The most common three technological schemes for producing tablets: using wet or dry granulation and direct compression.
The main stages of the tablet manufacturing process are as follows:
- - weighing, after which the raw material goes to screening using vibrating sifters;
- - granulation;
- - calibration;
- - pressing to obtain tablets;
- - packing in blisters.
- - package.
Preparation of raw materials for tabletting is reduced to their dissolution and hanging.
Weighing of raw materials is carried out in fume hoods with aspiration. After weighing, the raw material goes to screening using vibrating screeners.
Mixing. The medicinal and auxiliary substances that make up the tablet mixture must be thoroughly mixed for their even distribution in the total mass. Obtaining a compositionally homogeneous tablet mixture is a very important and rather complicated technological operation. Due to the fact that the powders have different physicochemical properties: dispersion, bulk density, moisture, fluidity, etc. At this stage, paddle-type batch mixers are used, the shape of the blades can be different, but most often worm or Z-shaped. Mixing is often carried out in a granulator as well.
Granulation. This is a process of converting a powdery material into grains of a certain size, which is necessary to improve the flowability of the tabletted mixture and prevent its delamination. Granulation can be "wet" or "dry". The first type of granulation is associated with the use of liquids - solutions of excipients; in dry granulation, wetting liquids are either not used, or they are used only at one specific stage in the preparation of the material for tabletting.
Wet granulation consists of the following operations:
- - grinding substances into fine powder;
- - moistening the powder with a solution of binders;
- - rubbing the resulting mass through a sieve;
- - drying and processing of granules.
Shredding. Usually, the operations of mixing and uniform moistening of the powder mixture with various granulating solutions are combined and carried out in one mixer. Sometimes mixing and granulating operations are combined in one apparatus (high-speed mixers - granulators). Mixing is achieved by vigorous forced circular mixing of the particles and pushing them against each other. The mixing process to obtain a mixture homogeneous in composition lasts 3 - 5 minutes. Then the granulating liquid is fed to the premixed powder into the mixer, and the mixture is mixed for another 3 - 10 minutes. After the completion of the pelletizing process, the unloading valve is opened and the finished product is poured out with the slow rotation of the scraper. Another design of the apparatus is used to combine the operations of mixing and granulation - a centrifugal mixer spruce - granulator.
Hydration. It is recommended to use water, alcohol, sugar syrup, gelatin solution and 5% starch paste as binders. The required amount of binding substances is established empirically for each tableting mass. For this, in order for the powder to be granulated at all, it must be moistened to a certain degree. Sufficiency of moisture is judged as follows: a small amount of mass (0.5 - 1 g) is squeezed between the thumb and forefinger: the resulting "cake" should not stick to the fingers (excessive moisture) and crumble when dropped from a height of 15 - 20 cm (insufficient moisture). Moistening is carried out in a mixer with S (sigma) -shaped blades that rotate at different speeds: front - at a speed of 17 - 24 rpm, and back - 8 - 11 rpm, the blades can rotate in the opposite direction. To empty the mixer, the body is overturned and the mass is pushed out using the blades.
Rubbing (actually granulating). Granulation is carried out by rubbing the resulting mass through a sieve of 3 - 5 mm (No. 20, 40 and 50). Punching sieves made of stainless steel, brass or bronze are used. The use of woven wire sieves is not allowed in order to avoid wire scraps getting into the tablet mass. Rubbing is carried out using special rubbing machines - granulators. The granulated mass is poured into a vertical perforated cylinder and rubbed through the holes using springy blades.
Drying and processing of granules. The resulting ranules are scattered in a thin layer on pallets and sometimes dried in air at room temperature, but more often at a temperature of 30 - 40? C in drying cabinets or drying rooms. Residual moisture in granules should not exceed 2%.
Compared with drying in drying ovens, which are inefficient and in which the drying time reaches 20 - 24 hours, drying of granules in a fluidized (fluidized) bed is considered more promising. Its main advantages are: high intensity of the process; reduction of specific energy costs; the possibility of complete automation of the process.
But the pinnacle of technical excellence and the most promising is the apparatus in which the operations of mixing, granulating, drying and dusting are combined. These are the well-known devices SG-30 and SG-60, developed by the Leningrad NPO Progress.
If the wet granulation operations are carried out in separate apparatuses, then after the drying of the granules, a dry granulation operation follows. After drying, the granulate does not represent a uniform mass and often contains lumps of adhered granules. Therefore, the granulate re-enters the wiper. After that, the resulting dust is sifted from the granulate.
Since the granules obtained after dry granulation have a rough surface, which complicates their further pouring out of the hopper during the tabletting process, and in addition, the granules can adhere to the matrix and punches of the tablet press, which causes, in addition to weight disturbance, flaws in the tablets, resort to the operation of "dusting" the granulate. This operation is carried out by free application of finely divided substances on the surface of the granules. Gliding and loosening substances are introduced into the tablet mass by dusting
Dry granulation. In some cases, if the medicinal substance decomposes in the presence of water, dry granulation is used. To do this, briquettes are pressed from the powder, which are then grinded, receiving grains. After sifting out the dust, the grains are tableted. Currently, dry granulation is understood as a method in which a powdery material is subjected to an initial compaction (compression) and a granulate is obtained, which is then tableted - a secondary compaction. At the initial compaction, dry adhesives (MC, CMC, PEO) are introduced into the mass, providing adhesion of particles of both hydrophilic and hydrophobic substances under pressure. Proven for dry granulation of PEO in combination with starch and talc. When using one PEO, the mass sticks to the punches.
Compression (actually tableting). It is the process of forming tablets from a granular or powdery material under pressure. In modern pharmaceutical production, tabletting is carried out on special presses - rotary tablet machines (RTM). Pressing on tablet machines is carried out by a press tool consisting of a matrix and two punches.
The technological cycle of tableting on the RTM consists of a number of sequential operations: material dosing, pressing (tablet formation), its ejection and dropping. All of the above operations are carried out automatically, one after the other, using the appropriate actuators.
Direct pressing. It is a pressing process for non-granular powders. Direct compression makes it possible to exclude 3 - 4 technological steps and, thus, has an advantage over tableting with preliminary granulation of powders. However, despite the apparent advantages, direct pressing is slowly being introduced into production.
This is due to the fact that for the productive operation of tablet machines, the pressed material must have optimal technological characteristics (flowability, compressibility, moisture, etc.) Only a small number of non-granular powders have such characteristics - sodium chloride, potassium iodide, sodium and ammonium bromide, hexomethylenetetramine, bromcamphor and other substances having an isometric particle shape of approximately the same particle size distribution, not containing a large number of fine fractions. They compress well.
One of the methods for preparing medicinal substances for direct compression is directed crystallization - they achieve the preparation of a tabletted substance in crystals of a given flowability, compressibility and moisture content by means of special crystallization conditions. This method is used to obtain acetylsalicylic acid and ascorbic acid.
The widespread use of direct pressing can be ensured by increasing the flowability of non-granular powders, high-quality mixing of dry medicinal and auxiliary substances, and a decrease in the tendency of substances to exfoliate.
Dedusting. To remove dust fractions from the surface of tablets coming out of the press, dedusting devices are used. The tablets pass through a rotating perforated drum and are cleaned of dust, which is sucked off by a vacuum cleaner.
After the production of tablets, the stage of their packaging in blisters on blister machines and packaging follows. In large industries, blister and cartoning machines (the latter also include a forger and a marker) are combined into a single technological cycle. Manufacturers of blister machines complete their machines with additional equipment and supply the finished line to the customer. At low-productivity and pilot plants, it is possible to perform a number of operations manually, in this regard, this work provides examples of the possibility of purchasing individual items of equipment.
