Usage: in medicine. The invention relates to effervescent tablets or granules containing a framework material, a basic effervescence component, an acidic effervescence component, a sweetener, as well as macro- and microelements and, possibly, vitamins as active substances. Effervescent tablets and granules contain 20-50 wt.% mannitol as a framework material, 8-25 wt.% potassium bicarbonate as the main component of effervescence, 9-27 wt.% malic acid as an acid component of effervescence, 0.4-2 .2 wt.% aspartame as a sweetener. In addition, the invention relates to a process for the preparation of such effervescent tablets or granules. Tablets or granules have high chemical stability and are easily compressed. 2 s. and 5 z.p. f-ly, 3 tab.

The invention relates to sugar- and sodium-free effervescent tablets or granules, as well as to a method for their preparation. In particular, the invention relates to effervescent tablets and granules, consisting of a frame material, a basic component for gas evolution and disintegration (hereinafter referred to as effervescence), an acidic effervescence component, a sweetener, as well as macro- and microelements and, possibly, vitamins. In addition, the invention relates to a process for the preparation of such tablets and granules. It is known that at present one of the most popular pharmaceutical forms for introducing drugs, vitamins and minerals into the body is the so-called effervescent tablet. In addition to commercial reasons, a number of factors contribute to the spread of this form in terms of pharmaceutical action: reduction of gastric irritation, improved absorption, etc. When such tablets are dissolved in water, an effervescent or carbonated drink containing carbon dioxide is obtained. The observed disintegration of effervescent tablets is due to the presence of a mixture containing an acid and a base; when interacting with water, this mixture destroys the tablet with the release of carbon dioxide. Great care is required in the manufacture and packaging of effervescent tablets; accordingly, in practice, the direct pressing method is preferable to "wet" methods. Most effervescent tablets contain, in addition to active agents, three main components: a binder and framework material, an acidic effervescent component and a basic effervescent component. Usually, sugars (lactose, sucrose, glucose), sorbitol, xylitol or starch are used as a binder and framework material, citric acid, tartaric acid, fumaric acid or adipic acid are used as the acid component of effervescence, and sodium bicarbonate is used as the main component of effervescence. , sodium carbonate and magnesium carbonate. Among other components commonly used in effervescent tablets, preferably used agents such as sweeteners, for example sugars, saccharin, sodium cyclamate and aspartame; flavors and flavoring agents; lubricating agents such as polyethylene glycols, silicone oils, stearates and adipic acid. The literature describes effervescent tablets containing lactose as a framework material, citric acid as an acidic effervescent agent, a mixture of sodium and potassium bicarbonates as the main effervescent agent, and aspartame as a sweetener. In addition to water and fat-soluble vitamins, these tablets contain inorganic substances as active agents, which are biologically better absorbed in the chelate form. However, this composition of the tablets does not allow to exclude sodium compounds, which is a disadvantage, since it is well known that the introduction of an excess of sodium into the body causes a number of undesirable physiological effects. Another disadvantage of the known composition is the presence of citric acid in the amount of 20 - 45 wt. %, which can also have a harmful physiological effect. The literature describes effervescent tablets containing a mixture of calcium and potassium carbonates as the main effervescent agent. A significant disadvantage of this composition is the unpleasant soapy taste of potassium bicarbonate. In addition, the use of calcium carbonate adversely affects the dissolution time of the tablet. The literature describes effervescent tablets containing potassium bicarbonate as the main effervescence component, malic acid and citric acid as the acid effervescence component, a mixture of sorbitol and maltodextrin as a framework and binder material, and calcium sucrose as a sweetener. This composition is used as a means of reducing acidity and painkiller; its disadvantage is the unsatisfactory low shelf life due to the presence of sorbitol. Additionally, sorbitol is not recommended for widespread use in soft drinks, as some people have poor stomach tolerance for it. The objective of the invention is to obtain chemically stable, easily compressible effervescent tablets and granules with improved physical properties, without sodium and sugar, containing evenly distributed macro- and microelements and, possibly, vitamins. The invention is based on the fact that the task can be completely solved by using the following basic substances to obtain effervescent tablets and granules: mannitol as a framework material, malic acid as an acidic effervescence component, potassium bicarbonate as the main effervescence component and aspartame as a sweetener. The invention is further based on the fact that the use of mannitol makes it possible to introduce salts of macro- and microelements with a high content of water of crystallization into tablets. Accordingly, the invention overcomes the technical difficulties due to which effervescent tablets and granules with such substances have hitherto been known to be impossible to obtain, since their high water content prevented their compression and at the same time caused them to dissolve prematurely. The invention is also based on the fact that when using mannitol in tablets or granules, macro- and microelements form complexes with mannitol, due to which it is possible to eliminate the incompatibility of components during the technological process, the final product will be chemically stable, and the resulting complexes with mannitol will be more easily absorbed by the body , that is, it is better to use. The invention is also based on the fact that when mannitol, malic acid and aspartame are used together, potassium bicarbonate alone can be used as the main component of effervescence, as a result of which it becomes possible to exclude sodium ions from the composition of tablets. In addition, in this combination, there is no poor compressibility inherent in potassium bicarbonate, i.e. its high adhesion to the surface of dies and