TECHNOLOGICAL SCHEME FOR TABLET PRODUCTION.
PREPARATION OF MEDICINES AND AUXILIARY SUBSTANCES. DIRECT PRESSING. OBTAINING TABLETS USING GRANULATION. TYPES OF GRANULATION. COATING OF TABLETS WITH COATINGS. TYPES OF SHELLS. APPLICATION METHODS. STANDARDIZATION OF TABLETS. NOMENCLATURE
1. Tablets as a dosage form.
Pills- a solid dosage form obtained by pressing or molding medicinal substances or a mixture of medicinal and auxiliary substances, intended for internal or external use.
These are solid porous bodies consisting of small solid particles connected 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, cleanliness and hygiene of tablets.
Accuracy of dosing of medicinal substances introduced into tablets.
Portability /small volume/ of tablets, providing convenience for dispensing, storing and transporting medications.
Good preservation of medicinal substances in tablets and the possibility of increasing it for unstable substances by applying protective coatings.
Masking the unpleasant taste, smell, and coloring properties of medicinal substances by applying coatings.
The possibility of combining medicinal substances with incompatible physical and chemical properties in other dosage forms.
Localization of drug action in the gastrointestinal tract.
Prolongation of the action of drugs.
Regulating the sequential absorption of individual medicinal substances from a tablet of complex composition - creating multilayer tablets.
10.Prevention of errors when dispensing and taking medications, achieved by pressing inscriptions on the tablet.
Along with this, the tablets have some flaws:
During storage, tablets may lose disintegration (cement) or, conversely, collapse.
With tablets, auxiliary substances are introduced into the body, which sometimes cause side effects (for example, talc irritates the mucous membranes).
Certain medicinal substances (for example, sodium or potassium bromides) form concentrated solutions in the dissolution zone, which can cause severe irritation of the mucous membranes.
These disadvantages can be overcome by selecting excipients, crushing and dissolving the tablets before administration.
Tablets can come in a variety of shapes, but the most common is round 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. According to production method:
pressed - produced at high pressures on tablet machines;
trituration - obtained by molding wet masses by rubbing into special forms, followed by drying.
2. By application:
oral - taken orally, absorbed in the stomach or intestines. This is the main group of tablets;
sublingual - dissolve in the mouth, medicinal substances are absorbed by the oral mucosa;
implantation - implanted/sewn/ under the skin or intramuscularly, providing a long-term therapeutic effect;
tablets for extemporaneous preparation of injection solutions;
tablets for preparing rinses, douches and other solutions;
tablets for special purposes - urethral, vaginal and rectal.
The material for producing tablets by direct compression must have good compressibility, flowability, optimal humidity, have approximately the same granulometric composition and isometric particle shape.
Technological diagram:
1) Weighing – measuring the starting material.
2) Grinding.
An essential requirement for the direct compression method is the need to ensure uniformity of the active component content. To achieve high homogeneity of the mixture, they strive for the finest grinding of the drug. For this purpose, mills for ultrafine grinding are used, for example, jet mills - the material is crushed in a stream of energy carrier (air, inert gas) supplied to the mill at a speed reaching several hundred m/s.
3) Mixing. Direct pressing in modern conditions is the pressing of a mixture consisting of drugs, fillers and excipients => mixing is necessary to achieve homogeneity. High homogeneity of the mixture is achieved in centrifugal mixers.
4) Pressing.
On a rotary tablet machine (RTM). To avoid delamination and cracks of tablets, it is necessary to select the optimal pressing pressure. It has been established that the shape of the punches affects the uniform distribution of pressing forces over the diameter of the tablet: flat punches without chamfers contribute to obtaining the strongest tablets.
For direct pressing, RTM-3028 is recommended, which has a device for vacuum supply of powders into the matrix. At the moment of loading the material through a hole connected to a vacuum line, air is sucked out of the matrix cavity. In this case, the powder enters the matrix under vacuum, which ensures high speed and increases dosing accuracy. However, there are disadvantages - the vacuum design quickly becomes clogged with powder.
