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Tableting

Marvin "Popcorn" Sutton

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The technology of manufacturing tablets is called tabletting and involves several successive operations to obtain the desired form.
The tablet is a dosage form made by pressing drugs or a mixture of drugs and excipients. It is intended for internal oral use. Tablets are one of the most common and promising forms of substances and make up a large part of the total amount of drugs.
This is because tablets have a number of advantages over other forms of substances:
Accuracy of dosing substances introduced into the tablet: the homogeneity (uniformity) distribution of the active substance in the tablet, the correct weight of both the tablet and its constituent drugs.
The dosing accuracy depends on the homogeneity of the tablet mass, which is ensured by careful mixing of drugs and excipients and their uniform distribution in the total mass. The dosing accuracy also depends on the rapidity and failure of filling the matrix socket of the tablet machine. If less material than the matrix socket can accept is dispensed in the short time the funnel stays over the matrix opening, the weight of the tablets received will be insufficient. The required filling rate of the matrix socket depends on the shape of the funnel, the inclination angle, and whether the particles of the material to be pelletized have sufficient slip. Often the friction forces between the individual particles due to the roughness of their surface are so great that the matrix socket is not completely filled or not filled at all due to the delay of the powder in the funnel. In these cases, antifriction agents are added to the material to reduce friction between the particles by giving them a smooth surface. Usually small powders, which tend to stick to the surface of the funnel, have poor sliding properties, so it is necessary to artificially increase the particle size to the optimal value by granulating the material.
The delamination causes a change in the weight of the tablets. In some cases, the delamination can be prevented by installing a small agitator in the funnel, but a more radical measure is to equalize the particle sizes by granulating the material.
When talking about homogeneity of material, we also mean homogeneity of its particle shape. Particles having different spatial outline at approximately the same mass will be placed in the matrix nest with different compactness. This will also cause fluctuations in the mass of the tablets. The alignment of the shape of the particles is achieved by the pelletizing process. It is difficult to achieve homogeneity of granules, therefore, by varying the ratio of granulate fractions by experiment, it is possible to establish the optimal composition corresponding to the best flowability and high quality of tablets at a certain pressure of pressing.
Quality of tablets: preservation of substances in the pressed state; mechanical durability; hardness/ brittleness. Tablets must have sufficient strength to remain intact under mechanical influences during packaging, transportation and storage.
Mechanical strength is due to the interlocking of the particles. Pelletizing is performed by pressing with the help of tablet machines at a pressure of 50-300 MPa (usually 250 MPa, less often higher). At the beginning of the pressing process the pellet mass is compacted, the particles become closer together and the conditions for the forces of intermolecular and electrostatic interaction are created. The forces of intermolecular interaction are manifested when the particles approach each other at a distance of 10 "6-10 "7 cm.
The process of pressing the tablet mass can be divided into three stages.
Mechanical strength depends on the amount of pressure in the pressing process, and it is important to trace how the pressure will increase during pressing. In impact tablet machines (eccentric) the pressure increases sharply, as a result of which the surface of the tablet under impact of the punches is strongly heated (mechanical energy is converted into thermal energy) and the substances fuse, forming a continuous cementing layer.

In rotary tablet machines, the pressure builds up gradually, which gives better results because it provides a longer exposure to pressure on the tablet mass. The longer the pressure is applied, the more completely the air is removed from the pellet material, which can have a damaging effect on the pellets once the pressure is released. In addition, the heating of the tablet at the surface is significantly reduced, which eliminates the harmful effects of the increased temperature on the tablet's constituent substances.
The use of high pressing pressure can have a negative effect on tablet quality and contribute to tablet machine wear. High pressure can be compensated by adding substances that have a large dipole moment and ensure particle adhesion at relatively low pressures. Water, having sufficient dipole moment, is a "bridge" between these particles. Water will interfere with binding of particles of hardly soluble and insoluble drugs. In such cases, the addition of substances with higher adhesive strength (solutions of starch, gelatin, etc.) is required, and again it is necessary to resort to granulation to introduce into the pelletized mass of binding agents that increase the plasticity of the drugs; this manifests a property called adhesion, which causes the particles to stick to each other.
Solubility and break apart - the ability to disintegrate or dissolve within the time frame specified by the relevant scientific and technical documentation for certain types of tablets.
The tablet must have the necessary break apart with sufficient mechanical strength. Too high strength of the tablet affects its break apart and release of the drug substance - the break apart time increases, which has a negative impact on the quality of the tablet. Break apart depends on a number of reasons:
- the amount of binding agents: the tablets should contain as much of them as necessary to achieve the required strength;
- the compression pressure: too much pressure impairs the break apart from tablet;
- the quality of the loosening agents that contribute to the break apart from tablets;
- the properties of the substances in the tablet, their ability to dissolve in water, to be wet by water, to swell; tablets with readily soluble substances will disintegrate faster and require less disintegrants.
The portability of the tablets provides ease of use, dispensing, storage and transportation of the substances.
Tablets are flat or biconvex plates of round, oval or other shapes. The diameter of the tablets varies from 3 to 25 mm, the most common being 5-14 mm in diameter. The height of the tablets should be 30-40% of their diameter.
Tablets over 9 mm in diameter may have a notch that is applied to them during pressing. The notches make it easy to break the tablet and divide it into 2 or 4 doses to vary the dosage of the substance.

