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What is the latest granulation technology in 2022? (including process flow and equipment introduction)

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Granulation is an operation in which materials in powder, molten liquid, aqueous solution, etc. are processed into granules of a certain shape and size. Almost all solid formulations are prepared without the granulation process. The granules made may be the final product (granules), or maybe an intermediate product (tablets). If there is a small amount of air in the powder gap during granulation, the air is not easily discharged when pressurized. After the pressure is removed, the air inside the tablet expands and causes the tablet to be loosened and cracked. After granulation and tablet pressing, the pressure can be evenly transferred, coupled with the uneven surface of the particle’s “inter-embedding” effect, which can overcome the quality problems of loose lobes.

The purpose of granulation is to: ① make the particles have good fluidity, in the drug delivery, packaging, filling, and other aspects of easy-to-achieve automation, continuous and quantitative; ② to prevent the separation phenomenon caused by differences in particle size, density, for the uniform mixing of various ingredients; ③ to prevent the operation of dust flying and adhesion on the wall, to avoid environmental pollution and loss of raw materials; ④ adjust the heap density, improve the dissolution Performance; ⑤ make the pressure transfer evenly in the process of tablet pressing; ⑥ when the formulation and operation are appropriate, it can improve the efficacy and stability of the drug; ⑦ easy to take.

Principle of granule forming

The granule is formed by countless powder particles agglomerated together by some kind of bonding force. The mutual synthesis of powder particles and adhesion and cohesion are related. Adhesion refers to the combination of different kinds of powder or powder on the surface of the solid, and cohesion refers to the combination of the same kind of powder. For anhydrous drug powder, interparticle forces are mainly intermolecular forces (van der Waals forces) and electrostatic forces, even when the surface distance between particles is 10 μm, intermolecular forces still have a significant role. The electrostatic force between the powders in the particles is weak and has little effect on the particles, while the effect of intermolecular forces is strong and can make the particles maintain the necessary strength. The presence of moisture between the powder can cause the adhesion of the powder. If only part of the gap between the powder is filled with liquid, the liquid bridge formed will be surface tension and capillary suction to make the powder combined, if the gap between the powder is filled with the body, and extended to the edge of the gap, the surface tension of the particle surface and the entire liquid space capillary suction can make the powder combined; when the surface of the powder is completely surrounded by liquid, although there is a particle internal gravitational force exists, Powder can still be combined with each other by virtue of the surface tension of liquid droplets. After drying the wet particles, there can still be a small amount of water remaining, and the contact points between the powders melt due to heat during drying, or due to the solidification of the adhesive, or due to the role of the soluble material (drug or excipients) recrystallization between the powders to form a solid bridge, thus strengthening the bond between the powders.

Granulation technology refers to the operation of mixing extracts of medicinal herbs with suitable excipients or with some fine powder of medicinal herbs to make dry granules with a certain shape or size. Granules often refer to solid particles with a particle size of 0.1-3.0 mm. There are roughly three ways of particle forming: ① by tiny particles (powder) gathered into shape, or solid particle surface is covered, so that the particle size becomes larger; ② by the aggregates of particles or formed material and then broken into smaller granules; ③ by molten material dispersion, cooling, curing and granules. Therefore, in a broad sense, crystallization, and crushing also belongs to the category of granulation. Granular material particle size, adhesion, and cohesion are significantly reduced, thereby improving the fluidity of the material, and compressibility; granulation can also reduce or eliminate the mixture between the components due to differences in particle size, density, and segregation, to avoid uneven preparation content or excessive weight differences; granulation can also adjust the heap density, improve the dissolution performance, as well as reduce the fine powder fly and adhesion to the wall, to prevent environmental pollution and powder loss. to prevent environmental pollution and powder loss.

In pharmaceutical production, granulation as a particle processing process can achieve a certain process or dosage form requirements of the corresponding purpose, almost all solid preparation and quality related to the preparation of particles made can be the final formed product can also be intermediates. Granules, pills, drops, etc. must be formed by granulation; tablets, capsules, etc., need to improve the fluidity and compressibility of particles with the help of granulation, so as to facilitate filling, dosing, and compression; granulation methods can be applied to produce the expected rapid or long-acting effect of the preparation.