Hardware diagram for tablet production
TS-1 Preparatory
Sieves with hole sizes 0.2-0.5 mm
TS-2 Mixing
Worm-blade type mixer
TS-3 Tableting
TS-4 Tablet quality control
Micrometer
Analytical balances
Device "Erveka", for def. compressive strength
Friabilator for defined abrasion resistance
"Swinging basket" device
Rotating basket device
Spectrophotometer
TS-5 Packaging and labeling
Automatic machine for packing tablets into cellless packaging
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 binding agent.
humidification: if it is necessary 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– binding agent, for the strength of granules and tablets
Stearic acid– a sliding substance (lubricating and preventing sticking) – facilitates the easier ejection of tablets from the matrix, preventing the formation of scratches on their edges; anti-stick agents prevent the mass from sticking to the walls of the punches and dies, as well as the particles sticking together.
Talc- a gliding substance (just like stearic acid + provides gliding - this is its main effect) - uniform flow of tablet masses from the hopper into the matrix, which guarantees the accuracy and consistency of the dosage of the drug. The result is uninterrupted operation of the tablet machine and high quality 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 compression, add 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 release of drugs. With MCC it is possible to produce durable, but not always easily disintegrating tablets. To improve the disintegration of tablets with MCC, it is recommended to add ultraamylopectin.
Direct pressing shows the use of modified starches. The latter enter into chemical interaction with drugs, significantly affecting their release and biological activity.
Often used milk sugar as a means of improving the flowability of powders, as well as granulated calcium sulfate, which has good fluidity and ensures the production of tablets with sufficient mechanical strength. Cyclodextrin is also used, which increases the mechanical strength of the tablets and their disintegration.
Direct pressing in modern conditions, this 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 uniformity of the active component content. To achieve the 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 cracks. With direct pressing, the top and bottom of the tablet are most often separated in the form of cones. One of the main reasons for the formation of cracks and delaminations in tablets is the heterogeneity 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 powder mass in the radial direction, which leads to uneven tablet density. When the pressing pressure is removed due to elastic deformation of the matrix walls, the tablet experiences significant compressive stresses, which lead to cracks in its weakened sections due to the uneven density of the tablet due to external friction responsible for the transfer of powder mass in the radial direction.
Friction on the side surface of the matrix also influences during tablet ejection. Moreover, most often, delamination occurs at the moment when part of the tablet leaves the matrix, since at this time the elastic aftereffect of part of the tablet appears when pushed out of the matrix, while the part of it located in the matrix does not yet have the opportunity to deform freely. It has been established that the uneven distribution of pressing forces along the diameter of the tablet is influenced by the shape of the punches. Flat, non-chamfered punches produce the strongest tablets. The least durable tablets with chips and delaminations were observed when pressing with deep-sphere punches. Flat punches with a chamfer and spherical punches with a normal sphere occupy an intermediate position. It is also noted that the higher the pressing pressure, the greater the prerequisites for the formation of cracks and delaminations.
6 Disadvantages Low bioavailability (compared to powders and liquid dosage form) Insufficient stability in certain climatic conditions The phenomenon of cementation of tablets Impossibility of administration to an unconscious patient Irritant effect of explosives Severe irritation of the mucous membranes in the zone of dissolution and absorption
7 Classification of tablets 1. By production method: - pressed (tablets themselves) – 98%; - trituration 2. By composition: - simple - complex 3. By structure: - homogeneous - frame - multilayer - with or without coating - retard (from microcapsules), etc.
8 4. By the nature of the coating: - Coated - Pressed - Film 5. By area, method and place of application: - For internal (gastric, sublingual, cheek) - For external (preparation of solutions, vaginal, rectal, ophthalmic) - Implantation
14 Shape and size of particles Anisodiametric (asymmetrical, different axes). Elongated shape - the length significantly exceeds the transverse dimensions (sticks, needles, etc.), or lamellar, when the length and width are significantly greater than the thickness (plates, scales, tablets, leaves, etc.).
18 Wettability a) with complete wetting, the liquid completely spreads over the surface of the powder; b) by partial wetting, water partially spreads on the surface; c) with complete non-wetting, a drop of water does not spread, maintaining a shape close to spherical. Wettability proportionally affects the disintegration of tablets.