Production of tablets.
The mass subjected to tabletting must have a set of properties that meet the above requirements: dosing accuracy, mechanical strength and disintegrability.
Tablets are made by pressing powders on tabletting machines. This is the main method of tablet production.
The choice of optimal technological scheme of tablets production depends on the physicochemical and technological properties of drugs, their amount in the tablet, resistance to environmental factors, etc.
Currently, three main methods of tablet production are used: by direct compression of substances, dry and wet granulation.

The technology of tablet production is divided into several stages:
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The choice of raw materials for tablets must be approached with the utmost importance. Raw materials for the pharmaceutical industry are particularly high-quality organic and inorganic substances. The restrictive requirements placed on these semifinished products relate not only to purity, but also to the strictly defined technical parameters resulting from a correctly conducted production process. For this reason, it is worth paying attention to manufacturers of pharmaceutical raw materials that apply high production standards. Raw materials for tablets are divided into two categories: active ingredients and excipients. The composition of the tablet is carefully selected by technologists, so that the product meets the specified parameters. Just below, you will see more detailed characteristics of active and excipients.
An example of the composition of a tablet:
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When making pills, the first thing to do is to choose the main active ingredient. The most common active ingredient in pills is MDMA (3,4-methylenedioxymethamphetamine), which is a club drug and is popular with many young people. But you can use any substance that can have its effect when taken orally.
Different substances have different effects on a person and are divided into classes: empathogens, stimulants, psychedelics and others. So, you should carefully study what effect and after what dosage will come when taking the drug, to do this, use any available literature and the Internet. And also, it is recommended to study the effect of the dosage of the drug on the volunteers, before you start its mass production. It is especially important to conduct biotests on volunteers, if you are going to use several active substances in the composition of the pill, in order to calculate the optimal proportions of cross-acting substances. It is highly discouraged to use more than two main active ingredients, because the risk of individual intolerance increases.
When choosing an active ingredient, you need to proceed from several factors: availability of raw materials, quality, cost, demand. Popular substances, their combinations with each other, as well as their dosages can be easily found on the Internet on thematic forums.
Examples of active substances in tablets: Methylenedioxymethamphetamine (MDMA), Methylenedioxyamphetamine (MDA), Fluoramphetamine (4FA), Methylone (bk-MDMA), Mephedrone (4MMC), Methamphetamine, Amphetamine, Mescaline, 4-bromo-2,5-dimethoxyphenethylamine (2-cb), 3,4,5-trimethoxy-alpha-methylphenyl-amine (TMA), Ketamine , Phencyclidine, 5-MeO-DiPT and many others...
Excipients are substances used in the manufacturing process to give the desired properties to the tablets. These substances are divided into classes:
Anti-adhesives - excipients that reduce adhesion or sticking of granulate or powder of tablet mass to the end surface of the punch, used in the technological process of production of tablets at the stage of pressing.
One of the problems of pellet production is obtaining good flowability of granulate in feeding devices (funnels, hoppers). The obtained pellets or powders have a rough surface, which makes it difficult to suck them from the feed hopper into the matrix sockets. In addition, the pellets may adhere to the walls of the matrix and punches due to the friction developed in the contact areas of the particles with the tablet press tool. To eliminate or reduce these undesirable phenomena, antifriction agents represented by the sliding group and the lubricating group are used.
Sliding agents adsorb on the surface of the particles (pellets), eliminate or reduce their roughness, increasing their fluidity (flowability). Lubricants not only reduce friction in the contact areas, but also greatly facilitate deformation of particles due to adsorption reduction of their strength by penetrating into the micro crevices. The function of lubricants is to overcome the frictional force between the pellets and the matrix wall, between the pressed tablet and the matrix wall at the moment of pushing out of the matrix by the bottom punch.
Talc is one of the substances representing the type of lamellar silicates, which are based on layers of dense hexagonal packing. The layers are bound to each other by residual van der Waals forces, the weakest of all chemical bonds. Due to this property and high dispersion of particles, they are capable of deformation and good sliding.
Antioxidants - excipients that prevent undesirable oxidation of the active or other excipient due to strong reducing properties or other mechanisms of interaction of the excipient.
Flavoringagents - excipients intended to give pills the desired smell, usually the smell of fruit, berries, mint, vanilla, etc.
Buffers - excipients intended to regulate the pH of the tablet environment.
Taste-maskingagents - excipients intended to give tablets the desired taste, usually the taste of fruit, berries, chocolate, etc. As a Taste-masking agents now proposed to use natural and synthetic substances in the form of solutions, syrups, extracts, essences. Of the syrups especially widespread sugar, cherry, raspberry, from the sweetening substances - sucrose, lactose, fructose, sorbitol, saccharin. The most promising is sorbitol, a substitute for sucrose, which forms viscous solutions and also stabilizes some medicinal substances. In addition to the above substances, various taste-masking compositions are used for taste correction, the macromolecules of which seem to envelop the molecules of the medicinal substance and the taste receptors on the tongue. These include agar, alginates, methylcellulose and pectins. Essential oils also have a corrective effect: peppermint, anise, orange.
Dyes are added to improve the appearance of the tablets, as well as to indicate the therapeutic group of drugs, such as sleeping pills, poisonous. In addition, some dyes are stabilizers of photosensitive drugs.
Dyes approved for use in pharmaceutical technology are classified into groups:
- Mineral pigments (titanium dioxide - white pigment, iron oxide), which are used in the form of finely ground powders;
- dyes of natural origin (chlorophyll, caratinoids), though they have the following drawbacks: low colouring ability, low resistance to light, oxidants and reducing agents, to changes in pH, temperature changes;
- synthetic dyes: indigo (blue), tartrazine (yellow), acid red 2C, tropeolin, eosin. Sometimes a mixture of indigo and tartrazine is used, which has a green color.
Disintegrants are auxiliary substances used to disintegrate tablets or dissolve drugs. According to the mechanism of action, disintegrants are divided into three groups:
a) Swelling - break the tablet by swelling in a liquid medium. This group includes powders of alginic acid and its salts, amylopectin, etc.
b) Improving wettability and water permeability - starch, polysorbate-80, etc.
c) Gas-forming substances: a mixture of citric and tartaric acids with sodium hydrogen carbonate or calcium carbonate - when dissolved components of the mixture release carbon dioxide and destroy the tablet.
Colourants - auxiliary substances used to give color to tablets.
Fillingagents - excipients used to give a given volume or weight to the tablets. Fillers determine the technological properties of the mass for tabletting and physical and mechanical properties of the finished tablets.
Binders - excipients used to ensure the strength of tablets by binding components; in the manufacturing process, they are used in solid (dry) form. Binders agent are used for granulation and providing the necessary strength of pellets and tablets. For this purpose water, ethyl alcohol, solutions of gelatin, starch, sugar, sodium alginate, natural gum, cellulose derivatives, polyvinylpyrrolidone, etc. are used. When adding substances of this group, it is necessary to take into account the possibility of deterioration of tablet disintegrability and the rate of release of the drug substance.
Glidants - excipients used in the manufacturing process of tablets at the stage of pressing to improve fluidity of granules or powder by reducing friction between the particles.
Lubricants - auxiliary substances that help to reduce the frictional force between the surface of the tablet and the walls of the punch cell in which the tablet is formed, used in the technological process of manufacturing tablets in the pressing stage,
Humectants - excipients used to bind components in tablets and other solid dosage forms; used in the manufacturing process in the form of a solution.