dies, which does not allow it to be pressed at a relative moisture content of 45% or higher. Therefore, even in this respect, the invention is based on overcoming a technical stereotype. This is confirmed by the fact that in the literature in column 1, lines 27 - 32 it is stated: "The use of potassium bicarbonate and potassium carbonate alone does not lead to the desired results, since, firstly, potassium compounds give the composition an unpleasant soapy aftertaste, and secondly secondly, the high sensitivity to moisture when introducing potassium salts causes great technical difficulties. The invention is also based on the fact that when malic acid is used together as an acidic effervescent component with mannitol, the composition obtained can be compressed quite well. This fact is unexpected, since malic acid alone is known to be difficult to compress and technologically difficult to process, since due to its low melting point it melts when milled. On the other hand, the fact established by the authors makes it possible to use malic acid in relatively large quantities, and this also uses the property of malic acid to improve the taste, as well as the possibility of optimizing the pH value with its help. Finally, the invention is based on the fact that when mannitol, potassium hydrogen carbonate, malic acid and aspartame are used together, it is possible to obtain a composition with a low energy content that does not cause gastrointestinal disorders. Tablets from this composition have a very high fracture strength, they quickly dissolve with gas formation and form a clear solution, although the composition contains incompatible vitamins, macro- and microelements and components (potassium bicarbonate, malic acid, salts of macro- and microelements with a high content of water of crystallization ), each of which in itself has poor compressibility. The invention, based on the above facts, relates to effervescent tablets and granules containing a framework material, a basic effervescence component, an acidic effervescent component and a sweetener, as well as macro- and microelements and possibly vitamins as active substances. In accordance with the invention, effervescent tablets and granules contain 20-50 wt.%, preferably 30-40 wt.% mannitol as a framework material, 8-25 wt. %, preferably 14 - 18 wt.% potassium bicarbonate as the main component of effervescence, 9 - 27 wt.%, preferably 15 - 21 wt.% malic acid as an acid component of effervescence and 0.4 - 2.2 wt.%, preferably 0.6 to 1.5 wt.% aspartame as a sweetener, and, if necessary, flavoring, wetting and other additives commonly used in the manufacture of effervescent tablets, in amounts necessary to ensure that the sum of the components is 100%. The invention furthermore concerns a process for the preparation of effervescent tablets or granules. In accordance with the invention, four types of granules are prepared by homogenization and granulation: vitamin-containing granules, granules containing an acidic effervescence component, granules containing a basic effervescence component, granules containing trace elements, and a homogenizate containing external phase substances, followed by joint homogenization of the obtained four types granules and substances of the external phase and tableting the obtained granules. When preparing tablets, a total of 20-50 wt.%, preferably 30-40 wt.% mannitol, 8-25 wt.%, preferably 14-18 wt.% potassium bicarbonate, 9-24 wt.%, preferably 15-21 wt.% wt.% malic acid, 0.4 - 2.2 wt.%, preferably 0.6 - 1.5 wt.% aspartame, as well as macro- and microelements and vitamins necessary for the introduction, and, possibly, flavoring, lubricating and other additives commonly used in the manufacture of effervescent tablets. Effervescent tablets or granules obtained by the proposed method preferably contain magnesium, zinc, iron (II), copper (II), manganese (II), chromium (III) anions, as well as molybdenum (VI) anions and selenium (IV). Preferably, the iron ions in the tablet composition are used in the form of iron (II) sulfate heptahydrate, zinc ions - in the form of zinc sulfate heptahydrate, copper ions - in the form of copper sulfate pentahydrate, manganese ions - in the form of manganese sulfate monohydrate, molybdenum ions - in the form of heptamolybdenate tetrahydrate ammonium, selenium ions - in the form of selenous acid, magnesium ions - in the form of magnesium sulfate heptahydrate, chromium ions - in the form of chromium (III) chloride hexahydrate. Vitamins are preferably added to the composition in the following amounts: 0.01 - 0.5 wt.% vitamin B 1 , 0.01 - 0.25 wt.% vitamin B 2 , 0.01 - 0.5 wt. % vitamin B 6 , 0.001 - 0.01 wt.% vitamin B 12 , 0.1 - 2 wt.% nicotinamide, 0.01 - 0.5 wt.% vitamin A, 0.0015 - 0.015 wt.% vitamin D , 0.1 - 5 wt.% vitamin C, 0.01 - 0.1 wt.% folic acid, 0.1 - 0.5 wt.% pantothenic acid, 0.01 - 7 wt.% vitamin E and 0.001 - 0.01 wt.% vitamin H. Tablets obtained by the proposed method, along with macro- and microelements and vitamins, may contain flavoring and flavoring additives, for example, orange, lemon or pineapple flavors, wetting agents, for example, polyethylene glycols, silicone oils , stearates or adipic acid, absorption enhancing agents such as tartaric acid and glycerin, as well as any other additives commonly used in the manufacture of effervescent tablets. The main advantages of the invention are as follows. 1. Tablets are chemically stable, easy to compress and have excellent physical properties. 2. Tablets and granules contain evenly distributed active substances, that is, macro- and microelements, as well as vitamins. 3. After dissolving the tablets in water, a transparent drink with a pleasant taste is obtained, which does not contain sediment. 4. In the presence of mannitol, it becomes possible to use malic acid as an acidic effervescence component in relatively large quantities, while enhancing the beneficial effect of this acid as an antioxidant, flavoring agent and pH optimizing agent. 5. When using mannitol, you can get effervescent tablets with a low calorie content and enriched with macro- and microelements and vitamins, the use of these tablets is also possible for people with diabetes. 6. In previously known effervescent tablets containing vitamins and minerals, trace elements are used in a form containing no water of crystallization, or in a form with a low content of water. On the other hand, the invention presents the possibility of using substances with a high content of water of crystallization, which in themselves have poor compressibility, or they cannot be compressible at all, however, they are the most stable forms of inorganic compounds and therefore can be obtained or purchased at a lower cost and with high degree of purity. 