20 Technological properties of tableted materials Fractional (granulometric) composition or particle size distribution of the material, determined by sieve analysis. PS depends on: - the shape and size of particles. PS affects: - the degree of flowability of the powder - the stability of the tablets - the accuracy of drug dosage - the qualitative characteristics of the tablets
21 Bulk mass (density) the mass of a unit volume of freely poured material NM depends on: - fractional composition, - humidity, - density of the powder. Determined by freely filling the powder into a certain volume, followed by shaking by weighing with an accuracy of 0.01 g. NM affects: - on powder flow
23 Porosity - the presence of voids between particles and inside individual particles The greater the porosity, the less substance is placed in the mold Open porosity - between and inside the particles there is an outlet to the outside Determination of porosity: - by pressing to zero porosity - by displacement method - open pores are replaced with liquid under vacuum (determining the difference in volumes before and after evacuation)
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27 Cases of direct pressing Simple direct pressing By forced feeding of the tablet material from the funnel of the tablet machine into the matrix, which requires special devices Pressing with preliminary crystallization of substances Pressing with auxiliary substances
28 Cases of direct pressing Pressing with preliminary crystallization of substances (acetylsalicylic and ascorbic acids). Pressing with auxiliary substances (bromocamphor, hexamethylenetetramine and PAS-sodium, loosening and antifriction substances are added to the composition of the pressing mass)
29 AUXILIARY SUBSTANCES IN TABLET TECHNOLOGY Fillers are used to give the tablet a certain mass (the content is not standardized) - Starch, glucose, sucrose, lactose, basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, white clay, gelatin, microcrystalline cellulose (MCC ), methylcellulose (MC), sodium salt of carboxymethylcellulose, calcium carbonate, disubstituted calcium phosphate, glycine, dextrin, amylopectin, ultraamylpectin, sorbitol, mannitol, pectin and other sucrose,
30 New excipients for tableting: modified starch - Starch-1500 (Colocron, USA), Tablettose (Meggle, Germany), sorbitol and “conjugated” calcium carbonate and sorbitol - Formaxx® CaCO3 70 (Merck KGaA), Povidone 630-S ( BASF, Germany), compressed sucrose - Compri Sugar® (Suedzucker AG), sorbitol for direct compression - Parteck® SI (Merck KGaA), mannitol for direct compression - Parteck® M (Merck KGaA), microcrystalline cellulose - Microcel® MC 102 ( Blanver Farmoquimica Ltda), a combination of lactose monohydrate with two types of PVP - Ludipress (BASF, Germany) and others. The following disintegrants are used: croscarmellose sodium - Explocel and Solutab® (Blanver Farmoquimica Ltda), sodium starch glycolate (Avebe, the Netherlands) and sodium starch glycolate - Explosol® (Blanver Farmoquimica Ltda).
31 Binders are introduced in dry form or in a granulating solution into the composition of masses for tableting during granulation to ensure the strength of granules and tablets (not standard, 1-5%) - Purified water, ethyl alcohol, starch paste, sugar syrup, solutions: carboxymethylcellulose CMC ), hydroxyethylcellulose (OEC), hydroxypropylmethylcellulose (OPMC); polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, etc.
32 Disintegrants Provide rapid mechanical destruction of tablets in a liquid medium 1) swelling agents - substances that burst the tablet after swelling upon contact with liquid (not the norm). - alginic acid and its sodium salt, - amylopectin, - ultra amylopectin, - methylcellulose (MC), - sodium salt of carboxymethylcellulose (Na KMC), - microcrystalline cellulose, - agar-agar - polyvinylpyrrolidone (PVP).