The material for obtaining tablets by the direct compression method should have good compressibility, flowability, optimal moisture content, have approximately the same particle size distribution and isometric particle shape.
Technology system:
1) Weighing - measuring the source material.
2) Grinding.
An essential requirement for the direct compression method is the need to ensure the uniformity of the content of the active ingredient. To achieve high homogeneity of the mixture, they strive for the finest grinding of the drug. For this, mills for ultrafine grinding are used, for example, jet mills - grinding of the material occurs in a stream of energy carrier (air, inert gas) supplied to the mill at a speed of several hundred m / s.
3) Mixing. Direct pressing in modern conditions is the pressing of a mixture consisting of drugs, fillers and auxiliary substances => mixing is necessary to achieve homogeneity. High homogeneity of the mixture is achieved in centrifugal mixers.
4) Pressing.
On a rotary tablet machine (RTM). In order to avoid delamination and cracking of the tablets, it is necessary to select the optimal pressing pressure. It has been established that the shape of the punches affects the uniformity of the distribution of the pressing forces along the diameter of the tablet: flat punches without chamfers contribute to obtaining the most durable table.
For direct pressing, RTM-3028 is recommended, which has a device for vacuum feeding of powders into the matrix. At the moment of loading the material, air is sucked out of the die cavity through the hole connected to the vacuum line. In this case, the powder enters the matrix under the action of a vacuum, which ensures high speed and increases the dosing accuracy. However, there are drawbacks - the vacuum design quickly becomes clogged with powder.
Hardware diagram for the production of tablets
TS-1 Preparatory
Sieves with aperture size 0.2-0.5 im
TS-2 Mixing
Worm-blade mixer
TS-3 Tabletting
TS-4 Quality control of tablets
Micrometer
Analytical balance
The device "Erveka", for def. compressive strength
Freeabilizer for abrasion resistance
Rocking basket device
Rotating basket device
Spectrophotometer
TS-5 Packaging and labeling
Cellless Tablet Packing Machine
A) Starch- filler (needed, because there is little drug - less than 0.05 g); a disintegrant that improves the wettability of the tablet and promotes the formation of hydrophilic pores in it, i.e. reduces disintegration time; starch paste is a binder.
humidification: if you want to add a small amount of humectant, then the binder is introduced into the mixture in dry form, if the amount of humectant is large, then the binder is introduced in the form of a solution.
Gelatin- a binder for the strength of granules and tablets
Stearic acid- a sliding substance (lubricating and anti-sticking) - facilitates the easier ejection of the tablets from the matrix, preventing the formation of scratches on their edges; anti-adhesion prevent the mass from sticking to the walls of punches and dies, as well as adhesion of particles to each other.
Talc- sliding substance (as well as stearic acid + provides sliding - this is its main effect) - uniform outflow of the tableted masses from the hopper into the matrix, which guarantees the accuracy and consistency of the drug dosage. The consequence is the smooth operation of the tablet machine and the high quality of the tablets.
Aerosil, talc and stearic acid- they remove the electrostatic charge from the granulate particles, which improves their flowability.
To increase the compressibility of medicinal substances during direct pressing, the following is added to the powder mixture. dry adhesives - most often microcrystalline cellulose (MCC) or polyethylene oxide (PEO)... Due to its ability to absorb water and hydrate individual layers of tablets, MCC has a beneficial effect on the drug release process. MCC can be used to make tablets that are strong, but not always well-disintegrating. To improve the disintegration of tablets with MCC, it is recommended to add ultraamylopectin.
Direct pressing shows application modified starches. The latter enter into chemical interaction with medicinal substances, significantly influencing their release and biological activity.
Often use milk sugar as an agent that improves the flowability of powders, as well as granular calcium sulfate, which has good fluidity and provides tablets with sufficient mechanical strength. Cyclodextrin is also used to increase the mechanical strength of the tablets and their disintegration.
Direct pressing in modern conditions, it is the pressing of a mixture consisting of medicinal substances, fillers and excipients. An essential requirement for the direct compression method is the need to ensure the uniformity of the content of the active ingredient. In order to achieve a high homogeneity of the mixture, necessary to ensure the therapeutic effect of each tablet, they strive for the finest grinding of the medicinal substance.
Difficulties in direct compression are also associated with tablet defects such as delamination and cracking. In direct compression, the top and bottom of the tablet are most often detached in the form of cones. One of the main reasons for the formation of cracks and delamination in tablets is the inhomogeneity of their physical, mechanical and rheological properties due to the influence of external and internal friction and elastic deformation of the matrix walls. External friction is responsible for the transfer of the powder mass in the radial direction, which leads to uneven tablet density. When the pressing pressure is removed due to the elastic deformation of the matrix walls, the tablet experiences significant compression stresses, which lead to cracks in its weakened sections due to the uneven tablet density due to external friction, which is responsible for the transfer of the powder mass in the radial direction.
It exerts influence and friction on the lateral surface of the matrix during the expulsion of the tablet. Moreover, most often stratification occurs at the moment when a part of the tablet leaves the matrix, since at this time an elastic aftereffect of a part of the tablet appears when it is pushed out of the matrix, while the part of it, which is in the matrix, does not yet have the ability to freely deform. It was found that the uneven distribution of the pressing forces over the tablet diameter is influenced by the shape of the punches. Flat, non-chamfered punches provide the strongest tablets. The least strong chipped and delaminated tablets were observed when pressed with deep sphere punches. Chamfered flat punches and spherical punches with a normal sphere occupy an intermediate position. It was also noted that the higher the pressing pressure, the more prerequisites for the formation of cracks and delamination.
FOR PRACTICAL (SEMINARS)
ACTIVITIES
Course 4
Discipline: DESIGN OF CHEMICAL AND PHARMACEUTICAL PRODUCTION
Compiled by:
Murzagalieva E.T.
Almaty, 2017
Practical lesson number 10
Lesson plan.
Development of a technological line for the production of pharmaceutical products.
Basic technological schemes for the production of solid and liquid dosage forms.
When drawing up a project for an industrial enterprise, it is necessary to determine the types and sizes of buildings, their required areas, the number of workers, the number and types of equipment, the amount of raw materials, materials, energy and fuel required for the enterprise. It is also necessary to develop a plan of the enterprise and the internal layout of workshops. All these tasks are solved based on the data of the adopted production process.
Therefore, when starting the design of an industrial building, it is necessary first of all to study the technological process of this production. The basis for the architectural and construction development of the project is technological production scheme, which is a graphical representation of the functional relationship between individual production processes carried out in a given workshop.
A careful study of the technological scheme of the functional connection of the premises makes it possible to establish a rational sequence of the location of the departments and premises of the workshop, and this scheme is the initial basis for designing the building plan.
A schematic flow diagram of production with a description of the process by stages. The technological scheme should include all the main and auxiliary processes, units for the preparation and regeneration of catalysts, auxiliary materials, purification of polluted water, neutralization of gas emissions and waste processing. The basic technological scheme should include units for mechanization of loading and unloading operations and units for dosing.
Solid dosage forms - type of dosage forms characterized by the constancy of volume and geometric shape due to the properties of hardness and elasticity. Solid dosage forms include: briquettes, granules, medicinal sponges, pills, caramels, capsules, pencils, microcapsules, microspheres, liposomes, pellets, medicinal films, powders, chewing gums, fees, tablets.
Dragee- solid dosage form obtained by layer-by-layer application of medicinal substances on microparticles of excipients using sugar syrups
Briquette- a solid dosage form obtained by pressing medicinal substances or crushed medicinal plant materials (or a mixture of various types of herbal raw materials) without the addition of auxiliary substances and intended for the preparation of solutions, infusions (briquette for infusion) and decoctions (briquette for decoction).