The total list of excipients :
Loosening: swelling gas improving wettability and water permeability wheat starch, potato, corn, rice, pectin, gelatin, methylcellulose, carboxymethyl cellulose, amylopectin, agar-agar, alginic acid, potassium and sodium alginate, etc. Mixture of sodium hydrogen carbonate with citric or tartaric acid, etc. wheat starch, potato starch, corn starch, rice starch, sugar, glucose, polysorbate 80, aerosil, etc. Binders: purified water, ethyl alcohol, starch paste, sugar syrup, carboxymethylcellulose, oxyethylcellulose, oxypropyl methylcellulose solutions, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, alginic acid etc.
Antifriction slip, lubricants: starch, talc, aerosil, polysorbate-80, etc. stearic acid, calcium and magnesium stearate, etc.
Corrigents of taste, smell, color: sugar, glucose, fructose, sucrose, xylitol, mannitol, sorbitol, glycine, asparkam etc. essential oils, fruit juice concentrates, menthol, vanillin, fruit essences etc. indigo carmine, tartrazine (yellow), acid red 2C.
Dyes: tropelin, eosin, carotene, chlorophyll, ruberozum, titanium dioxide, activated carbon, calcium carbonate, white clay, iron oxide, etc.
In the manufacture of pharmaceutical forms of powdered material, in addition to mixing and pressing, there are operations of grinding, granulation and tabletting.
Requirements for rooms:
Weighing of starting materials usually should be carried out in a separate weighing room designed for that use. This explicit requirement for a weigh-in area reflects the importance of the process. In addition to the requirements regarding layout, surfaces, etc., the rooms should also be separate from the other rooms in the production area. During the planning phase, the location of the weigh-in process should be established depending on the defined material and personnel flows. Permanent weigh-in in multi-functional rooms is thus not recommended. This is understandable, as the weigh-in system must be very precisely defined with balances and processes, in order to prevent cross-contamination, mix-ups or confusion.
Requirements of balances:
Balances and measuring devices must have the appropriate measuring range and required precision. They must be calibrated regularly and this must be documented. Due to the importance of the initial weight for the subsequent processes and for the quality of the final product, the checks should be carried out frequently, i.e. in line with the utilisation of the weigh-in area. Usually, daily performance testing should be carried out, in addition to the calibration. For balance faults discovered retrospectively in the course of the day, the number of critical initial weights can be reduced until the time of the performance test (example: daily: performance test with 3 different weights within the calibration range). Calibrations and performance tests are documented in the log book.