7. With the combined use of mannitol, malic acid and aspartame, it is possible to achieve a uniform distribution of macro- and microelements and vitamins, even if their amount is very small relative to the weight of the finished tablet. Uniform distribution of vitamins is ensured without adverse effects on the properties of these low-stable substances during technological operations. 8. The invention makes it possible to obtain effervescent tablets containing incompatible active substances, such as vitamins, as well as macro- and microelements. 9. In the production of tablets, macro- and microelements form complexes with mannitol, which are more preferable from the point of view of the chemical stability of the tablet, as well as the absorption and biological action of active substances. 10. The invention makes it possible to obtain tablets using effervescent agents (potassium bicarbonate and malic acid) and inorganic substances with a high content of water of crystallization (sources of macro- and microelements), which, due to their properties, could not previously be used in the production of effervescent tablets. In addition, the resulting effervescent tablets have high mechanical strength, and when they are dissolved, rapid gas evolution occurs and a clear solution is formed. The invention is further illustrated by non-limiting examples. EXAMPLE 1 The granules ready for pressing are four types of granules and a so-called external phase. Granules I Vitamin B 1 - 7.29 g Vitamin B 2 - 7.50 g Vitamin B 6 - 10.94 g Ca-pantothenate - 38.215 g Nicotinamide - 85.00 g Mannitol - 500.00 g After sieving, the substances are homogenized, mixed with ethanol, granulated, then the wet granules are dried and again granulated. Granules II Iron (II) sulfate heptahydrate - 99.55 g Malic acid - 1500.00 g
Mannitol - 1500.00 g
After screening, the substances are homogenized, mixed with ethanol, granulated, dried, then re-granulated and dried. Granules III
Potassium bicarbonate - 3800.00 g
Mannitol - 3800.00 g
After sifting and homogenization, the mass is mixed with a water-ethanol mixture, then, after drying, it is re-granulated. Granules IV
Mannitol - 3925.00 g
Magnesium sulfate heptahydrate - 1571.50 g
Glycine - 150.00 g
Succinic acid - 250.00 g
Mannitol - 75.00 g
Selenic acid - 0.1635 g
Ammonium heptamolybdenate tetrahydrate - 0.690 g
Manganese (II) sulfate monohydrate - 15.38 g
Copper (II) sulfate pentahydrate - 29.47 g
Zinc sulfate heptahydrate - 219.95 g
After grinding, homogenization and washing of the mass, it is granulated with distilled water, then dried, re-granulated and finally dried. Substances of the external phase
Vitamin C - 300.00 g
Malic acid - 3000.00 g
Polyethylene glycol - 710.00 g
Aspartame - 200.00 g
Lemon flavor - 1000.00 g
After sieving and grinding, the substances of the external phase are homogenized. This mixture is further mixed with granules I, II, III and IV and again homogenized. From the granules obtained in this way, about 5000 tablets with a diameter of 32 mm, weighing about 4.5 g were pressed. Example 2. The same operations were repeated as in example 1, with the difference that vitamin E was added to the vitamins, and the quantities of the components were changed as follows :
Component - Quantity (g)
Iron sulfate (II) (FeSO 4 7H 2 O) - 99.56
Zinc sulfate (II) (ZnSO 4 7H 2 O) - 109.97
Copper sulfate (II) (CuSO 4 5H 2 O) - 14.74
Manganese sulfate (II) (MnSO 4 H 2 O) - 7.69
Ammonium molybdate [(NH 4) 6 Mo 7 O 24 4H 2 O] - 0.276
Selenic acid (H 2 SeO 3) - 0.082
Magnesium sulfate (MgSO 4 7H 2 O) - 608.34
Vitamin B 1 (thiamine HCl) - 3
Vitamin B 2 (riboflavin) - 3.5
Vitamin B 6 (pyridoxine HCl) - 4
Nicotinamide - 40
Vitamin C - 175
Pantothenic Acid (Ca-pantothenate) - 15
Vitamin E (DL-Alpha Tocopherol) - 25
Succinic acid - 100
Glycine - 75
Malic acid - 2750
Potassium bicarbonate (KHCO 3) - 2300
Mannitol - 6500
Aspartame - 200
Pineapple flavor - 1000
Polyethylene glycol - 750
About 5000 tablets with a diameter of 25 mm and a weight of about 3 g were obtained from granules ready for pressing. Example 3. The operations described in example 1 were repeated, with the difference that chromium was added to trace elements, and vitamins B 12 , A, D , H and folic acid, and the amounts of components were changed as follows:
Component - Quantity (g)
Iron sulfate (II) (FeSO 4 7H 2 O) - 373.35
Zinc sulfate (II) (ZnSO t4 7H 2 O) - 329.97
Copper sulfate (II) (CuSO 4 5H 2 O) - 39.29
Manganese sulfate (II) (MnSO 4 H 2 O) - 38.46
Ammonium molybdate [(NH 4) 6 Mo 7 O 24 4H 2 O] - 1.38
Selenic acid (H 2 SeO 3) - 0.2
Magnesium sulfate (MgSO 4 7H 2 O) - 5069.5
Chromium (III) chloride (CrCl 3 6H 2 O) - 1.28
Vitamin B 1 (thiamine HCl) - 7.5
Vitamin B 2 (riboflavin) - 8.5
Vitamin B 6 (pyridoxine HCl) - 10
Vitamin B 12 (cyanocobalamin) - 0.01
Nicotinamide - 95
Vitamin A - 5
Vitamin D - 0.05
Vitamin C - 450
Folic acid - 1
Pantothenic Acid (Ca-pantothenate) - 35
Vitamin E (DL-Alpha Tocopherol) - 50
Vitamin H (biotin) - 325
Succinic acid - 300
Glycine - 180
Malic acid - 6000
Potassium bicarbonate (KHCO 3) - 5000
Mannitol - 11500
Aspartame - 300
Orange flavor - 1500
Polyethylene glycol - 2000
About 5000 tablets with a diameter of 35 mm and a weight of 6.6 g were obtained from granules ready for pressing. aspartame - up to 150 g, and the amount of mannitol was increased to 16000 g. About 5000 tablets with a diameter of 32 mm, weighing 6.6 g were obtained from ready-to-compress granules. Example 5. The operations described in example 3 were repeated, with the difference that the amount malic acid was increased to 10,000 g, potassium bicarbonate to 9,000 g, aspartame to 800 g, and the amount of mannitol was reduced to 8,000 g. About 5,000 tablets with a diameter of 32 mm and a weight of about 7.7 g were obtained from ready-to-compress granules. composition and storage properties. Three batches of tablets (1, 2 and 3) were tested for the stability of the composition and properties during storage for 3 months under the following conditions, conventionally designated (A), (B) and (C):
(A) temperature 25 o C2 o C, rel. humidity 605%;
(B) temperature 25 o C2 o C, rel. humidity 855%;
(B) temperature 30 o C2 o C, rel. humidity 605%. Literature
1. Pharmaceutical Dosage Form: Tablets, Vol. 1, 2nd edition, A. Lieberman ed., 1989, Marcel Dekker, Inc. 2. Pat. USA 4725427. 3. Pat. USA 4678661. 4. Pat. US 4704269. 5. Martindale. The Extra Pharmacopoeia, 19th ed, London, 1989, p. 1274.