Caramel- a solid dosage form with a high invert sugar content, intended for use in the oral cavity. Homeopathic caramel contains a homeopathic medicine.
Implant- a sterile solid depot dosage form for injection into body tissues. Implants include: implantable tablets, depot tablets, subcutaneous capsules, implantable rods.
Microcapsules- capsules consisting of a thin shell of polymeric or other material, spherical or irregular, with a size of 1 to 2000 microns, containing solid or liquid medicinal substances with or without the addition of excipients. Microcapsules are part of other, final dosage forms - capsules, powder, ointment, suspension, tablets, emulsions.
Therapeutic system- dosage form (delivery system) with controlled (prolonged) release of a drug substance at a rate set in advance, after a certain time, in a certain place, in accordance with the real need of the body. According to the principle of release, therapeutic systems are distinguished: physical (diffusion, osmotic, hydrostatic) and chemical immobilized, chemically modified; at the site of action: gastrointestinal (oral), ophthalmic, intrauterine, cutaneous (transdermal), dental.
Tablets- a solid dosage form obtained by pressing powders and granules containing one or more medicinal substances with or without auxiliary substances.
Among the tablets are distinguished:
Actual tablets (pressed)
Trituration tablets (molded; microtablets)
Uncovered, covered
Effervescent
Gastrointestinal (enteric)
Modified release
For use in the oral cavity
For the preparation of a solution or suspension, etc.
The technology for the preparation of tablets consists in mixing drugs with the required amount of excipients and pressing on tablet presses.
Most drugs do not have properties that ensure their direct compression: isodiametric crystal shape, good flowability (fluidity) and compressibility, low adhesion to the tablet press tool. Direct pressing is carried out: with the addition of auxiliary substances that improve the technological properties of active substances; by forcibly feeding the tabletting material from the hopper of the tabletting machine into the matrix; with preliminary directional crystallization of the pressed substance.
Shredding
Sifting some soft conglomerates of powders are removed or by rubbing them through perforated plates or sieves with a certain hole size. In other cases, sieving is an integral part of grinding to obtain a mixture with a certain granulometric composition.
Shredding It is used to achieve homogeneous mixing, eliminate large aggregates in clumping and sticking materials, increase technological and biological effects. Powder grinding leads to an increase in the strength and the number of contacts between particles and, as a result, to the formation of strong conglomerates.
Granulation- aimed at the enlargement of particles - the process of converting powdered substances into grains of a certain size
Currently, there are three main granulation methods:
- dry granulation, or granulation by grinding - compression of a dry product, the formation of a plate or briquette, which is crushed into granules of the desired size. Used for drugs that decompose in the presence of water, enter into chemical interactions;
- wet granulation- moistening of powders with poor flowability and insufficient ability to adhere between particles, a solution of binders and granulation of a wet mass. The most effective and strong binding substances are cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone; gelatin and starch are considered less effective.
Tabletting (pressing) consists in double-sided compression of the material in the matrix using the upper and lower punches. Pressing on tablet machines is carried out with a press tool consisting of a matrix and two punches. Rotary tablet machines (RTM) are currently used. RTMs have a large number of dies built into the matrix table and punches, which ensures high productivity of tablet presses. The pressure in the RTM builds up gradually, which ensures soft and uniform compression of the tablets.
Liquid dosage forms(ZhLF) - preparations obtained by mixing or dissolving active substances in a solvent, as well as by extracting active substances from plant material.
Solubility- the property of substances to dissolve in different solvents (amount of solvent per 1.0 substance)
Concentrated solutions Is a non-dosed type of pharmaceutical preparation used for the preparation of dosage forms with a liquid dispersion medium by dilution or in a mixture with other medicinal substances.
SOLVENTS USED IN LIQUID MEDICINAL TECHNOLOGY
Conditions for obtaining purified water
(pr. Ministry of Health of Ukraine No. 139 dated 06/14/93)
separate room, the walls and floor of which are lined with facing tiles;
It is prohibited to carry out works that are not related to the receipt of purified water;
Collectors for water from stainless steel or glass (as an exception);
Water cylinders are placed in glass boxes painted with white oil paint.
SCHEME OF TECHNOLOGY AND QUALITY CONTROL OF LIQUID DOSAGE FORMS
PREPARATION OF POTIONS
Potions- liquid dosage forms for internal use, which are dosed in spoons (tablespoons, dessert, tea).
Drops Are liquid dosage forms for internal and external use, dosed in drops.
Liquid dosage forms manufacturing scheme
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Tpill technology
The most common three technological schemes for obtaining tablets (Scheme 1):
Using wet granulation
Using dry granulation
Direct pressing
tablet making granulation
Preparation of medicinal and auxiliary substances
The pharmaceutical industry receives medicinal and auxiliary substances, as a rule, meeting the requirements of GF XI and GOST, in crushed and sieved form, therefore, the preparation of materials is reduced to unpacking the powders and weighing them. If the starting materials do not meet the required fractional composition specified in the regulations, they are crushed. The choice of equipment for this operation is determined by the properties of the processed materials and the degree of grinding.
For preliminary grinding of coarse-crystalline materials (sodium chloride, sugar, etc.) to medium size, hammer mills are used, to small and fine ones - dismembrators and ball mills. Ultrafine grinding of raw materials, for example, to increase the efficiency of glidants or to achieve uniform mixing of drugs with a low dosage, is obtained in a gas jet mill.
When grinding solid materials on these machines, a homogeneous product is practically not obtained, therefore sieving is necessary to separate larger particles. Careful selection of the fraction makes it possible to obtain a product of a certain granulometric composition. In the production of tabletted dosage forms, the starting bulk materials are usually sieved on machines with a vibration principle of operation.
Mixing the components that make up the tablets
The medicinal and auxiliary substances that make up the tablet mixture must be thoroughly mixed for their uniform distribution in the total mass. Obtaining a tablet mixture that is homogeneous in composition is a very important and at the same time a rather complicated technological operation, due to the fact that the powders have different physicochemical properties: dispersion, bulk density, moisture, fluidity, etc.
Dry and wet granulation. Applied equipment. Definition and purpose of granulation
The granulation (granulation) process is an important, sometimes integral process in the production of solid dosage forms. On the modern pharmaceutical market in Russia and abroad, a large number of equipment used for this process is currently represented, which is constantly being improved and modernized, meeting the latest requirements of the pharmaceutical industry.
Granulation (granulation) - directional enlargement of particles, i.e. the process of converting a powdery material into particles (granules) of a certain size.
The goals of granulation are as follows:
· Prevention of stratification of multicomponent tableting masses;
· Improving the flowability of powders and mixtures thereof;
· Ensuring a uniform rate of powder flow into the matrix of the tablet machine;
· Ensuring greater accuracy of dosing;
· Ensuring a uniform distribution of the active component, and, consequently, a greater guarantee of the medicinal properties of each tablet.
Delamination of the tabletted mass usually occurs due to the difference in particle sizes and the difference in the specific gravity of the medicinal and auxiliary components included in its composition. Such delamination is possible with various vibrations of the tablet machines and their funnels. Layering of the tablet mass is a dangerous and unacceptable process that causes almost complete separation of the component with the highest specific surface area from the mixture and a violation of its dosage. Granulation prevents this hazard, since particles of different sizes and specific gravity stick together during the production of granules. The resulting granulate, provided that the sizes of the resulting granules are equal, acquires a fairly constant bulk density. The strength of the granules also plays an important role: strong granules are less prone to abrasion and have better flowability.