The operation process and method

Material preparation

According to the different granulation processes, the materials required for granulation are divided into two categories of solid materials and liquid materials. Solid materials usually need to be crushed into a 100-purpose powder and fed according to the prescription ratio, so the preparation work includes the production of materials to receive, crushing, weighing, and other operational units. Liquid materials are usually binders, which need to be prepared according to the prescribed concentration before granulation, and the general liquid preparation method is used. The liquidity materials required for the spray granulation process are then done in the leaching preparation, where the extract is concentrated to a certain degree and then spray-dried to produce granules directly.

Mixing

Mixing operation in the production of granules includes the pre-mixing of solid materials and kneading (soft material) after the addition of the binder two steps. The mixing operation needs to ensure the homogeneity of the mixture and to ensure that the moisture content of the soft material is appropriate. This is mainly through the control of the mixing time and the amount of binder to achieve two ways, and the two tasks need to coordinate with each other. As the mixing time increases, the viscosity of the material may gradually increase, which may eventually lead to difficulties in granulation. But the mixing time is not enough, the binder is not uniformly dispersed, and the quality of the particles can not be guaranteed. The criterion for good soft material production is “pinch it into a ball, touch it and it will fall apart”.

Forming

Forming includes two steps: wet granulation and drying. Wet granulation refers to the use of granule-forming equipment to make the material into granules, is the second key operation in addition to the yard soft material. The wet pellets must be uniform in size, complete, and free of long strips and excessive fines. Wet pellets that do not meet these requirements need to be re-granulated. The drying operation is operated and controlled as described above for drying production.

Other

Other dried pellets need to be reported by filling out the intermediate inspection form according to the normal procedure. Transfer to the intermediate station for the next process. The pellet ingestion station needs to pay attention to the prevention of objects when stored. The production site needs to be cleared according to the clearing SOP.

Granulation process

Extrusion granulation process

Extrusion granulation process includes “pretreatment → mixing → soft material → sieving → drying → granulation → pressing” and other processes. A team usually completes the work tasks of each process within a shift. However, the division of the position is different, generally setting up pre-treatment and mixing, soft material and granulation and drying, granulation and total mixing, tablet pressing, and other positions. Each post personnel needs to coordinate with each other to work. If it is a Chinese medicine preparation, the pre-treatment work also includes extraction, which should be carried out in accordance with the leaching preparation operating procedures to leach the intermediates produced by the preparation as raw materials into the granulation process.

Fluidized granulation process

The fluidized granulation process is the use of fluidized granulation equipment for the production process. First of all, the powder material is added to the fluidization chamber, and the hot air flow is passed to make it boil, and then the adhesive sprayed into the gun is attached to the surface of the powder to make it sticky, and the particles are made by collision and adhesion in the fluidization chamber. In the hot environment, the water in the binder is evaporated and removed, and finally, dry particles are obtained. Obviously, the fluidized granulation process of drug pretreatment, mixing, granulation quality inspection, and other work is similar to the extrusion granulation process, only the forming method is different, so only need to configure the fluidized granulation a post.

Agitated pelletizing process

Extrusion granulation process of soft material and sieving granulation two operations into one, in a post, to complete. The difference with the extrusion granulation process is that the equipment used is different, and the post settings and process flow are basically the same.

Other granulation technology processes

Such as the use of dry powder granulator granulation or spray granulation, etc., can also be directly sieved drug particles.

Granulation technology and equipment

Oscillating granulator

A swing granulator is mainly composed of granulation and transmission parts, including the machine base, motor, pulley, worm, worm gear, rack, drum, screen, and tube clamp. The screen adopts metal mesh, is easy to install and disassemble, has adjustable tightness, a lubrication system, and smooth operation of the production process. The appearance of whole machine is made of stainless steel plate, in line with GMP standards. The working principle of swing type granulator is: the equipment is extrusion type over sieve device, it uses the reciprocal rotation of the prism mounted on the machine shaft to extrude the soft material from the screen into granules, which can be used for making granules and whole granules.