The permissible tolerance must be specified for the respective weighing range, taking into account the measurement inaccuracies, i.e. the tolerated deviation from the target value.

The equipment and utensils used when handling the raw materials must meet the requirements made of surfaces in pharmaceutical production. These must be taken into account when selecting product contact parts, such as scoops (welded seams between handle and pan, rivets, etc., which make cleaning difficult), dosage systems (dosing augers), (pneumatic) loading systems and couplings.
Grinding of a drug is used to achieve homogeneity of mixing, elimination of large aggregates in lumpy and sticky materials, increase technological and biological effects.

Grinding powders leads to a certain increase in strength and in the number of contacts between the particles and, as a result, to the formation of strong conglomerates. Using this property, the coal industry obtains strong granules from crushed powders by the rolling method.

Fine grinding of drug powders, despite the possible advantages of bioavailability, has not been widely used, except in isolated cases, in the technology of solid dosage forms production. This is due to the fact that the crystal is a rigidly formed structure with minimal free and high internal energy. Therefore, significant external forces are required for its destruction. At the same time, friction increases in the crystal system simultaneously with comminution, which reduces the applied external load to values that can cause only elastic or insignificant plastic deformation. Therefore, the efficiency of comminution, especially in crystalline substances with a high melting point, decreases rapidly.

In order to increase the plastic deformation, some amount of liquid phase is introduced into the powder to be milled.

The increase of free energy of crystals during milling can cause mechanical and chemical destruction of drugs and decrease their stability during storage.

Grinding of highly plastic substances with low melting points, such as sliding and lubricants, can lead to a significant increase in their effectiveness in tablet making.

Some soft conglomerates of powders can be eliminated by sifting them or by rubbing them through perforated plates or sieves with specific hole sizes. In other cases, sieving is an integral part of grinding to obtain a mixture with a specific particle size distribution.

Grinding is also used for processing of substandard granules and tablets.

For the grinding of powders and granules, a number of devices with different working bodies are proposed. Often crushing units are part of the complex of equipment for processing of initial substances and final products - granules (granulators, pellet blenders, classifiers, etc.).

Due to the small quantities of milled materials in factories for these purposes, in particular, for grinding of substandard granules, pelletizers, ball and hammer mills, micromills, etc. are used.
The constituent ingredients of the tablet mixture of the drug and excipient must be thoroughly mixed to distribute them evenly in the total mass. Obtaining a homogeneous tablet mixture is a very important and rather complicated technological operation. Due to the fact that powders have different physical and chemical properties: dispersity, bulk density, moisture, fluidity, etc. At this stage, batch mixers of paddle type are used, the shape of the blades can be different, but most often worm or zetoblade.
Direct compression is a combination of various technological methods that improve the basic technological properties of the tablet material: flowability and compressibility and obtain tablets from it, bypassing the granulation stage.

The method of direct pressing has a number of advantages. It allows achieving high labor productivity, significantly reduce the technological cycle time by eliminating a number of operations and stages, eliminating the use of several positions of equipment, reduce production space, reduce energy and labor costs. Direct compression makes it possible to obtain tablets from moisture-, heat-labile and incompatible substances. Today, however, less than 20 types of tablets are produced by this method. This is due to the fact that most of the drugs do not have the properties that ensure direct compression. These properties include: isodiametric shape of crystals, good flowability and compressibility, low adhesive ability to the tablet press tool.

At present, tabletting without granulation is carried out in the following ways:
by adding auxiliary substances that improve the technological properties of the material;
by forced feeding of the material to be pelletized from the hopper of the tablet machine into the matrix;
with predirected crystallization of the pressed substance.

Of great importance for direct compression are the size, strength of the particles, compressibility, fluidity, moisture and other properties of substances. For example,the oblong particle shape is acceptable for sodium chloride tablets, while the round shape is almost incompressible. The best flowability is observed in coarse powders with an equiaxial particle shape and low porosity - such as lactose and other similar preparations in this group. Therefore, such preparations can be compacted prior to granulation. Drug powders with a particle size of 0.5 - 1.0 mm, an angle of natural slope of less than 42°, a bulk weight of more than 330 kg/m3, and porosity of less than 37% have proved to be the best.