Granulation is necessary to improve the flowability of the tabletted mass as a result of a significant decrease in the total surface of the particles when they stick together into granules and, consequently, to reduce the friction between the particles during movement.
Types of granulation
There are currently two granulation methods:
· Dry granulation, or granulation by grinding;
· Wet granulation.
Dry granulation
Dry granulation is a method in which a powdery material (a mixture of medicinal and auxiliary substances) is compacted to obtain a granulate. Dry granulation is used in cases where wet granulation affects the stability and / or physicochemical characteristics of a medicinal substance, as well as when medicinal and auxiliary substances are poorly compressed after the wet granulation process.
If medicinal substances undergo physical changes during drying (melting, softening, color change) or enter into chemical reactions, they are briquetted, i.e. briquettes are pressed from the powder on special briquetting presses with large matrices (25 by 25 mm) under a high pressure. The resulting briquettes are crushed using mills, fractionated using sieves, and tablets of a given weight and diameter are pressed on tablet machines.
It should be noted that in the manufacture of tablets, dry granulation is used less frequently than wet granulation or direct compression.
The main stages of the dry granulation process:
1. mixing of powders;
2. compacting;
3. shredding;
4. sieving;
5. dusting;
6. mixing.
Some stages may be missing.
Briquetting granulation can also be used when the drug has good compressibility and does not require additional binding of particles with binders.
The most famous method of dry granulation is the compaction method, in which dry powder is compacted, giving it the shape of granules under a certain pressure (Fig. 4).
Currently, using the dry granulation method, dry binders (for example, microcrystalline cellulose, polyethylene oxide) are introduced into the composition of the tableting mass, which provide adhesion of both hydrophilic and hydrophobic particles under pressure. The adhesion of particles to each other occurs under the influence of forces of different nature. At the first stage, molecular, electrostatic, and magnetic forces act. Then there is the formation of bonds between the particles, after which capillary forces begin to act. At the second stage, the process of agglomeration occurs due to the formation of solid bridges as a result of sintering of particles, partial melting or crystallization of soluble substances. Further, the formation of solid bridges between the particles occurs due to a chemical reaction, the process of solidification of binders or crystallization of insoluble substances.
Dry Granulation Equipment
The dry granulation process is carried out on special equipment.
The combined installation combines the processes of compacting, grinding and separating the obtained granules (Fig. 5).
1 - capacity; 2 - vibrating sieve; 3 - granulator; 4 - grinder; 5 - regulating device; 6 - roller press; 7 - auger; 8 - mixer; 9 - pipeline for supplying raw materials to the mixer; 10 - granulator mesh; 11 - feeder.
The principle of operation of the pellet press (Fig. 6) is as follows: rotating in different directions, rolls 1 and 2 capture the powdery mixture and push it through the holes in the wall of the hollow rolls. Inside the hollow rolls, a knife 4 cuts off the resulting granules.
1, 2 - pressing rolls;
3 - vertical auger;
Wet granulation
Powders with poor flowability and insufficient adhesion between particles are subjected to wet granulation. In special cases, binder solutions are added to the mass to improve the adhesion between particles. Granulation, or wiping of a wet mass, is carried out in order to compact the powder and obtain uniform grains - granules with good flowability.
Wet granulation includes successive stages:
· Grinding substances into fine powder and mixing dry medicinal substance with excipients;
· Mixing of powders with granulating liquids;
· Granulation;
· Drying of wet granules;
· Dusting of dry granules.
Grinding and mixing is carried out in mills and mixers of various designs previously presented. The resulting powder is sieved through a sieve. In order for the powder to be granulated, it must be moistened to a certain degree. For this, the powders are mixed with granulating liquids. The optimal amount of humidifier is determined experimentally (based on the physicochemical properties of the powders) and is indicated in the regulations. If there is not enough humidifier, then the granules will crumble after drying, if there is a lot, the mass will be viscous, sticky and poorly granulated. The mass with optimal moisture is a moist, dense mixture that does not stick to the hand, but crumbles into separate lumps when squeezed.
Binders are necessary in order to bind the powder particles and prevent damage to the surface of the finished tablets, that is, to increase the strength of the tablets and resistance to fracture.
A diagram of the wet granulation mechanism is shown in Figure 4.32. The binding (granulating) liquid falls on the solid particles of the powder, wetting it and forming liquid "bridges". When a mixture of active and auxiliary substances with a granulating liquid is dehydrated, the binding liquid "bridges" gradually turn into solid "bridges" and, as a result, agglomerates (final granules with a "snowball" structure) are formed.
The connection of particles occurs due to molecular, electrostatic and capillary forces. The formation of "bridges" can occur due to a chemical reaction.
Wet granulation remains the most widely used blending method for tablet production. There are at least four different variations of the method:
1. Granulation of a mixture of medicinal and auxiliary substances using a binder solution.
2. Granulation of a mixture of medicinal and auxiliary substances with a binder and a pure solvent.
3. Granulation of a mixture of medicinal and auxiliary substances and part of the binder using a solution of the remaining part of the binder.
4. Granulation of a mixture of medicinal and auxiliary substances using a part of the binder solution, followed by adding the rest of the dry binder to the finished granular material.
There are a number of factors that determine which method to use. For many formulations, Method 1 produces tablets with faster disintegration times and faster drug release than Method 2. In many cases, Method 1 results in slightly harder tablets than Method 2. Method 3 is used when you cannot use method 1 (for example, when the tabletting mixture cannot absorb the required amount of liquid). In case of difficulties related to decay time, it is recommended to use method 4.
Wet granulation binders
Certain requirements are imposed on the granulating liquid, one of them is that the granulating liquid should not dissolve the active substance. Water, ethanol aqueous solution, acetone and methylene chloride can be used as the granulating liquid. A wide range of substances are used as binding agents for wet granulation in modern pharmaceutical production, for example, starch (5-15% g / g), starch derivatives, cellulose derivatives that improve the plasticity of granules, as well as gelatin (1-3% g / g). d) and PVP (3-10% y / y).
The most common and effective binder for wet granulation in the modern pharmaceutical industry is a synthetic polymer such as Kollidon(PVP), various grades of which (Kollidon 25, 30 and 90 F) are widely available on the market. Granules obtained with PVP are hard, free flowing, and form harder tablets with low friability. Polymer PVP improves the solubility of the active substance through the formation of complexes. In addition, PVP acts as a crystallization inhibitor.
In addition to Kollidon, there are a large number of substances used in the pharmaceutical industry as binders. Let's consider two of them.
Plasdone Povidone is a series of synthetic water-soluble homopolymers of N - vinyl - 2 pyrrolidone. Plasdon polymers have excellent adhesion properties, good film-forming properties, surfactant properties and high solubility in water and many solvents used for pharmaceutical purposes. Due to this combination of properties, these polymers are widely used in a variety of pharmaceuticals. Plasdon polymers have long been used as binders in wet granulation.
Plasdone S - 630 Copovidone is a synthetic 60:40 linear polymer of N-vinyl-2 pyrrolidone and vinyl acetate. With its unique properties Plasdone S - 630 is well suited as a binder for tablets in direct compression and dry granulation applications, as well as a binder for wet granulation.
Equipment for the wet granulation process
The granulate is obtained in the process of granulation of wet mass on special machines - granulators. The principle of operation of granulators is that the material is wiped with blades, spring rolls or other devices through a perforated cylinder or mesh.
To ensure the wiping process, the machine must work at an optimal level so that the wet mass passes freely through the holes of the cylinder or mesh. If the mass is sufficiently moistened and moderately plastic, then it does not seal the holes and the process proceeds without difficulty. If the mass is viscous and seals the holes, the machine is overloaded and it is necessary to periodically turn off the motor and wash the drum blades.