39 Dyes to improve the appearance and designate the therapeutic group of drugs - indigo (blue), - tartrazine (yellow), - osine - a mixture of indigo and tartrazine (green) - titanium dioxide (white). -natural dyes: chlorophyll, carotenoids, colored fatty sugars
46 Dry granulation 1) Granulation by grinding - granules are obtained from a dried tablet mass, previously moistened. Spanish Excelsior, vertical granulators 2) If moistening is impossible - grinding briquettes 3) Granulation by melting - for substances that do not collapse at the melting temperature
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57 Marmerizer Marmerizer plate Rotation speed rpm Run-in time 2 min
65 Selecting the shape and size of tablets The main requirement is the purpose of the tablets and the dose of the drug (for children - without sharp edges and corners, vaginal - torpedo-shaped, rings) The shape ensures the structural and mechanical properties of the tablets (strength) The optimal ratio of the height and diameter of the tablet is height 30-40 % of the diameter of OST “Tablets, types and sizes”
67 Crank-and-pin tablet machines Translate rotational movements into translational ones Low productivity M.b. sled and shoe machines (they differ in the principle of movement of the loading funnel) Have 1 set of press tools The worker is the upper punch, the lower one pushes out the tablet
72 Phases of the tableting process 1. compaction-pre-pressing occurs when the particles of the material are brought together and compacted without deformation due to the displacement of the particles relative to each other and filling the voids. Begins at low pressures, energy is spent to overcome internal resistance
75 Ejection The upper punch begins to rise, the lower one follows it and stops exactly at the die cut, pushing the tablet onto the table surface. The speed of movement of the upper punch must be higher than the lower one, otherwise the tablet will be destroyed. In the RTM, by the movement of the rotor, the tablet is brought to a special cut-off knife and directs the tablet into the tray
81 Coating of tablets. appearance, mechanical density, hide the unpleasant taste, smell and staining properties of tablets, protect from environmental influences, localize or prolong the effect of a medicinal substance, protect the mucous membranes of the gastrointestinal tract from the destructive effects of drugs
83 Primer is carried out with the aim of creating a rough surface on the tablets - a base layer, on which it is then easy to build up another layer that will adhere well. Moisten with sugar syrup and evenly sprinkle with flour, and after 3-4 minutes with basic magnesium carbonate. The operation is repeated 2-3 times.
85 Grinding. Smoothing of surfaces, roughness, small protrusions and chips on the surface of the shells is carried out in a rotating obductor with a small amount of sugar syrup with the addition of 1% gelatin. The tablets are then dried for 3040 minutes.
88 Coatings soluble in gastric juice - diethylaminomethylcellulose, -benzylaminocellulose, -para-aminobenzoates of sugars and cellulose acetate, etc. Tablets are coated with solutions of these substances in organic solvents: ethanol, isopropanol, acetone.
89 Enteric soluble coatings - cellulose acetylphthalyl, - cellulose metaphthalyl, - polyvinyl acetate phthalate, - dextrin, - lactose, - mannitol phthalates, - copolymers of vinyl acetate with acrylic, methacrylic acids; -polyacrylic resins. Film formers are applied to the tablet in the form of solutions in ethanol, isopropanol, ethyl acetate, acetone, toluene or mixtures of these solvents.
90 Insoluble coatings are films with a microporous structure. -synthetic cellulose derivatives (ethylcellulose and cellulose acetate) Apply to tablets in the form of solutions in ethanol, isopropanol, acetone, chloroform, ethyl acetate, toluene. 92 Fluid Bed Coating 95 Filling and packaging of tablets Contour cell packaging As a thermoformable film, rigid unplasticized or weakly plasticized polyvinyl chloride is most often used, which is well molded and heat-sealed with various materials (foil, paper, cardboard, coated with a thermovarnish layer).
Preparation of raw materials
Using a weighing device, we weigh out the components (ascorbic acid, sugar, starch, talc, calcium stearate) that meet the requirements of N.D.
For 100 kg of tablets we need to weigh out:
Ascorbic acid 20.0
Starch 17.6
Sugar 60.0
Talc 1.6
Calcium stearate 0.8
Next, we sift all the components separately on a rotary-vibrating sieve. The sifted material is poured into the hopper (5), from where it enters the sieve (1), where, due to the operation of two vibrator weights (3), a vibration is created that causes the entire mass of powder to rotate along the sieve and the receiver cone (2). The presence of two unbalances at different levels of the shaft imparts circular oscillatory movements to all grid points in the vertical and horizontal planes. The oscillation frequency is regulated by the drive belt drive (4), and their amplitude is controlled by the angle of the vibrator weights. The sieve is sealed with a lid during operation (Figure 1).