Claim

1. An effervescent tablet or granule containing a framework material, a basic effervescence component, an acidic effervescence component, a sweetener, as well as macro- and microelements and possibly vitamins as active substances, characterized in that it contains 20 to 50 wt.% mannitol as a framework material, 8 - 25 wt.% potassium bicarbonate as the main component of effervescence, 9 - 27 wt.% malic acid as an acid component of effervescence, 0.4 - 2.2 wt.% aspartame as a sweetener, as well as possibly flavorings, lubricants and other additives commonly used in the manufacture of effervescent tablets, in amounts necessary to bring the sum of the components to 100%. 2. Effervescent tablet or granule according to claim 1, characterized in that it contains 30 - 40 wt.% mannitol, 14 - 18 wt.% potassium bicarbonate, 15 - 21 wt.% malic acid and 0.6 - 1.5 wt.% aspartame. 3. An effervescent tablet or granule according to claim 1, characterized in that it contains cations of magnesium, zinc, iron (II), copper (II), manganese (II), chromium ((III) and anions as macro- and microelements 4. An effervescent tablet or granule according to claim 1, characterized in that it contains iron ions in the form of ferrous sulfate heptahydrate, zinc ions in the form of zinc sulfate heptahydrate, copper ions in the form of pentahydrate copper sulfate, manganese ions - in the form of manganese sulfate monohydrate, molybdenum ions - in the form of ammonium heptamolybdenate tetrahydrate, selenium ions - in the form of selenious acid, magnesium ions - in the form of magnesium sulfate heptahydrate, chromium ions - in the form of chromium (III) chloride hexahydrate. 5. An effervescent tablet or granule according to claim 1, characterized in that it contains vitamins in the following amounts relative to the weight of the composition: 0.01 - 0.5 wt.% vitamin B 1 , 0.01 - 0.25 wt. % vitamin B 2 , 0.01 - 0.5 wt.% vitamin B 6 , 0.001 - 0.01 wt.% vitamin B 12 , 0.1 - 2 wt.% nicotinamide, 0.01 - 0.5 wt. % vitamin A, 0.0015 - 0.015 wt.% vitamin D, 0.1 - 5 wt.% vitamin C, 0.01 - 0.1 wt.% folic acid, 0.1 - 0.5 wt.% pantothenic acid, 0.01 - 7 wt.% vitamin E and 0.001 - 0.01 wt.% vitamin H. 6. Method for producing effervescent tablets or granules, characterized in that four types of granules are prepared by homogenization and an acidic effervescence component, granules containing a basic effervescence component, granules containing trace elements, and a homogenizate containing external phase substances, followed by co-homogenization of the obtained four types of granules and external phase substances, and tableting the obtained granules. 7. The method according to claim 6, characterized in that when obtaining tablets in the aggregate, 20 - 50 wt.%, preferably 30 - 40 wt.%, mannitol, 8 - 25 wt.%, preferably 14 - 18 wt.%, are used, potassium bicarbonate, 9 - 24 wt. %, preferably 15 - 21 wt.%, malic acid, 0.4 - 2.2 wt.%, preferably 0.6 - 1.5 wt.%, aspartame, as well as introduced macro- and microelements, vitamins and, possibly , flavoring, lubricating and other additives commonly used in the manufacture of effervescent tablets.

The important role of excipients in realizing the potential activity of active substances in dosage forms, as well as in the technological process, is determined by a number of requirements for them. They must have the necessary chemical purity, stability of physical parameters, and pharmacological indifference. Together, they must ensure the optimality of the technological process, have a residual production base, and an affordable cost. Each case of the use of specific excipients and their quantity requires a special study and scientific justification, since they must ensure sufficient stability of the drug, maximum bioavailability and its inherent spectrum of pharmacological action.

dosage form effervescent tablet

All raw materials used for the production of effervescent tablets must have good water solubility.

Baking powders.

organic acids.

The number of organic acids suitable for the production of effervescent tablets is limited. The best choice is citric acid: a carboxylic acid containing three functional carboxylic groups, which usually requires three equivalents of sodium bicarbonate. Anhydrous citric acid is commonly used in the production of effervescent tablets. However, the combination of citric acid and sodium bicarbonate is very hygroscopic and tends to absorb water and lose reactivity, so the humidity level in the work area must be strictly controlled. Alternative organic acids are tartaric, fumaric, and adipic, but they are not as popular and are used when citric acid is not applicable.

Bicarbonates

Sodium bicarbonate (NaHCO 3) can be found in 90% of effervescent tablet formulations. In the case of using NaHCO 3 , the stoichiometry must be precisely determined depending on the nature of the active substance and other acids or bases in the composition. For example, if the active substance is acid-forming, then the NaHCO 3 rate can be exceeded to improve the solubility of the tablet. However, the real problem with NaHCO 3 is its high sodium content, which is contraindicated in people with high blood pressure and kidney disease.