The granulator (Fig. 7) contains a working chamber 1, in which wet material to be granulated is fed through the hopper. Screws 3 are installed in the chamber on two parallel shafts 2. The screws move and wipe the material through a perforated plate that forms the bottom of the working chamber.
Rice. 7
Fig. 8 shows a granulator, the principle of operation of which is as follows: granulated material is poured into hopper 1, which is pushed through granulating mesh 4 using screws 2 rotating in opposite directions. The resulting granulate enters the guide hopper 3, then into the mobile container 5.
1 - bunker; 2 - screws; 3 - guiding hopper; 4 - granulating mesh; 5 - mobile container.
In a rotary transfer granulator, granules are formed by pressing the product in the space between the "fingers" of the rolls, which rotate towards each other. The length of the product is controlled by the design of the rolls (fig. 9).
The advantages of this granulator are high punching speed and controlled product length. The disadvantage is low productivity.
Mixers - granulators. Usually, the operations of mixing and uniform moistening of the powder mixture with various granulating solutions are combined and carried out in one mixer. Mixing is achieved by vigorous forced circular mixing of the particles and pushing them against each other. The mixing process to obtain a homogeneous mixture takes 3 - 5 minutes. Then the granulating liquid is fed to the premixed powder into the mixer, and the mixture is mixed for another 3 - 10 minutes. After the completion of the granulation process, the unloading valve is opened and the finished product is poured out with a slow rotation of the scraper.
Another design of the apparatus for combining the operations of mixing and granulation is a centrifugal mixer - granulator (Fig. 4.40).
1 - case; 2 - rotor; 3 - truncated cone; 4 - branch pipe for liquid inlet; 5 - branch pipe for introducing a bulk component; 6 - storage device for the finished product; 7 - mesh; 8 - protective screen; 9 - branch pipes for air (gas) inlet.
The granulating liquid enters through the nozzle 4 and spreads over the surface of the rotor 2. The free-flowing component through the nozzle 5 falls on the layer of the liquid component and is introduced into it under the action of centrifugal forces. The finished mixture, having reached the cone 3, flows through the holes under the action of centrifugal forces, is dispersed and captured by the air flow entering through the nozzles 9 from the bottom up. The resulting granules settle in the conical part of the granulator, and air is removed from the apparatus through the mesh 7. The size of the granules depends on the operating mode of the rotor, the air pressure and the geometry of the cone perforation. The disadvantages are the complexity of the shaft design and the difficult cleaning of the granulator.
Vertical granulators from Glatt. For small batch sizes (up to 800 l) and / or frequent product changes, drying and cooling of the granulates can also be done in a vertical granulator. In wet granulation, the powder is loaded into a granulator, then moistened or melt-dusted. The tangential forces arising during the operation of the Z-shaped rotor blades ensure intensive mixing of the powder and the rapid formation of granules with a high density when adding binders solutions. The shredder on the side wall of the tank prevents the formation of large agglomerates. A diagram of a vertical granulator and its components are shown in Fig. 4.41.
This unit combines mixing and wet granulation processes. There is repeated grinding and mixing due to the centrifugal forces created by the Z-shaped rotor rotating at the bottom. The result is uniform, finely dispersed granules. The granulate at the outlet of the vertical granulators is characterized by a compact structure with good flowability, since the product is mechanically compacted during the process.
The great advantages of the vertical granulator lie in the gentle drying of the product in a vacuum of up to 10 mbar and in a comparatively small technological space, which is quickly and easily cleaned. Additional air supply through the nozzles at the rotor blades significantly accelerates the drying of the particles.
In fig. 4.42 vertical granulators from Glatt are presented, which can be easily integrated into the technological chain with vertical or horizontal arrangement of elements. Loading of the vertical granulator can be carried out using containers with lifting and transporting devices, as well as loading devices, or pneumatically using vacuum product supply systems. The granules are discharged from the working chamber either by gravity or by means of a vacuum system into a fluidized bed unit or a container.
Rice. 4.42 Glatt Vertical Granulators
Mixers - granulators with high shear force from OYSTAR Huttlin. To carry out the mixing process in this apparatus (Fig. 4.43) there is an innovative mixing device, with the help of which a completely new type of mixing is achieved. The disadvantage of most conventional mixing mechanisms is their geometry, which results in poor product mixing at low speeds. In addition, there are many parts in the chamber where the product can stick to the walls and thus fall out of the granulation process and subsequent drying. This innovative design provides excellent, thorough mixing of the product even at low blade speeds. At the same time, sticking to the walls and the formation of dead zones are excluded in the working chamber due to the central cone - a device that provides gas supply for bubbling.
Rice. 4.43 OYSTAR Huttlin High Shear Mixer Granulator
As for the granulation process, this equipment produces granules of the highest quality due to high-quality and controlled mixing of the product and uniform atomization of the liquid. The particle size of the granules can be varied and controlled by optimizing the process parameters depending on the type of product and the selected binder.
Getting the extrudate
Extrudate (Fig. 4.45) is obtained as a result of punching on special devices - extruders. After extrusion (punching), either cutting or spherization of microgranules takes place, followed by drying. To carry out the extrusion process, screw (5-15 atm.) And radial-forcing extruders are used.
In a screw extruder, the screw rotates in the drum and the material is pressed through the holes in the plate at the end of the drum (Fig. 4.46, a).
In a radial-punching extruder, the extrudate is pressed radially and exits through the holes (Fig. 4.46, b).
The advantages of the presented extruders are as follows:
· Ensuring good mixing;
· high performance;
· The possibility of using the generated heat;
· Easy cleaning and replaceability of internal parts.
The disadvantage is the formation of stagnant zones.
The rotary-cylindrical extruder consists of two cylinders: the first - rotating with holes - granulating, the second - a solid empty cylinder rotating towards the first (Fig. 4.47). When pushing, due to the rotation of two cylinders, a high pressure is created, as a result of which a product of high density and a certain length is obtained.
The advantages of a rotary-cylindrical extruder are the creation of high pressure during extrusion, the creation of a high density, a certain length of the product and the absence of dead zones.
The disadvantage is the difficulty in cleaning the equipment.
Press - extruder is used at low productivity. Its design resembles a tablet machine (fig. 4.48).
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Obtained by pressing or molding medicinal substances or mixtures of medicinal and auxiliary substances, intended for internal or external use.
These are solid porous bodies consisting of small solid particles bound to each other at points of contact.
Tablets began to be used about 150 years ago and are currently the most common dosage form. This is explained next positive qualities:
Complete mechanization of the manufacturing process, ensuring high productivity, purity and hygiene of the tablets.
Accuracy of dosage of medicinal substances introduced into tablets.
Portability / small volume / of tablets, ensuring the convenience of dispensing, storing and transporting drugs.
Good preservation of medicinal substances in tablets and the possibility of increasing it for unstable substances by applying protective coatings.
Masking of unpleasant taste, odor, coloring properties of medicinal substances through the application of shells.
Possibility of combining medicinal substances incompatible in physical and chemical properties in other dosage forms.
Localization of the action of the drug in the gastrointestinal tract.
Prolongation of the action of medicinal substances.
Regulation of the sequential absorption of individual medicinal substances from a tablet of complex composition - the creation of multilayer tablets.
Along with this, the pills have some limitations:
During storage, tablets may lose disintegration (cement) or, conversely, collapse.
With tablets, excipients are introduced into the body, sometimes causing side effects / for example, talc irritates the mucous membranes /.
Individual medicinal substances / for example sodium or potassium bromides / form concentrated solutions in the dissolution zone, which can cause severe irritation of the mucous membranes.
