers advantages in reducing the degradation of organic substances and improving the stability and solubility of drugs.