They consist of a sufficient number of isodiametric particles of approximately the same fractional composition and, as a rule, do not contain a large number of small fractions. What they have in common is the ability to pour out of the funnel evenly under the action of their own mass, i.e., the ability to spontaneously dispense by volume, as well as fairly good compressibility.

However, the vast majority of drugs are not capable of spontaneous dosing due to a significant (over 70%) content of fines and surface irregularities of the particles, causing a strong inter-particle friction. In these cases, auxiliary agents are added to improve the flow properties and belonging to the class of sliding auxiliary agents.

By this method tablets of vitamins, alkaloids, ephedrine hydrochloride and others are produced.

Predirected crystallization is one of the most difficult methods of obtaining drugs suitable for direct pressing. This method is carried out by two methods:
recrystallization of the finished product in the required mode;
by selection of certain conditions of crystallization of the synthesized product.

Applying these methods, a crystalline drug substance with crystals of sufficient isometric (equiaxial) structure is obtained, which freely emerges from the funnel and as a result is easily subjected to spontaneous volumetric dosing, which is a prerequisite for direct compression.

To increase the pressability of drugs in direct compression, dry adhesives - most often microcrystalline cellulose (MCC) or polyethylene oxide (PEO) - are added to the powder mixture. Thanks to its ability to absorb water and hydrate the individual layers of the tablets, MCC has a favorable effect on the release of the medication. MCC can be used to make tablets that are strong but not always break down well.

The addition of ultraamylopectin is recommended to improve the degradability of MCC tablets.

Modified starches are indicated for direct compression. The latter enter into chemical interaction with the drugs, significantly affecting the release and their biological activity.

Milk sugar is often used to improve the flowability of powders, as well as granulated calcium sulfate, which has good fluidity and provides tablets with sufficient mechanical strength. Cyclodextrin is also used to increase the mechanical strength of tablets and their degradability.

For direct tabletting, maltose is recommended, providing a uniform filling rate and as a substance with low hygroscopicity. A mixture of lactose and crosslinked polyvinylpyrrolidone is also used.

The technology of making tablets is that the drugs are thoroughly mixed with the required amount of excipients and pressed on tablet machines. The disadvantages of this method are the possibility of stratification of the tablet mass, changes in dosage during pressing with a small amount of active ingredients and the high pressure used. Some of these disadvantages are minimized in tabletting by forcing the pressed substances into the matrix. Realization of this method is made by some constructive changes of machine parts, i.e. by vibration of a shoe, rotation of a matrix in a certain angle during pressing, installation of star agitators of various designs in a charging funnel, suction of material into a matrix aperture by self-created vacuum or by special connection with a vacuum line.

Apparently, the most promising would be the forced feeding of pressed substances on the basis of vibration of charging funnels combined with an acceptable design of tedders.

But, despite the advances in direct compression in the production of tablets, this method is used for a limited range of pharmaceutical substances.
Granulating is the process of turning a powdered material into grains of a certain size. This is necessary to improve the fluidity of the pelletized mass, which is the result of a significant reduction in the total surface area of the particles when they stick together into granules and, consequently, a corresponding reduction in the friction that occurs between these particles during movement. Stratification of a multicomponent powder mixture usually occurs due to differences in particle size and specific gravity values of its constituent medicinal and excipient components. This stratification can occur due to different vibrations of the tablet machine or its funnel. Loosening of the tablet mass is a dangerous and unacceptable process, which in some cases leads to almost complete separation of the component with the highest specific gravity from the mixture and to failure of its dosage. Granulation avoids this danger because it allows particles of different sizes and densities to stick together. The resulting granulate, provided the size of the resulting granules is the same, acquires a fairly constant bulk mass. The strength of the granules also plays an important role: strong granules are less prone to abrasion and have better flowability.
Granulation can be "wet" and "dry". Wet granulation involves the use of fluids - solutions of auxiliary substances; in dry granulation, wetting fluids are not used, or are used only in one particular step of material preparation for granulation.
The dry granulation method consists of mixing powders and moistening them with adhesive solutions in enamel mixers, followed by drying them to a lumpy mass. The mass is then turned into a coarse powder using rollers or a disc mill. Pelletizing by grinding is used when the moistened material reacts with the material when wiped. In some cases, if the preparations decompose in the presence of water, enter into chemical reactions of interaction during drying or undergo physical changes (melting, softening, color change) - they are subjected to briquetting. For this purpose, briquettes are pressed from the powder on special briquetting presses with large matrices (25-50 mm) under high pressure. The resulting briquettes are crushed on roller or disk mills, fractionated using screens and pressed on pellet machines to pellets of a given mass and diameter. Pelletizing by the briquetting method can also be used in cases where the drug substance has good compressibility and does not require additional binding of the particles with binders.