The tablets come in different shapes, but the most common is a round shape with a flat or biconvex surface. The diameter of the tablets ranges from 3 to 25 mm. Tablets with a diameter of more than 25 mm are called briquettes.
2. Classification of tablets
1. By production method:
pressed - obtained at high pressures on tablet machines;
trituration - are obtained by molding wet masses by rubbing into special forms, followed by drying.
oral - taken orally, absorbed in the stomach or intestines. This is the main group of tablets;
sublingual - are absorbed in the mouth, medicinal substances are absorbed by the oral mucosa;
implantation - implanted / sewn / under the skin or intramuscularly, provide a long-term therapeutic effect;
tablets for extemporal preparation of injection solutions;
tablets for the preparation of rinsing, douching and other solutions;
special-purpose pills - urethral, vaginal and rectal.
Dosing accuracy- there should be no deviations in the mass of individual tablets in excess of the permissible standards. In addition, deviations in the content of medicinal substances in a tablet should also not exceed the permissible limits.
Strength- tablets should not crumble under mechanical stress during packaging, transportation and storage.
Disintegration- tablets must disintegrate (disintegrate in liquid) within the time limits established by the normative and technical documentation.
Solubility- the release (release) of active substances into liquid from tablets should not exceed a certain time. The speed and completeness of the intake of active substances into the body (bioavailability) depends on the solubility.
1. Fractional (granulometric) composition. This is the particle size distribution of the powder. Determination of the fractional composition is carried out by sifting the powders through a set of sieves, followed by weighing each fraction and calculating their percentage.
Fractional composition depends on the shape and size of the powder particles. Most substances have anisodiametric (asymmetric) particles. They can be elongated (sticks, needles, etc.) or lamellar (plates, scales, leaves, etc.). A minority of medicinal powders have isodiametric (symmetric) particles - in the form of a cube, polyhedron, etc.
2. Bulk density (mass). The mass of a unit volume of powder. Expressed in kilograms per cubic meter (kg / m 3). Distinguish between free bulk density - (minimum or aerated) and vibrational (maximum) Determine the free bulk density by pouring powder into a certain volume / for example, a measuring cylinder / with subsequent weighing. Vibration bulk density is determined by pouring a sample of powder into a cylinder and measuring the volume after vibration compaction. Bulk density depends on fractional composition, moisture content, shape particles, density (true) and porosity of the material.
The true density of the material is understood as the mass per unit volume in the absence of pores / voids / in the substance.
Bulk density affects the flowability of powders and dosing accuracy. It is used to calculate a number of technological indicators:
a) Vibration compaction ratio( K v ) is found as the ratio of the difference in vibrational (p v) and free (p „) densities to vibrational density:
The smaller K v, the higher the dosing accuracy.
b) Relative density calculated as the ratio of bulk density to density / true / material in percent.
The relative density characterizes the fraction of the space occupied by the powder material. The lower the relative density, themes a larger volume of powder is required to obtain a tablet. This tends to reduce the productivity and dosing accuracy of the tablet machine.
3. Looseness (fluidity) is a complex parameter characterizing
the ability of the material to pour out of the container under its own gravity,
forming a continuous steady stream.
Looseness increases under the influence of the following factors: an increase in particle size and bulk density, isodiametric shape of particles, a decrease in interparticle and external friction and moisture. When processing powders, their electrification (formation of surface charges) is possible, which causes adhesion of particles to the working surfaces of machines and to each other, which impairs flowability.
Looseness is mainly characterized by 2 parameters: the rate of precipitation and the angle of repose.
The pouring rate is the mass of powder pouring out of a fixed-size hole in a vibrating conical funnel per unit of time (g / s).
When loose material is poured from the funnel onto a horizontal plane, it is scattered along it, taking the form of a cone-shaped hill. The angle between the generatrix of the cone and the base of this slide is called the angle of repose, expressed in degrees.
Walter M.B. with co-authors proposed a classification of material flowability. See materials are divided into 6 classes depending on the pouring rate and the angle of repose. Good flowability - at a pouring rate of more than 6.5 g / s and an angle of less than 28 °, poor - respectively, less than 2 g / s and more than 45 °.
4. Moisture content (humidity)- moisture content in powder / granulate / in percent. The moisture content has a great influence on the flowability and compressibility of powders, therefore the tabletting material must have the optimum moisture for each substance.
The moisture content is determined by drying the test sample at a temperature of 100-105 ° C to constant weight. This method is accurate but inconvenient for its duration. For a quick determination, use the method of drying with infrared rays (within a few minutes on express moisture meters).
5. Compressibility of powders is the ability to mutual attraction and cohesion under pressure. The strength of the tablets depends on the degree of manifestation of this ability, therefore the compressibility of the tablets is estimated by the compressive strength of the tablets in Newtons (N) or MegaPascals (MPa). For this, a sample of powder weighing 0.3 or 0.5 g is pressed in a matrix with a diameter of 9 or 11 mm, respectively, at a pressure of 120 MPa. Compressibility is considered good if the strength is 30-40 N.
Compressibility depends on the shape of the particles (anisodiametric compressed better), humidity, internal friction, electrification of powders.
6. Force of ejection of tablets from the matrix. It characterizes the friction and adhesion between the lateral surface of the tablet and the wall of the die. Taking into account the ejection force, the addition of auxiliary substances is predicted.
The ejection force increases with a large percentage of fines, grinding, optimum moisture content and pressing pressure. The pushing force (F v) is determined in Newtons and the pushing pressure (P „) is calculated in MPa according to the formula:
, where
S b - lateral surface of the tablet, m 2
4. Theoretical foundations of pressing
The method of pressing medicinal powder materials refers to a solid phase joining process ("cold welding"). The entire pressing process can be schematically divided into 3 stages. These stages are interconnected, but in each of them mechanical processes occur, which differ from each other.
At the first stage, the convergence and compaction of particles occurs without deformation due to the filling of voids. At the second stage, elastic, plastic and brittle deformation of powder particles, their mutual sliding and the formation of a compact body with sufficient mechanical strength arise. At the third stage, volumetric compression of the formed compact body occurs.
There are several mechanisms for combining powder particles during pressing:
Strong contact can be formed as a result of mechanical interception of irregularly shaped particles or their wedging into interparticle spaces. In this case, the more complex the surface of the particles, the more firmly the tablet is compressed.
Under the influence of the pressing pressure, the particles come closer together and conditions are created for the manifestation of the forces of intermolecular and electrostatic interactions. The forces of intermolecular attraction (Vander-Waals) are manifested when particles approach each other at a distance of about 10 -6 -10 -7 cm.
The moisture present in the material to be pressed has a significant effect on the pressing process. In accordance with the theory of P.A. Rebinder, the forces of interparticle interaction are determined by the presence of liquid phases on the surface of solid particles. In hydrophilic substances, adsorption water with a film thickness of up to 3 microns is dense and tightly bound. In this case, the tablets have the greatest strength. Both a decrease and an increase in humidity lead to To decrease in the strength of the tablets.
5. The main groups of excipients for tableting
The auxiliary substances impart the necessary technological properties to the tableted powders. They affect not only the quality of the tablets, but also the bioavailability of the medicinal substance; therefore, the choice of excipients for each tabletted medicinal product must be scientifically substantiated.
All excipients are divided into several groups for their intended purpose:
Fillers (thinners)- these are substances used to give a tablet a certain mass with a small dosage of active ingredients. For these purposes, sucrose, lactose, glucose, sodium chloride, basic magnesium carbonate, etc. are often used. In order to improve the bioavailability of hardly soluble and hydrophobic drugs, water-soluble diluents are mainly used.