Highly effective disinfectants, such as cross-linked polyvinylpyrrolidone (PVP, crospovidone) of the trademarks Kolidon CL, Poliplasdon XL, sodium carboxymethylcellulose (NaCMC) of the trademarks Ac - Di-Sol, Primellose; sodium starch glycolate, represented by the brands Primelose, Explotab, Vi - vastar P 134. These super-zentegrants can be added before granulation (inside the granules) or after granulation (dusting). They are added in a small amount of 0.5-5%.

As fillers (to obtain tablets with a dosage of the active substance up to 10 mg), potato starch is most often used, introduced into the granulate, as well as sucrose, lactose, glucose, magnesium carbonate, calcium carbonate, urea, mannitol, microcrystalline cellulose, etc.

When pressing complex powders and granulates, binders are of particular importance, which are used to improve fluidity, increase the accuracy of dosing of powdered material, and ensure the necessary properties of granules and tablets. The choice of binders and their quantity depends on the physicochemical properties of the pressed materials, which excludes the use of microcrystalline or powdered cellulose, dibasic calcium phosphate, etc. Mainly, only two water-soluble binders can be used in production - sugars (dextrates or glucose) and polyols (sorbitol, mannitol). Since the size of an effervescent tablet is relatively large (2-4 g), the choice of excipient is crucial in tablet production. A filler with good binding characteristics is needed in order to simplify the formulation and reduce the amount of excipients. Dextrates and sorbitol are commonly used excipients. The table compares both excipients.

Comparison of dextrates and sorbitol for effervescent tablets

Sorbitol is suitable for the production of sugar-free tablets, although this polyol can cause bloating and discomfort at high levels. Adhesion to tablet press punches is a particular difficulty associated with the use of sorbitol, but good compressibility makes this excipient suitable for formulations that are difficult to manufacture. The hygroscopicity of sorbitol may limit its use in effervescent tablets due to the high susceptibility of these tablets to moisture. But despite this, sorbitol remains one of the most used polyols in the production of effervescent tablets.

Dextrates are spray crystallized dextrose containing a small amount of oligosaccharides. Dextrates are a high-purity product consisting of white free-flowing large-pore spheres (Fig. 1).

Rice. 1.

This material has good fluidity, compressibility and the ability to crumble. Excellent water solubility results in fast disintegration and the requirement to use less lubricant. Dextrates have good fluidity, which allows the production of engraved tablets, eliminating the problem of material sticking to punches.

To ensure the production of high-quality tablets, increase the flowability of the granulate, prevent sticking of the tablet mass, facilitate the ejection of the tablet from the matrix, reduce the energy consumption of the pressing process and increase the wear resistance of the press tool, a group of antifriction auxiliary substances is widely used. They are divided into three subgroups:

• sliding (starch, talc, kaolin, aerosil, skimmed milk powder, polyethylene oxide-4000);
• Lubricants (stearic acid and its salts, vaseline oil, tween, polyethylene oxide-400, silicon carbons);
• Anti-caking agents (talc, starch, stearic acid and its salts).

However, some widely used anti-friction agents, such as talc, stearic acid and its salts, are used only in dispersible effervescent granules and tablets, since they are insoluble in water and cannot be used in the technology for the manufacture of drugs intended to obtain clear solutions. .

Preservatives used in the manufacture and storage of granules and tablets include benzoates, sorbic acid salts, p-hydroxybenzoic acid esters. The antimicrobial activity of benzoates and salts of sorbic acid depends on the pH value and rapidly decreases at pH over 4.0; p-hydroxybenzoates do not have this disadvantage. The activity of parabens is influenced by the way they are introduced into the tablets: dry mixing with the granulate, wet mixing of the preservative solution with the granulate, spraying an aqueous solution of the preservative on the granulate, spraying the alcoholic solution of the preservative (the last two methods give the best results).

According to the classification of excipients, the following types of corrigents are distinguished: color, taste and smell. Dyes and pigments in the production of solid dosage forms, including tablets, are used to improve the presentation of the finished product, as well as markers indicating the special properties of this drug: its belonging to a certain pharmacotherapeutic group (hypnotics, narcotic drugs) ; high level of toxicity (poisonous) and others. From domestic pharmaceutical dyes, indigo carmine (blue) is used; tropeolin 0 (yellow); acid red 2C (red); titanium dioxide (white), etc. Abroad, for coloring solid dosage forms, coloring substances belonging to the group of pigments are used.

The compositions may include substances that correct the taste and smell of a fizzy drink: cinnamon, mint, anise, laurel, eucalyptus, clove, thyme, citrus (lemon, orange, grapefruit), cedar, nutmeg, sage, etc. oils. odorants also use vanillin and fruit essences.

Requirements for excipients:

• 1. Chemical purity.
• 2. Stability.
• 3. Pharmacological indifference.
• 4. Must ensure the optimality of the technological process.
• 5. Must have a residual production base.
• 6. Affordable cost.

Manufacturing technology of effervescent tablets.

The technology of effervescent tablets is determined by the specifics of their composition, as well as the physicochemical and technological properties of the components. As a rule, these are uncoated multicomponent tablets of large diameter (up to 50 mm) and large weight (up to 5,000 mg), the moisture content in them should not exceed 1%, and the disintegration time should not exceed 5 minutes. in 200 ml of water.

The main difficulty in creating effervescent dosage forms is to prevent the chemical interaction of their organic acids and alkali metal salts during the manufacturing and storage of drugs. Even small amounts of moisture in the tablet mass can provoke interaction between these components. During the chemical reaction, water is formed, which can significantly affect the quality of the tablets, leading to their further destruction. To obtain conditioned tablets that meet the stability requirements, tableting masses are often used by wet or dry granulation, or by direct compression.