Currently, the dry granulation method introduces dry bonding agents (e.g., microcrystalline cellulose, polyethylene oxide) into the tablet mass of powders, which under pressure provide binding of particles, both hydrophilic and hydrophobic substances.
Wet granulation consists of the following operations:
a) Grinding the tablet mass. This procedure is usually carried out in ball mills, and we wrote about it above. The powder obtained after that is sifted through vibrating sieves.
Vibrating sieves are highly efficient, effective and reliable devices for sifting powdered, granular and lumpy materials and can be used for dewatering materials. The sieves are usually delivered in a twin-deck configuration (sieving into three fractions). On customer's request, the baskets can be provided with one additional deck (separation of material into 4 fractions) or only one deck can be left (separation of material into 2 fractions) and meshes with required size of meshes can be installed. The sieves are available in stainless steel or carbon steel.
b) Moistening. As binders are recommended to use water, alcohol, sugar syrup, gelatin solution and 5% starch binder. The required amount of binders is established experimentally for each tablet mass. In order for the powder to granulate at all, it must be moistened to a certain degree. The adequacy of hydration is judged as follows: a small amount of mass (0.5 - 1 g) is squeezed between your thumb and index finger; the resulting "cake" should not stick to your fingers (excessive hydration) and crumble when dropped from a height of 15 - 20 cm (insufficient hydration). 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 tipped, and the mass is pushed out by the blades.
c) Granulation is carried out by rubbing the resulting mass through a 3 - 5 mm sieve (number 20, 40 and 50) Apply punched sieves of stainless steel, brass or bronze. Not allowed to use woven wire sieves to avoid getting into the pellet mass of fragments of wire. Grinding is carried out with the help of special grinding machines - granulators. In a vertical perforated cylinder poured granulated mass and rubbed through the holes with the help of spring paddles.
d) Drying and processing the pellets. The granules are spread out in a thin layer on pallets and dried, sometimes in the air at room temperature, but more often at 30-40 °C in a drying chamber. The residual moisture in the pellets should not exceed 2%.