Binders are used for granulation and ensuring the required strength of granules and tablets. For this purpose, water, ethyl alcohol, solutions of gelatin, starch, sugar, sodium alginate, natural gums, cellulose derivatives (MC, NaKMLJ, OPMC), polyvinylpyrrolidone (PVP), etc. are used. When adding substances of this group, it is necessary to take into account the possibility of deteriorating the disintegration of tablets and the rate of drug release.
Baking powder used to ensure the necessary disintegration of tablets or dissolution of medicinal substances. By the mechanism of action, baking powder is divided into three groups:
b) Improving wettability and water permeability- starch, tween-80, etc.
v) Gas-forming substances: a mixture of citric and tartaric acids with sodium bicarbonate or calcium carbonate - when dissolved, the components of the mixture release carbon dioxide and break the tablet.
4. Sliding and lubricating(anti-friction and anti-adhesive) substances - reduce the friction of particles with each other and with the surfaces of the press tool. These substances are used in the form of the smallest powders.
a) Sliding - improve the flowability of tablet mixtures. These are starch, talc, aerosil, polyethylene oxide 400.
5) Lubricating - reduce the force of ejection of tablets from the matrix. This group includes stearic acid and its salts, talc, hydrocarbons, polyethylene oxide 4000.
In addition, the above substances (from both groups) prevent the adhesion of powders to punches and die walls and remove electrostatic charges from the surface of the particles.
Dyes added to the composition of tablets to improve the appearance or designate a therapeutic group. For this purpose, they use: titanium dioxide (white pigment), indigo carmine (blue), acid red 2C, tropeolin 0 (yellow), ruberosum (red), flavorosum (yellow), cerulesum (blue), etc.
Flavoring agents- substances used to improve taste and smell. For these purposes, sugars, vanillin, cocoa, etc. are used.
6. Tablet technology
The most common three technological schemes for obtaining tablets: using wet, dry granulation and direct compression.
The technological process consists of the following stages:
1. Preparation of medicinal and auxiliary substances.
weighing (measuring);
grinding;
screening;
Mixing of powders.
Granulation (no stage in direct compression).
Pressing.
Coating tablets with shells (stage may be absent).
Quality control.
Packaging, labeling.
Most profitable direct pressing(without the granulation stage), but for this process the powders to be pressed must have optimal technological properties. Only a small number of non-granular powders, such as sodium chloride, potassium iodide, sodium bromide, etc., have such characteristics.
Directional crystallization is one of the methods for preparing medicinal substances for direct compression. The method is. that by selecting certain crystallization conditions, crystalline powders with optimal technological properties are obtained.
The technological characteristics of some medicinal powders can be improved by the selection of excipients. However, most of the medicinal substances require a more complex preparation - granulation.
Granulation is the process of converting a powdery material into particles (grains) of a certain size. A distinction is made between 1) wet granulation (with moistening of the powder before / or during the granulation process) and 2) dry granulation.
6.1. Wet granulation
Wet glaning can be performed with pushing (wiping) wet masses; in a suspended (fluidized) bed or spray drying.
Wet push-through granulation consists of the following sequential operations: mixing medicinal and auxiliary substances; mixing powders with granulating liquids; wiping (pushing) the moistened masses through sieves; drying and dusting.
Mixing and wetting operations are usually combined and carried out in mixers. Wiping the moistened masses through sieves is carried out using granulators (wipers).
The resulting granules are dried in various types of dryers. Drying in a fluidized bed is the most promising. A fluidized bed of powder (granulate) is formed in a chamber with a false (perforated) bottom, through which hot air passes with a high pressure. Its main advantages are the high intensity of the process, a decrease in specific energy costs, the possibility of complete automation of the process, and the preservation of the flowability of the product. The Penza plant "Dezkhimoborudovanie" produces dryers of this type SP-30, SP-60, SP-100.
In some machines, the operations of granulation and drying are combined. For medicinal substances that cannot withstand contact with the metal of the nets in a wet state, moistening of the masses with subsequent drying and grinding into "grains" is also used.
Dusting of the granulate is carried out by free application of finely divided substances (sliding, lubricating, loosening) on the surface of the granules. Dusting of the granulate is usually carried out in mixers.
Suspended (fluidized) bed granulation allows you to combine the operations of mixing, granulating, drying and dusting in one apparatus. Granulation in a fluidized bed of material consists in mixing the powders in a suspended bed, followed by moistening them with a granulating liquid with continued stirring. For granulation, granulating dryers such as SG-30, SG-60 are used.
Spray drying granulation. The essence of this method lies in the fact that a solution or aqueous suspension is sprayed by nozzles in a drying chamber through which heated air passes. When spraying, a large number of droplets are formed. The droplets quickly lose moisture due to their large surface. This produces spherical granules. This method is advisable for thermolabile substances, since contact with hot air in this case is minimal.
Dry (pressed) granulation- is the compaction of powders or their mixtures in special granulators without moisture to obtain durable granules. This method is usually used in cases where the drug is decomposed in the presence of water.
Dry granulation is carried out:
briquetting,
melting ,
directly by forming pellets (press pelletizing).
Briquetting carried out on briquetting machines or
The firm "HUTT" (Germany) has proposed a number of granule-forming machines, in which the mixture of powders is compacted immediately to obtain granules.
To increase the flowability of the granules, they are rolled to a spherical shape in a special apparatus-marmer.
Pressing(actually tableting) is carried out using special presses - tablet machines.
The main parts of the tablet machine of any system are pressing pistons - punches and dies with holes - sockets. The lower punch enters the hole of the die, leaving a certain space into which the tableted mass is poured. After that, the upper punch is lowered and compresses the mass. Then the upper punch rises, and after it the lower one rises, pushing out the finished tablet.
For tabletting, two types of tablet machines are used: KTM - crank (eccentric) and RTM - rotary (revolving or carousel). For machines of the KTM type, the matrix is stationary, the loading device moves when filling the dies. In machines of the RTM type, the matrices move together with the matrix table, the loading unit (feeder with a funnel) is stationary. The machines also differ in the pressing mechanism. In KTM the lower punch is motionless, pressing is carried out by the upper punch of a sharp-impact type. In RTM, pressing is carried out smoothly, with both punches, with preliminary pressing. Therefore, the quality of the tablets obtained at RTM is higher.
Machines of the KTM type are of low productivity and are used to a limited extent. The main distribution was received by machines of the RTM type with a capacity of up to 500 thousand tablets per hour.
Tablet machines are manufactured by:"Kilian" and "Fette" (Germany), "Manesti" (England), "Stoke" (USA), etc. In Russia, machines produced by MNPO "Minmedbiospeitekhoborudovanie" and NPO "Progress" in St. Petersburg are widely used. The device of machines of the RTM type, and of the KTM-type in the textbook Muravyov I.A., p. 358.
Modern tablet machines of the RTM type are complex devices with vibrating-type feeders, vacuum feeding of powders into matrices, ensuring uniformity of dosing. They usually have automatic control of tablet weight and compression pressure. The construction of the machines ensures explosion safety. Dust collectors are used to remove dust fractions from the surface of tablets leaving the press.
Finished tablets are either packed or coated.
7. Coating of tablets with shells
The term "coating" for tablets has a twofold meaning: it refers to both the coating itself and the process of applying it to the core. As a structural element of the dosage form, the coating of tablets (shell) has two main functions: protective and therapeutic.
In this case, the following goals are achieved:
Protection of the contents of the tablets from adverse environmental factors (light, moisture, oxygen, carbon dioxide, mechanical influences, digestive enzymes, etc.).
Correction of the properties of tablets (taste, odor, color, strength, staining properties, appearance).