Obtaining effervescent tablets by direct compression of the components of the tablet mass is reduced to the fact that the dry powder mixture without granulation is pressed on a tablet press. According to a number of authors, when obtaining effervescent tablets by direct compression, high-speed tablet machines should be used with powdering of punches and matrices with fine magnesium stearate powder. Direct compression technology is the most modern, most acceptable technology for the production of solid dosage forms. Effervescent tablet powder is very susceptible to moisture and the presence of even a small amount of water can cause a chemical reaction. Direct pressing is a cost-effective technology that saves production time and reduces the number of production cycles. The direct pressing technology does not require special equipment and is suitable for water-sensitive materials. The main advantages of direct pressing are the simplicity and low cost of the technology. Equipment for direct pressing consists of fewer elements, requires less space, and its maintenance is less costly in financial and time terms. Reducing the number of steps in the process itself leads to more cost-effective production.

The mass fraction of the gas-forming mixture in effervescent tablets is 25-95%. In preparation for pressing, it is necessary to exclude the contact of the tablet mass with water, so as not to cause a gas formation reaction and loss of carbon dioxide. Direct compression of the powder mixture is therefore considered the first choice technology, since it does not require the use of wet granulation. However, it is known that in the solid phase, when acidic and alkaline components come into contact, they interact and lose carbon dioxide. For example, when storing a mixture of anhydrous citric acid and sodium bicarbonate for 50 hours, the loss reached 1% of the mass and was inversely proportional to the particle size of the powders. To reduce such losses before pressing, the components are dried at acceptable gentle temperatures and tableting is started immediately after dry mixing, avoiding technological downtime.

In direct compression, the powder mixing step is critical to tablet quality. In order to achieve a uniform distribution of all components in the mixture, to prevent the rejection of tablets in appearance (marbling or mosaic) and in terms of uniform dosing of the active substance, it is necessary to resort to fine grinding of powders. This negatively affects such technological properties of tablet mixtures necessary for pressing as flowability (fluidity), compressibility and slip. The modern range of excipients and modern designs of tablet presses sometimes make it possible to solve emerging technological and technical problems, but in other cases it is necessary to apply preliminary wet granulation of a mixture of powders. In the technology of effervescent tablets, it is necessary to ensure the stability of both the gas-forming mixture and the active substance. When is direct compression technology not applicable?

• * in the case where there is a large difference between the bulk densities of the materials used, which can lead to desegregation of the tableting powder;
• * active substances having a small particle size are used in a small dosage. In this case, there may be a problem associated with the uniformity of the composition, but this can be avoided by grinding part of the filler and pre-mixing it with the active substance;
• * Sticky or oxygen sensitive substances require fillers with very good flow, water solubility and absorption characteristics, such as dextrates with their porous, round particles. This adjuvant used in direct compression technology is suitable for complex formulations and does not require additional binders or anti-binding agents.

Obviously, direct compression technology cannot be applied in every case, but should be the number one choice in the production of effervescent tablets, but in other cases, the wet granulation method should be used.

Three methods are commonly used:

Separate granulation. The powder mixture is divided into two parts, while the acidic and alkaline components are introduced into different parts. As a granulating liquid, aqueous solutions of macromolecular substances are used. This method is convenient for introducing moisture-containing ADV (crystal hydrates, hygroscopic substances, liquid, thick, dry plant extracts, etc.) into the PC composition. The dried granulates are combined, powdered and tableted.

joint granulation. The powdered mixture of components is granulated using 96% ethyl alcohol or alcoholic solutions of IUDs (collicut, collidones, povidone, shellac, etc.) as a granulating liquid. The dried granulate is powdered and tableted.

Combined granulation. The gas-forming mixture is granulated using 96% ethyl alcohol or an alcoholic solution of IUD as the granulating liquid. The mixture of the remaining components is granulated with an aqueous solution of IUD. The dried granulates are combined, powdered and tableted.

Thanks to the first method, fragmentation of the components is achieved, a decrease in the specific contact surface and reactivity; the use of the second and third methods also reduces the reactivity of the active and excipients of the drug. From the point of view of the simplicity of the technology and the stability of the preparations obtained, the method of joint granulation is more preferable. However, the reaction mixture of gas-forming components can affect the stability of the medicinal substance. Therefore, this method can only be recommended for dry substances of a neutral nature, stable when exposed to weak acids and alkalis. The separate granulation method is more versatile and can be used to introduce moisture-containing components (liquid, thick and dry plant extracts, crystalline hydrates, hygroscopic substances) into the composition of effervescent tablets or granules, as well as substances that are stable in an acidic or alkaline environment. In addition, separately prepared granules do not require special storage conditions (at low air humidity) before they are mixed. The negative aspects of separate granulation are: a two-stream scheme, the duration of the process, the lower stability of the granulates after mixing, the possible mosaic or marbling of the surface of the tablets.

There are 2 main problems in the technology of obtaining effervescent tablets.

• 1. Upon receipt of granulates of gas-forming components and their subsequent drying, the issue of the permissible residual moisture content of the granules is resolved. On the one hand, granules with low moisture content are poorly compressed, on the other hand, high moisture content of granules or tablets activates the interaction of gas-forming components during storage and, thus, contributes to the decomposition of the drug. As a rule, the value of this indicator is considered optimal in the range of 0.5-2%. However, an increase in residual moisture over 1.5-2% does not exclude the possibility of a reaction between the components during storage. Moisture that can be released from the effervescent part during storage of granules or tablets can be absorbed by a special adsorbent placed in the package, such as silica gel. In this regard, a significant part of the produced effervescent drugs is packaged in special polypropylene cases, the lids of which contain silica gel. The technology of effervescent tablets also uses substances (water repellents), which, when evenly distributed among the particles of the pressed material, are able to some extent to prevent the interaction between incompatible components in an environment with high humidity, and also partially localize the areas of the mass in which the chemical reaction has occurred. Applied to the granulate particles, for example, as a solution in non-aqueous volatile solvents, these substances form films several molecules thick on the surface of the granulate particles, preventing the penetration of moisture and the reaction between gas-forming components. In this capacity, for example, cellulose derivatives, paraffin and others are used.
• 2. Effervescent granules and tablets require rapid dissolution or dispersion when water is added. Accordingly, excipients (binders, diluents, sliding agents, etc.) should not prevent rapid wetting, penetration of water deep into the tablet and effervescent reaction throughout the entire volume of the medicinal product.