Usually, the operations of mixing and uniform moistening of the powdered mixture with different pelletizing solutions are combined and carried out in one mixer. Sometimes mixing and pelletizing operations are combined in one machine (high-speed mixers - pelletizers). Mixing is achieved by vigorous forced circular mixing of particles and their collision with each other. The mixing process to obtain a homogeneous mixture takes 3 - 5'. Then pelletizing liquid is added to the premixed powder in the mixer, and the mixture is stirred for another 3 - 10'. After the pelleting process is completed, the discharge valve is opened and the finished product is poured out with a slow rotation of the scraper. Another design of apparatus for combining mixing and pelletizing operations is the centrifugal mixer - pelletizer.
Compared to drying in drying cabinets, which are of low productivity and where drying time reaches 20 - 24 hours, drying of granules in fluidized bed (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.
If wet pelletizing operations are carried out in separate devices, then the drying of pellets is followed by a dry pelletizing operation. After drying, the pellets are not a uniform mass and often contain lumps of clumped granules. Therefore, the pellets are re-fed to the milling machine. After that, the resulting dust is sieved from the granulated.
Since the granules obtained after dry granulation have a rough surface, which makes it difficult to pour them out of the hopper in the process of tabletting, and in addition, the granules can stick to the matrix and punches of the tablet press, which causes, in addition to weight loss, defect in the tablets, the operation of "powdering" of granules is resorted to. This operation is performed by free application of finely ground substances on the surface of the pellets. By powdering, sliding and loosening agents are introduced into the pellet mass.
Dust fractions are removed from the surface of tablets coming out of the tablet press by dedusters (vibration tablet deduster and screw tablet deduster). The tablets pass through a rotating perforated drum and are cleaned of dust, which is sucked off by a vacuum cleaner.
Obtaining a tablet is a complex labor-intensive process consisting of several technological steps, each of which is very important because the tablet must meet a number of requirements: appearance, strength, average mass, disintegration, dissolution, abrasion resistance, etc. In this part, we will discuss the choice of shape and design from the technological side. The market is mainly dominated by round tablet shapes with different profiles. But recently, manufacturers are increasingly using distinctive marks on tablets, or choosing other forms of tablets. One of the reasons for the appearance of tablets with the logo and tablets of non-round shape is the manufacturer's desire to distinguish their product, to make it recognizable in the market.
Tablet design allows giving the product distinctive features, which easily identify it among similar ones and which influence consumer loyalty to the brand.
When choosing a tablet form, it is important to be creative in its design. The designer's imagination can suggest any shape: in addition to the traditional round, the tablet can be oval, elliptical, square, polygonal, etc. Thus, you can use different geometric shapes to give the tablet a brand identity.
The shape of the tablet is an important parameter in terms of its functionality - to simplify the packaging process, orientation of the tablet when applying the logo, as well as ease of use. The use of notch on the surface of the tablet makes it possible to divide the tablet into smaller controlled doses: one notch to divide the tablet into two parts, two notches to divide it into four parts (4-part incision). It is also possible to use a special notch shape if it is necessary to break the tablet with the press of a finger, which is very convenient for small-sized tablets.
The profile of the tablet is important when applying a film or sugar coating to the tablet. It can be changed to increase or decrease the surface of the tablet, which may be important to achieve the desired solubility or controlled release of the tablet's active ingredients.
The logo or image printed directly on the tablet by pressing or printing on the coating of the tablet is another way to give recognition to the brand. Images, drawings and signs can be used, which is very relevant to the industry.
The embossing of a punch is a very specialized area that requires attention and experience to ensure optimum performance. The press tool manufacturer will advise you on how to select the best character, style and font size in order to avoid problems such as chipping, deamination when producing tablets, and swelling, voids and erosion of the inside of the coating, etc. when applying the coating. The quality and professionalism of the relief application also determines the durability and service life of the press tool.
The design of the tablet, the press tool used, and its maintenance directly affect the quality of the produced tablet. Getting press tools made of high-grade steels with improved characteristics, minimum tolerances and fine polishing is only one side of the issue. Periodic evaluations of the press tool must be made, monitoring how consistently and accurately the tablets are produced. Proper routine maintenance of press tools, including cleaning, polishing, measuring and monitoring, as well as safe and reliable tool storage, can extend the life of press equipment.
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Pressing (tabletting). This 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 - rotary tablet machine (RTM).
Pressing on tablet presses is carried out - a press tool, consisting of a matrix and two punches.
The technological cycle of tablet presses is composed of a series of consecutive operations: dispensing of material, pressing (formation of a tablet), its ejection and dumping. All of these operations are carried out automatically one after the other by means of the corresponding actuators.
There are two types of tablet machines, differing in principle of operation, design, capacity: crank and rotary.
The crank models are single-position models and have no moving elements in their composition: the source material and the finished product are in a static position. Each stage of the technological cycle (loading, dosing, pressing, ejection) is responsible for a particular mechanism. Characteristically, the pressing is performed by a single piece of equipment, which allows for absolute homogeneity of the obtained tablets.
Rotary machines are more complex and are designed primarily for large pharmaceutical companies with mass production of drugs in large quantities. They are multi-position devices supporting continuous conveyor movement. Several dozens of presses operate at the same time, which dramatically increases the productivity of the machine. Another thing that affects both the productivity of the device and its cost is the number of charging funnels (one or two).
Among other advantages of rotary machines are uniform density and high quality of pellets, stability and uniformity of work, absence of dust. However, complexity of installation and balancing, the need for strict unification of several sets of presses, expensive operating costs limit their area of application and make them unprofitable for small enterprises. Therefore, when choosing equipment for the sites for the production of tablet dosage forms, it is recommended to consider the scale of activity, daily capacity, assortment structure and production plans of the enterprise.
Single punch tablet press also called eccentric press or single station press is the simplest machine for tablet manufacturing. Single punch tablet as the name implies employ a single set of station tooling that is a die and a pair of upper and lower punches.
The compaction force on the fill material is exerted by only the upper punch while the lower punch is static; such action equivalent to hammering motion and as a result, the single punch press is referred to as stamping process. The single punch tablet press produces about 60-85 tablets/min. The single punch tablet press can be manual or automatic.
Components/ funtional parts of a single punch tablet press:
Hopper
– This is connected to the feed shoe, and it is where the granules/powder mixtures are poured into prior to tableting or compression. The hopper can be filled manually or by using mechanical equipment during subsequent tableting.
Die cavity – The die cavity is where the powder granules are compressed into tablet. The die determines;
The diameter of the tablet;
The size of the tablet;
To some extent, the thickness of the tablet.
Punches – This comprises an upper and lower punch and they compress the powder into tablets of various shapes within the die.
Cam truck – This guides the position/movement of the punches.
Tablet adjuster – This is used to adjust the volume of the powder to be compressed and so determines the weight of the tablet.
Ejection adjuster – These facilities the ejection of the tablet from the die cavity after compression.
In the production of tablets using a single punch, the upper punch compresses the powder into tablets, while the lower punch ejects the tablet.
The sequence of events involved in the formation of a tablet.
The events involved in tablet production can be divided into 3 stages:
1) Filing.
2) Compression.
3) Ejection.

Filing:
Position 1 – The upper punch is raised and lower punch drops to create a cavity in the die.
Position 2 – Feed shoe moves over the die cavity and granules fall into the die cavity under the influence of gravity from the hopper.

Compression:
Position 3 – Feed shoe moves out of the way and the hopper punch descends to compress the granules/powder mixture into tablets by progressive reduction of the porosity of the die content and forcing of the particles into close contact with one another.