Figure 1 - Rotary-vibrating sieve
The finished product is sifted and screened out into different trays, from which it is poured into pre-prepared containers.
Preparing the humidifier
We need to prepare a starch paste as a moisturizer. It is prepared as follows: 0.15 kg of starch is moistened with 0.3 kg of cold water and stirred. The resulting suspension is poured into 3.0 kg of boiling water, boiled for 0.5-1 minutes until the solution clears, filtered and the volume of the solution is adjusted to 3 kg.
We calculate how much starch will be used for this:
20.0 kg - 100%
X = 3.0 kg starch paste
We need to prepare a 5% starch paste:
X = 0.15 kg of starch is needed to prepare starch paste
17.6 kg - 0.15 kg = 17.45 kg of starch, which will be used as a baking powder.
Preparation of the powder mixture
To prepare the dusting mixture, we take talc and stearic acid powders and mix them on a centrifugal mixer with a rotating cone. The centrifugal mixer consists of a body (1) on which a container (2) is installed.
The engine (3) and the drive rotate the working element - an open hollow cone (4), with its large base facing upward. At the bottom of the cone there are two diametrically located windows (5). The cone is covered by a frame mixer (6) installed coaxially with it, which receives rotation from the drive (7) located on the cover (8).
Talc and stearic acid powder is fed through the hatch (9), moves along the inner surface of the cone from bottom to top under the influence of centrifugal forces of inertia, is thrown out of the cone and forms a suspended layer, inside which intensive mixing of the components occurs.
In the space between the cone and the mixer container, the powder crosses the area through which the frame mixer blades pass. They additionally mix the powder and direct part of it through the windows (5) back into the cone. After mixing, the finished mixture is unloaded through a tray (10) with a gate (11) (Figure 2).
Figure 2 - Centrifugal mixer with rotating cone
Preparation of mass for tableting
Powder of ascorbic acid and milk sugar is placed in the SG-30 apparatus to carry out wet granulation and drying of the granulate (Figure 3). Operating principle of the SG-30 apparatus: the apparatus body (11) is made of three all-welded sections. The product tank (3) has the shape of a truncated cone, expanding upward and then passing into the sprayer shell (4), which is connected to the bag filter shell (5).
The reservoir with the initial components on the trolley (1) is rolled into the apparatus, lifted by a pneumatic cylinder (2) and compacted with the atomizer shell. The air flow is sucked in by a fan (8) driven by an electric motor (7), cleaned in air filters (12), heated to a predetermined temperature in a heating unit (16) and passes from bottom to top through an air distribution grate installed in the lower part of the product tank. In this case, the product comes into suspension and is mixed.
Then, granulating liquid is supplied to the fluidized layer of the initial components from the container (14) by a metering pump (13) through a nozzle, and the tablet mixture is granulated. Compressed air supplied to the pneumatic nozzle through a special system (15) is used not only to spray the granulating liquid, but also to remotely control the nozzle. During granulation, the bag filters are automatically shaken. The lifting device (6) is electro-pneumatically interlocked with a device that closes the dampers (10).
When the bag filters are shaken, the damper blocks the flow of fluidizing air to the fan, thus stopping the fluidization of the product and removing the air load from the bag filters. By shaking, the filters are cleared of the product in the form of dust, which is then granulated. A damper (9) with a manual control mechanism is located in the outlet part of the fan. It is designed to regulate the flow of fluidizing air. After a certain period of time, the spraying system is switched off and drying of the granulate begins.
The device operates in automatic mode. The time relay ensures the sequence and required duration of operations, as well as the cyclicity and duration of the process of shaking the bag filters and the synchronous operation of the damper.
At the end of the entire granulation cycle, the fan automatically turns off and the steam supply to the heating unit stops. The food tank is lowered. The cart along with the tank is rolled out of the dryer, and the granulate is sent for dusting.