Among the difficulties in obtaining effervescent dosage forms, the adhesion of their components, sticking to the metal surfaces of the mold, which leads to the production of low-quality tablets, is sometimes called. The elimination of such phenomena is achieved by the introduction of small amounts of antifriction substances that prevent sticking of materials on the surface of the punches.

Despite these difficulties in creating effervescent granules and tablets, these dosage forms are effective and easy to use, which clearly illustrates their wide and constantly growing range in the modern pharmaceutical market.

Figure 2 - The main stages in the development of technology for effervescent tablets and granules (flow diagram).

Standardization.

Quality control of tablets is usually carried out according to the following indicators: description, authenticity; determination of the mechanical strength of tablets; carbon dioxide content; residual moisture; Microbiological purity; quantitation; average weight and deviation in the average weight of tablets; dissolution time.

Description. The evaluation of the appearance of the tablets is carried out when viewed with the naked eye of 20 tablets. Provide a description of the shape and color of the tablets. The surface of the tablet should be smooth, uniform, unless otherwise justified. On the surface of the tablet, strokes, marks for division, inscriptions and other designations can be applied. Tablets with a diameter of 9 mm or more must be at risk.

Authenticity, foreign impurities. Tests are carried out in accordance with the requirements of a private pharmacopoeial monograph.

Determination of the mechanical strength of tablets. The determination of the mechanical strength of tablets is carried out on devices, some of which allow you to determine the compressive strength (split), others - for abrasion. An objective assessment of the mechanical properties of tablets can be obtained by determining their strength in both ways. This is due to the fact that a number of tablet preparations, while meeting the requirements for compression, have easily abraded edges and, for this reason, turn out to be of poor quality. It should be noted that the determination of compressive strength is not a pharmacopoeial method.

Average weight and variation in weight of individual tablets. Weigh 20 tablets to the nearest 0.001 g and divide the result by 20. The mass of individual tablets is determined by weighing 20 tablets separately to the nearest 0.001 g, the deviation in the mass of individual tablets (with the exception of tablets coated by the extension method) is allowed within the following limits:

• For tablets weighing 0.1 g or less ± 10%;
• weighing more than 0.1 g and less than 0.3 g ± 7.5%;
• · weighing 0.3 and more ± 5%;
• The weight of individual coated tablets obtained by the extension method should not differ from the average weight by more than ± 15%.

Only two tablets may have deviations from the average weight exceeding the specified limits, but not more than twice.

Coefficients of gas formation and gas saturation. The gas formation coefficient is the ratio of the mass fraction of released carbon dioxide M E to the theoretically possible M T: , characterizes the degree of reaction of the gas-forming mixture during production and storage. The gas saturation coefficient is the ratio of the mass fraction of carbon dioxide in the resulting solution M R to its mass fraction in the effervescent tablet M e: characterizes the actual saturation of the solution with carbon dioxide. To determine carbon dioxide in effervescent dosage forms, you can use the Chittick method, according to which its volume is fixed, displaced from the dosage form under the influence of a sulfuric acid solution, then the mass fraction of carbon dioxide in the dosage form is calculated using special tables.

Dissolution. A dissolution test is mandatory. It is carried out in 200-400 ml of water at a temperature of 37°C without stirring. The maximum allowable dissolution time is 3 minutes.

Residual moisture. This test is mandatory because the water content can affect the properties of the active substance, the stability of the formulation, etc. The determination is carried out in accordance with the requirements of the general pharmacopoeial articles "Loss on drying" or "Determination of water"

Microbiological purity. The purity test is carried out in accordance with the General Pharmacopoeia Monograph "Microbiological purity".

Quantitation. For analysis take a portion of crushed tablets (at least 20 tablets). If crushing of the tablet would result in degradation of the active ingredient or if a uniformly divided powder would be difficult to obtain, the test is carried out on the whole tablet or tablets. In this case, it is recommended to use at least 10 tablets.

The quantitation result can be taken as the average value obtained in the dosing uniformity test.

Marking. The packaging of soluble, effervescent and dispersible tablets should contain a warning about the need to pre-dissolve the tablets before use.

Pack of effervescent tablets.

Due to the physical properties of auxiliary materials, the packaging of effervescent tablets must protect them as effectively as possible from the ingress of moisture from the outside and from residual moisture that may be released during storage. The most common types of packaging are strip packaging using laminated paper or composite films (buflen, polyflen, multifoil) and canisters. The volume of the strip pack should be large enough to hold the tablets without stressing the foil and as small as possible to minimize the amount of "room" air - this can act as a trap for the tablets. Considering the very low air humidity during operations with effervescent tablets, the residual moisture in them is so low that a relative air humidity of even 10% is quite high for close contact in a closed package. The canisters are made of plastic, glass or extruded aluminum with built-in caps containing desiccants (granular silica gel, anhydrous sodium sulfate) to trap this moisture.

A modern effervescent tablet packing machine is the Romaco Siebler HM 1E/240, where the product fed to the horizontal line for packing effervescent soluble tablets can be controlled at eye level. The entire process of creating the strip packaging takes place in a horizontal plane at a comfortable working height of 90 cm. The smart separation system places the product precisely in the sealing section of the heat sealing machine.

Effervescent tablets are fed along conveyor belts specially designed for this purpose to four horizontal feed channels. In the next step, the products are placed into the nests by means of servo controlled movements. Packing speed is significantly increased due to the direct feeding of tablets into the horizontal sealing section.

Another advantage is that the effervescent tablets, which are sensitive to changes in humidity and temperature, are no longer exposed to the heat and fumes generated by the heat sealing section when packed horizontally. As a result, the amount of waste is significantly reduced. Integrating a horizontal heat sealing section into the line has the advantage that the product no longer has to be conveyed from the tablet press to the top of the machine, as is the case with the vertical feed. Accordingly, Romaco Siebler horizontal line sections are shortened, saving time, space and money.