Ejection:
Position 4 The upper punch retracts and the lower punch moves upwards too to eject the compressed tablet. The whole events repeat over and over again unit the feed material is exhausted.
Rotary tablet press is a mechanical device that unlike the single punch tablet press has several tooling stations which rotates to compress granules/powder mixture into tablets of uniform size, shape (depending on the punch design) and uniform weight. It was developed to increase the output of tablets.
In rotary tablet press, the compaction force on the fill material is exerted by both the upper and lower punches, leaving the powder granules to be compressed in the middle. This is known as accordion type of compression. The capacity of a rotary tablet press is determined by the rotation speed of the turrent and the number of stations on the press.

Components/Functional Parts of a Rotary Tablet Press (Multi-Station Tablet Press):

Hopper- The hopper holds the granules/powder mixture (API plus excipient) that are to be compressed into tablets.
Die cavity – This is where the powder granules are compressed into tablets and it determines:
The diameter of the tablet.
The size of the tablet
To some extent, the thickness of the tablet.
Feed paddle – Helps to force the feed/ the granules into the dies, especially during faster rotation.
Punches – This comprises the upper and the lower punches. They move within the die bore to compress granules into tablets.
Lower cam track – This guides the lower punch during the filling stage so that the die bore is over filled to allow accurate adjustment.
Cam tracks – This guides the movement of both the upper and lower punches.
Dept of fill/capacity control – This adjusts the lower punch track during the latter part of the full stage to ensure that the appropriate quantity of granules remains within the die prior to compression.
Recompression rollers – This roller gives the granules an initial compression force to get rid of excess air that might be entrapped in the die.
Main compression – This roller applies the final compression force needed for the formation of tablets.
Ejection cam– Guides the lower punch upwards, facilitating the ejection of tablets from the die cavity after compression.
Take-off Blade – This is fitted in front of the feeder housing and it deflects the tablet down the discharge chute.
Discharge chute – This is where the tablet passes through for collection after being deflected by the take-off blade.

Classification of Rotary Tablet Press.

Rotary tablet press can be classified into several ways, but the most important of these classifications is based on the type of tooling, with which the machine is to be used with. A tooling set comprises the die and its associated punches. Basically, there are two types of tooling:
1) “B” type
2) “D” type
The above type of configuration constitutes a majority of the tool configuration used today.

“B” Type​

The “B” type configuration has a normal, punch barrel diameter of 0.750 inches. (19 mm). The “B” type can be used with two types of die or can be said to have two different die sizes:

The “B” dies with a diameter of 1.1875 inches. (30.16 mm), suitable for all tablet sizes up to the maximum for the “B” punches.

The smaller “BB” dies (small “B” die) that has a diameter of 0.945 inches. (24 mm). This die type is suitable for tablets up to 9 mm diameter or 11 mm maximum.

“D” type​

This type has a larger nominal barrel diameter of 1 inch. (25.4 mm) and a die diameter of 1,500 inches. (38.10 mm) and thus is suitable for tablets with maximum diameter or maximum length of 25.4 mm.

Tabletting machines are designed to be used with either “B” or “D” tooling but not both. The compression force obtainable in a machine depends on the type of tooling used. Machines that are designed to “B” type tooling exert a maximum compression force of 6.5 tones, and machines, that use the “D” type configuration exert 10 tones compression force.

There are equally some special machines that are designed with the intention of exerting higher compression forces. The maximum force that can be exerted on a particular size and shape of tablet is governed by the size of the punch tip or the maximum force, for which the machine is designed.
Individual manufactures of tablet press have sought to achieve higher output by;
Increasing the effective number of punches.
Increasing the number of station.
Increasing the number of points of compression.
Increasing the rate of compression turrent speed.
Each of the above approaches has its own advantages and limitations.

Advantages of Rotary Tablet Press (Multi-station tablet press).

High productivity can be gained with a minimal amount of labour while saving money.
Rotary press has an output of between 9000 – 234000 tab/hour thus saves time and meets up with the high demand of tablet dosage form.
The powder filled cavity can be automatically managed by a moving feeder.
Rotary press decreases waste of valuable formulation in non-specific tablets.
The machine allows independent control of both weight and hardness.
Proper ordering, inspection, handling, and maintenance of the press tool is most important in making the right quality and quantity of tablets. The use of press tools that do not meet specifications can affect tablet quality, press efficiency and tablet production speed. Non-compliant press tools can also shorten punch life, reduce tablet press productivity, and cause serious damage to the press tool and poisons.
The quality of a press tool is far more important than its price. Faulty press tools can lead to tremendous product loss, reduced productivity, processing costs and/or rework of poor quality tablets.
It is very important to designate a person or unit within the company that is responsible for handling, maintaining and servicing the press tool, maintaining documentation (master files) and making copies of tablet and press tool drawings. Such a person, or persons, should be conscientious, adaptable, and most importantly, be well-trained in press tool handling techniques. Personnel with a basic knowledge of mechanics are ideal for such work; however, engineering knowledge is not a requirement.
 
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