Figure 3 - SG-30 device
Granulate dusting
Our powdering agents are talc and stearic acid, but during the dusting process we also add loosening agents - starch.
The dusting process takes place in a dusting machine. It is a conveyor with two bunkers mounted above it. We pour granulate into one bin, and dusting agents and baking powder into the second. The rate of supply of substances from the bunkers is controlled using dampers. Along the path of mass movement, so-called plows are installed, which mix the dusting layer.
The granulate is poured into a receiver that has electromagnets to catch metal objects that accidentally fall into the granulate. Then the powdered granules are poured from the receiver into containers and fed to tablet machines.
Tableting
The tableting process takes place in a rotary tableting machine RTM-41. From the hopper, the powder flows by gravity into a feeder-dispenser, fixedly mounted on the machine frame. The filling agitator uses blades to feed powder into the matrix, while the punches mounted in the pushers are lowered along a fixed copier and an adjustable copier to the full depth of filling the matrices. With further rotation of the rotor, the pusher follows the horizontal section of the copier to the dosing mechanism, which consists of a copier and an adjustable dispenser pivotally connected to it. The copier-dispenser moves the pusher with the punch upward, raising the powder in the matrix to a height corresponding in volume to the given tablet mass (0.051 g). At this time, the blades of the dosing agitator cut off the excess dose and transfer it back to the action area of the filling agitator. Since the blades are located 1.0-1.5 mm above the bottom of the feeder body, the edge of the feeder body also participates in dosing. The dose is finally cut off by a knife with a fluoroplastic plate pressed tightly to the table.
During further dose transfer, the lower pusher hits the horizontal copier, the upper one passes under the copier-chipper, which lowers the upper punches until they enter the matrix. The rollers carry out pre-compression, and the pressure rollers do the actual pressing. At the same time, on the RTM, the powder is kept under pressure due to the presence of a flat end on the pusher head, a 3-4 mm displacement of the axes of the upper and lower pressure rollers, and the introduction of special copiers placed at the level of the pressure roller at the time of pressing. The ejection of the tablet from the plane of the matrix onto the surface of the table mirror is carried out by an ejection mechanism consisting of 3 elements. The ejection roller lifts the tablet from the die wall. The ejection copier brings the tablet to the upper level, and the ejector is adjusted so that the tablet is removed from the matrix onto the table surface, then the rotor brings the tablet to the knife, which directs it to the tray and then into the receiving container.
Packaging of tablets
Ascorbic acid tablets are packaged in contour-free packaging, which is a double tape thermally glued in the form of a lattice, in the non-glued areas of which the packaged tablets are located.
The material for this packaging is cellophane coated with heat-sealing varnish and laminated film. To pack tablets in a two-layer cellophane tape, an A1-AU2-T machine is used. The machine works as follows. Ascorbic acid tablets are loaded into a vibrating feeder, consisting of a hopper and a cylindrical chamber, from the vibrating feeder along inclined guides they are fed to a remote device, with the help of which they are placed on the lower cellophane tape in two rows with a certain pitch.
The cellophane tape comes from the reel holders through a system of guide rollers. The tape from the second reel holder is placed on top.
Passing between heated drums, the cellophane strips are continuously welded and then cut with scissors with a certain number of tablets per package.
Quality control
Determination of average mass and disintegration. Maintain the requirements specified in the Global Fund XI, issue. 2, p. 154. The content of ascorbic acid should be 0.0475-0.0525 g, based on the average weight of one tablet. Disintegration is determined using a “swinging basket” device in accordance with the Global Fund XI, issue. 2, p. 158.
Absorption capacity
0.6 g of finely ground tablet powder is added to a 50 ml cylinder with a ground stopper, 35 ml of a 15% methylene blue solution is added, the mixture is shaken vigorously for 5 minutes, left for half an hour and filtered. The filtrate should be colorless or almost colorless.
The most common are three technological schemes for producing tablets: using wet or dry granulation and direct compression.