Wet Mixing Granulator

Mixing granulation technology is a granulation technology that is accomplished using a fast mixing granulator. Usually, the raw materials, auxiliary materials, and adhesives are added by the filling port, and the three-way stirring leaves are turned on to rotate at a certain speed. The powder materials and adhesives are fully mixed into wet soft materials in the cylindrical container by the bottom mixing prize, and then the wet granules are cut into uniform skins by the side-mounted high-speed crushing pulp. This machine adopts a horizontal cylinder structure, a reasonable structure. Flushing air seal drive shaft, universal washing can be switched into water. Fluidization granulation, into a number of nearly spherical, good fluidity. Reduce 25% binder than the traditional process, dry operation time is shortened, each batch of dry mixing 2 minutes granulation 1-4 minutes, efficacy is 4-5 times higher than the traditional process. Completed in the same closed container, pre-wetting – mixing – granulation process reduction in line with GMP norms. The whole operation has strict safety protection measures.

The structural features of the wet mixing and granulating machine are as follows.
(1) With the function of mixing and granulation, there is a filling port, air outlet, and water pipe interface on it.
(2) The mixing operation is in an airtight state, with very little dust flying.
(3) The gap of the rotating shaft has airflow for air sealing, so there is no spillage of dust.
(4) The discharge port is controlled by a pneumatic, and the pressure of the air source is >0.5MPa.
(5) It meets GMP requirements.

Fluidized bed granulation coating machine

Fluidized bed granulation technology is a method to keep the drug powder in a fluidized state of suspension under the action of bottom-up airflow, and the binder liquid is sprayed into the fluidized chamber from above or below to make the powder agglomerate into particles. The technology can be completed in one equipment boiling mixing, spray granulation, and air drying process (also can be coated), also known as one-step granulation.

Spray drying granulator

Spray granulation technology is used for the granulation of raw and auxiliary materials and binder mix, constantly stirring into a uniform suspension containing 50%-60% solids, and then pumping this suspension through the high-pressure pump nozzle or shaking the disk into a special atomizer atomized to form a fine droplet, so that the drying in the hot air flow to get a near-spherical fine particles method.

Features of spray granulation: solid powder particles are obtained directly from the liquid, the droplets have a large specific surface area, and the drying speed is fast, which is suitable for the treatment of heat-sensitive materials; the particles have good solubility, dispersibility, and fluidity, but are large and loose in texture.

Dry granulation

The fine powder of spray drying can be directly dry extruded into granules or dry infusion can be directly crushed into granules, and the dry infusion can also be first pressed into large pieces and then crushed into granules.

Quality control

Adhesive usage

The amount of binder is often an uncertain value, subject to the nature of the material, the nature of the binder itself, mixing equipment and production environment, and other factors, the use of improper easy causes the quality of the particles to fail. Generally speaking, the principle of using a binder in granulation operation is to add it in small amounts and in several times. The operator according to the moisture and viscosity of the material to control. If there are continuous quality failure problems, it is necessary to report to the process personnel to take appropriate measures to deal with, if necessary, according to the specified procedures to replace the binder.

Quality inspection of wet granules

The operator’s inspection of wet granules is mainly to observe the color of wet granules, particle size, and uniformity of the granules, to determine the humidity of the granules based on experience to determine whether the amount of binder is appropriate and to take timely measures to deal with it. The appearance of wet particles is solid and complete, no fine powder, or even sticky lump, or loose appearance, more fine powder, all indicate that the quality of wet particles is not qualified, and can not be released to the drying process.

Moisture check

Moisture check is mainly to control the degree of drying to determine the time to end the drying operation.

Control of the drying process

General granule drying controls the thickness of the granule in the material tray within 2.5cm and turns the granule when drying to 80%, in order to facilitate the complete drying of the granule. While fluidized granulation and spray granulation, mixing and granulation are completed simultaneously, the need to control the amount of feed and feed speed, steam pressure, binder sprayed into the amount and spray speed, etc., should depend on the specific circumstances of the equipment and materials, while the actual operation according to the conditions specified in the SOP.

Other

Such as the stirring speed when stirring granulation, the degree of tension between the screen and the roller when extruding granulation, etc.

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