Change in the therapeutic effect (prolongation, localization, mitigation of the irritating effect of medicinal substances).
According to the structure and method of application, tablet coatings are divided into three groups:
pelleted / "sugar" /;
film;
pressed;
Film coatings applied either by spraying (spraying) with a coating solution in a dragee boiler or fluidized bed, or by immersion in a film former solution (alternate dipping of nuclei on vacuum-fixing plates or in a centrifugal unit) followed by drying.
Pressed coatings applied in only one way by pressing on special double-pressing tablet machines.
Coating tablets with coatings is one of the stages in the general technological scheme of tabletting. In this case, finished tablets (usually biconvex) act as intermediates, i.e. cores, which are coated. Depending on the method of application and the type of shell, there are some differences in the number and performance of technological operations.
7.1. Dragee coatings
The application of the "sugar" shell is carried out by the traditional (with the doughing operation) and suspension methods.
Traditional option consists of several additional operations: priming (enveloping), infusion (testing), grinding (smoothing) and glossing (glossing). For priming, the cores of the tablets are moistened with sugar syrup in a rotating fan and sprinkled with flour until the surface of the tablets is evenly coated (3-4 minutes). Then the adhesive layer is dehydrated by sprinkling magnesium carbonate with basic or its mixtures with flour and powdered sugar, preventing the tablets from wetting and losing their strength. After 25-30 minutes, the mass is dried with hot air and all operations are repeated up to 4 times.
When testing, flour dough is layered on the primed kernels - a mixture of flour and sugar syrup (first with sprinkling of magnesium with basic carbonate, then without it) with the obligatory drying of each layer. In total, up to 14 layers are carried out (or until the weight of the coated tablet is doubled).
Grinding of the shell in order to remove irregularities and roughness is carried out after softening the surface with sugar syrup with the addition of 1% gelatin by rolling in a blower.
Therefore, the suspension version has become a more progressive method of pelleting.
Suspension option, when layering is carried out from a nozzle or by pouring a suspension of basic magnesium carbonate on sugar syrup with additives of IUD, aerosil, titanium dioxide, talc. The coating process is reduced by a factor of 6-8.
Regardless of the coating option, the coating process ends with the operation of glossing / polishing /. The mass for the gloss is wax melts with vegetable oils, cocoa butter melts or spermaceti emulsion, introduced into the heated mass of coated tablets at the last stage of panning. Gloss can also be obtained in a separate obductor, the walls of which are covered with a layer of wax or mass for gloss. Gloss not only improves the appearance of coated coatings, but also imparts some moisture protection to the coating and makes the coated tablets easier to swallow.
Advantages of coated coatings:
excellent presentation;
ease of swallowing;
availability of equipment, materials and technology;
the speed of release of medicinal substances.
Disadvantages of coated coatings:
duration of the process;
the danger of hydrolytic and thermal destruction of active ingredients;
a significant increase in mass (before doubling).
The application of a thin protective film to the tablets from a film former solution followed by removal of the solvent is possible:
1.Layer-by-layer spraying in a coating pan,
2.in a pseudo-boiling bed,
3. immersion in a film-forming solution of nuclei in the field of centrifugal forces with drying in a coolant current with the free fall of the tablets.
Tumbling (smoothing of sharp edges on the cores) and dedusting using an air jet, vacuum or sifting are common operations in applying a film coating (regardless of the method and equipment). This ensures uniform coating thickness over the entire surface of the tablets.
The actual coating of the cores is carried out most often by repeated periodic spraying of tablets with a solution of a film former from a nozzle in a coating pan or in a pseudo-boiling bed installation (with or without alternating drying).
Depending on the type of film former solvent, some operations of the coating process (s) and equipment vary. So, when using organic solvents (acetone, methylene chloride, chloroform-ethanol, ethyl acetate-isopropanol), an elevated temperature is usually not required for drying, but there is a need for capturing and recovering solvent vapors. Therefore, plants with a closed cycle are used (for example, UZTs-25).
When using aqueous solutions of film-forming agents, another problem arises: protecting the cores from moisture at the first stage of coating. For this, the surface of the nuclei is hydrophobized with oils after dedusting.
The immersion method is used very rarely. Known for its historical version of the alternate dipping of nuclei, fixed by vacuum on perforated plates, followed by drying. A modern modification of the immersion method in a centrifugal apparatus is described in the textbook, ed. L.A. Ivanova.
Advantages of film coatings:
implementation of all the goals of applying shells;
low relative mass (3-5%);
speed of application (2-6 hours).
Disadvantages of film coatings:
high concentrations of organic solvent vapors in the air (the need to capture or neutralize them)
limited choice of film formers.
This type of coating appeared due to the use of double-pressing tablet machines, which are a double rotor unit with a synchronous transfer carousel (transport rotor). An English machine of the Drykot type (manufactured by Manesti) has two 16-punch rotors, the domestic RTM-24 - two 24-cavity rotors. The productivity of the machines is 10-60 thousand tablets per hour.
On one rotor, the cores are pressed, which are transferred by a transport carousel with centering devices to the second rotor for pressing the shell. The coating is molded in two steps: first, the granulate for the lower part of the casing enters the die cavity; then the transfer carousel is centered there and the core is fed with a small pressing into the granulate; After the second portion of granulate is fed into the space above the tablet, the coating is finally compressed by the upper and lower punches. Advantages of pressed coatings:
full automation of the process;
speed of application;
no effect on the core of temperature and solvent.
Disadvantages of pressed coatings:
high porosity and therefore low moisture resistance;
Film-coated tablets are transferred further to filling and packaging.
8. Trituration tablets
Trituration tablets are called tablets, formed from a moistened mass by rubbing it into a special form, followed by drying. They are made in cases where it is necessary to obtain microtablets (diameter 1-2 mm) or if a change in the medicinal substance can occur during pressing. For example, nitroglycerin tablets are prepared as trituration to avoid explosion when exposed to high pressure nitroglycerin.
Trituration tablets are prepared from finely ground medicinal and auxiliary substances. The mixture is moistened and rubbed into a multi-hole matrix plate. Then, with the help of punches, the tablets are pushed out of the dies and dried. In another way) the drying of the tablets is carried out directly in the matrices.
Trituration tablets dissolve quickly and easily in water, since they have a porous structure and there are no insoluble excipients in them. Therefore, these tablets are promising for the preparation of eye drops and injection solutions.
9. Evaluation of the quality of tablets
The widespread use of tablets, due to a number of advantages over other dosage forms, requires standardization in many respects. All indicators of the quality of tablets are conventionally divided into physical, chemical and bacteriological. To physical indicators of quality tablets include:
geometric (shape, surface type, chamfer, thickness-to-diameter ratio, etc.);
physical (mass, accuracy of dosing mass, indicators of strength, porosity, bulk density);
appearance (coloration, spotting, preservation of shape and surface, presence of signs and inscriptions, type and structure of fracture in diameter;
lack of mechanical inclusions.
consistency of chemical composition (compliance with the quantitative content of the recipe, uniformity of dosage, storage stability, shelf life);
solubility and disintegration;
pharmacological indicators of the activity of medicinal substances (half-life, elimination constant, degree of bioavailability, etc.)
sterility (implantation and injection);
lack of microflora of the intestinal group;
limiting contamination with saprophytes and fungi.
Most of the world's pharmacopoeias have adopted the following basic requirements for the quality of tablets:
appearance;
sufficient strength;
disintegration and solubility;
Microbiological purity.
General article GF XI regulates:
tablet form (round or otherwise):
the nature of the surface (flat or biconvex, smooth and uniform, with inscriptions, symbols, risks);
limit amounts of sliding and lubricating additives;
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