Preparation of starting materials for tableting is reduced to their dissolution and hanging. Weighing of raw materials is carried out in fume hoods with aspiration. After weighing, the raw materials are sent for screening using vibrating sifters.
Mixing
The components of the tablet mixture of medicinal and excipients must be thoroughly mixed to distribute them evenly in the total mass. Obtaining a tablet mixture that is homogeneous in composition is a very important and rather complex technological operation. Due to the fact that powders have different physical and chemical properties: dispersion, bulk density, humidity, fluidity, etc. At this stage, batch mixers of the paddle type are used, the shape of the blades can be different, but most often worm-shaped or z-shaped.
Granulation
This is the process of converting powdered material into grains of a certain size, which is necessary to improve the flowability of the tablet 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 auxiliary substances; when dry granulating, wetting liquids are either not used, or they are used only at one specific stage of preparing the material for tabletting.
Wet granulation consists of the following operations:
- grinding substances into fine powder;
- moistening the powder with a solution of binding substances;
- rubbing the resulting mass through a sieve;
- drying and processing of granulate.
Grinding. This operation is usually carried out in ball mills.
Hydration. It is recommended to use water, alcohol, sugar syrup, gelatin solution and 5% starch paste as binders. The required amount of binders is determined experimentally for each tablet mass. In order for the powder to be granulated at all, it must be moistened to a certain extent. The sufficiency of hydration is judged as follows: a small amount of mass (0.5 - 1 g) is squeezed between the thumb and index finger; the resulting “cake” should not stick to your fingers (excessive moisture) and crumble when dropped from a height of 15–20 cm (insufficient moisture). Humidification is carried out in a mixer with S (sigma) - shaped blades, which rotate at different speeds: the front - at a speed of 17 - 24 rpm, and the rear - 8 - 11 rpm, the blades can rotate in the opposite direction. To empty the mixer, the body is tilted and the mass is pushed out using the blades.
Rubbing(actually granulation). Granulation is carried out by rubbing the resulting mass through a 3-5mm sieve (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 to avoid wire scraps getting into the tablet mass. Wiping is carried out using special wiping machines - granulators. The granulated mass is poured into a vertical perforated cylinder and rubbed through the holes using spring blades.
Drying and processing of granules. The resulting ranulas 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. The residual moisture in the granules should not exceed 2%.
Typically, the operations of mixing and uniformly moistening 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 through vigorous, forced circular mixing of the particles and pushing them against each other. The mixing process to obtain a homogeneous mixture lasts 3-5". Then granulating liquid is added to the pre-mixed powder into the mixer, and the mixture is mixed for another 3-10". After the granulation process is completed, the unloading valve is opened, and with the scraper slowly rotating, the finished product is poured out. Another design of the apparatus for combining mixing and granulating operations is a centrifugal mixer - granulator.
Compared to drying in ovens, which are low-productive and in which the drying time reaches 20–24 hours, drying granules in a fluidized (fluidized) bed is considered more promising. Its main advantages are: high intensity of the process; reduction of specific energy costs; possibility of complete automation of the process.
If wet granulation operations are performed in separate apparatuses, then dry granulation is followed by dry granulation. After drying, the granulate is not a uniform mass and often contains lumps of sticky granules. Therefore, the granulate is re-entered into the cleaning machine. After this, the resulting dust is sifted from the granulate.
Since the granules obtained after dry granulation have a rough surface, which makes it difficult for them to fall out of the loading funnel during the tableting process, and in addition, the granules can stick to the matrix and punches of the tablet press, which causes, in addition to weight loss, defects in the tablets, they resort to to the operation of “dusting” the granulate. This operation is carried out by freely applying finely ground substances to the surface of the granules. By dusting, gliding and loosening substances are introduced into the tablet mass.
Dry granulation
In some cases, if the drug substance decomposes in the presence of water, dry granulation is resorted to. To do this, briquettes are pressed from the powder, which are then ground to produce grits. After sifting out the dust, the grains are tabletted. Currently, dry granulation is understood as a method in which powdered material is subjected to initial compaction (pressing) to produce granules, which are then tableted - secondary compaction. During the initial compaction, dry adhesives (MC, CMC, PEO) are introduced into the mass, ensuring the adhesion of particles of both hydrophilic and hydrophobic substances under pressure. PEO in combination with starch and talc has been proven suitable for dry granulation. When using PEO alone, the mass sticks to the punches.
Pressing
Pressing (actually tableting). It is the process of forming tablets from granular or powdered material under pressure. In modern pharmaceutical production, tabletting is carried out on special presses - tablet presses, another name is a rotary tableting machine (RTM).
Pressing on tablet presses is carried out using a press tool consisting of a matrix and two punches.
The technological cycle of tableting on tablet presses consists of a number of sequential operations: dosing of material, pressing (forming a tablet), pushing it out and dumping it. All of the above operations are carried out automatically one after another using appropriate actuators.
Direct pressing. This is a process of pressing non-granular powders. Direct pressing eliminates 3–4 technological operations and thus has an advantage over tabletting with preliminary granulation of powders. However, despite the apparent advantages, direct pressing is slowly being introduced into production. This is explained by the fact that for the productive operation of tablet machines, the pressed material must have optimal technological characteristics (flowability, pressability, humidity, etc.). Only a small number of non-granulated powders have such characteristics - sodium chloride, potassium iodide, sodium and ammonium bromide, hexomethylenetetramine, bromocamphor and other substances that have isometric particle shapes of approximately the same granulometric composition and do not contain a large number of small fractions. They press well.
One of the methods for preparing medicinal substances for direct compression is directed crystallization - one achieves the production of a tablet substance in crystals of a given flowability, compressibility and humidity through special crystallization conditions. This method produces acetylsalicylic acid and ascorbic acid.
The widespread use of direct pressing can be ensured by increasing the flowability of non-granulated powders, high-quality mixing of dry medicinal and auxiliary substances, and reducing the tendency of substances to separate.
Dust removal
To remove dust fractions from the surface of tablets coming out of the tablet press, dedusters are used (vibrating tablet deduster and auger tablet deduster). The tablets pass through a rotating perforated drum and are cleaned of dust, which is sucked off with a vacuum cleaner.
Packing and packing
Tablets are available in various packaging designed for purchase by patients or medical institutions. The use of optimal packaging is the main way to prevent deterioration in the quality of tablet drugs during storage. Therefore, the choice of the type of packaging and packaging materials for tablets is decided in each specific case individually, depending on the physicochemical properties of the substances included in the tablets.
One of the most important requirements for packaging materials is the protection of tablets from exposure to light, atmospheric moisture, atmospheric oxygen, and microbial contamination.
For the packaging of tablets, traditional packaging materials such as paper, cardboard, metal, glass (cardboard coins, glass test tubes, metal cases, bottles for 50, 100, 200 and 500 tablets, iron cans with a pressed-on lid for 100 - 500 tablets) are currently used ).
Along with traditional materials, film packaging made from cellophane, polyethylene, polystyrene, polypropylene, polyvinyl chloride and various combined films based on them are widely used. The most promising are film contour packaging produced from combined materials by heat sealing: cellless (tape) and cell (blister).
For tape packaging, they are widely used in various combinations: laminated cellophane tape, aluminum foil, laminated paper, polymer film laminated with polyester or nylon. The packaging is made using heat sealing of two combined materials.
Packaging is carried out using special machines (Automatic tablet packaging machine). Cell packaging consists of two main elements: a film from which cells are thermoformed, and a heat-sealing or self-adhesive film for sealing the packaging cells after filling them with tablets. The thermoformable film most often used is rigid (unplasticized) or slightly plasticized polyvinyl chloride (PVC) with a thickness of 0.2-0.35 mm or more. PVC film is well shaped and heat-seals with various materials (foil, paper, cardboard, coated with a thermovarnish layer). It is the most common material used for packaging non-hygroscopic tablets.
Coating polyvinyl chloride film with polyvinyl chloride or halogenated ethylene reduces gas and vapor permeability: lamination of polyvinyl chloride with polyester or nylon is used to make cell packaging that is safe for children.