Horizontal line for packing Romaco Siebler HM 1E/240 effervescent soluble tablets.

The robotic transfer station can quickly be adapted to new packaging formats. When effervescent tablets are sealed in coated aluminum foil, the strip packaging is perforated and cut to size. The Siebler FlexTrans FT 400 transfer station transfers the finished tablet packs to the Romaco Promatic P 91 intermittent machine to place products in cartons. Loading robots transfer sealed packages from the conveyor belt to special trays at a speed of up to 400 packages per minute. The stacked packages are transferred directly to the cartoning machine. The robotic transfer station thus eliminates the need for complicated stacking sections.

Based on the principle of servo motor control, the robotic grippers can handle a variety of strip sizes and formats, from strips of ten for clinical use to single packs for the Asian market. For the first time on an effervescent tablet packaging line, fast format changes are possible thanks to in-line robotics. The robotic systems themselves are virtually maintenance-free and operate without the use of format change tools, resulting in lower operating costs. This innovative Siebler technology provides a new level of packaging line versatility and affordability, meeting the key requirements of contract packaging manufacturers.

The highly automated Romaco Siebler line facilitates constant control of the production process. Defective packages are instantly detected and removed from the line individually. Mandatory separation of complete cutting cycles is a thing of the past. More than twenty servo drives guarantee the accuracy and efficiency of the process. The four-row Siebler HM 1E/240 line for packing effervescent soluble tablets provides a maximum packing speed of 1500 pcs. in a minute. This approximates the capacity of an eight-row vertical effervescent tablet heat sealer. With a length of only 14 m and a width of 2.5 m, this line is compact. In general, the horizontal packaging line provides a high level of overall equipment efficiency.

One of India's largest generics manufacturers has relied on Romaco Siebler technology. Two horizontal packaging lines for effervescent tablets are currently in operation at this pharmaceutical company.

Edmont V. Stoyanov, Reinhard Vollmer

The principle of action of effervescent tablets is the rapid release of active and auxiliary substances due to the reaction between organic carboxylic acids (citric acid, tartaric acid, adipic acid) and baking soda (NaHCO 3) in contact with water. As a result of this reaction, unstable carbonic acid (H 2 CO 3) is formed, which immediately decomposes into water and carbon dioxide (CO 2). The gas forms bubbles that act as a super baking powder. This reaction is only possible in water. Inorganic icarbonates are practically insoluble in organic solvents, which makes the reaction impossible in any other medium. Technologically, a rapid dissolution reaction occurs between a solid and a liquid dosage form. Such a drug delivery system is the best way to avoid the disadvantages of solid dosage forms (slow dissolution and release of the active substance in the stomach) and liquid dosage forms (chemical and microbiological instability in water). Dissolved in water, effervescent tablets are characterized by rapid absorption and curative action, they do not harm the digestive system and improve the taste of the active ingredients. Which excipients are most suitable for the production of effervescent tablets? Is it possible to avoid lengthy and expensive laboratory studies to develop a suitable dosage form? Which production technology can be used: direct compression or wet granulation? These are the questions we would like to answer in this article by demonstrating effective ways to produce effervescent tablets.

Excipients

All raw materials used for the production of effervescent tablets must have good water solubility, which excludes the use of microcrystalline or powdered cellulose, dibasic calcium phosphate, etc. Mainly, only two water-soluble binders can be used in production - sugars (dextrates or glucose) and polyols (sorbitol, mannitol). Since the size of an effervescent tablet is relatively large (2-4 g), the choice of excipient is crucial in tablet production. A filler with good binding characteristics is needed in order to simplify the formulation and reduce the amount of excipients. Dextrates and sorbitol are commonly used excipients. Table 1 compares both excipients.

Sorbitol is suitable for the production of sugar-free tablets, although this polyol can cause bloating and discomfort at high levels. Adhesion to tablet press punches is a particular difficulty associated with the use of sorbitol, but good compressibility makes this excipient suitable for formulations that are difficult to manufacture. The hygroscopicity of sorbitol may limit its use in effervescent tablets due to the high susceptibility of these tablets to moisture. But despite this, sorbitol remains one of the most used polyols in the production of effervescent tablets.

Dextrates are spray crystallized dextrose containing a small amount of oligosaccharides. Dextrates Emdex® are a high-purity product consisting of white free-flowing large-pore spheres (Fig. 1).

This material has good fluidity, compressibility and the ability to crumble. Excellent water solubility results in fast disintegration and the requirement to use less lubricant. Dextrates have good fluidity, which allows the production of engraved tablets, eliminating the problem of material sticking to punches.

organic acids
The number of organic acids suitable for the production of effervescent tablets is limited. The best choice is citric acid: a carboxylic acid containing three functional carboxylic groups, which usually requires three equivalents of sodium bicarbonate. Anhydrous citric acid is commonly used in the production of effervescent tablets. However, the combination of citric acid and sodium bicarbonate is very hygroscopic and tends to absorb water and lose reactivity, so the humidity level in the work area must be strictly controlled. Alternative organic acids are tartaric, fumaric, and adipic, but they are not as popular and are used when citric acid is not applicable.

Bicarbonates
Sodium bicarbonate (NaHCO 3) can be found in 90% of effervescent tablet formulations. In the case of using NaHCO 3 , the stoichiometry must be precisely determined depending on the nature of the active substance and other acids or bases in the composition. For example, if the active substance is acid-forming, then the NaHCO 3 rate can be exceeded to improve the solubility of the tablet. However, the real problem with NaHCO 3 is its high sodium content, which is contraindicated in people with high blood pressure and kidney disease.

Direct compression technology or wet granulation?
Direct compression technology is the most modern, most acceptable technology for the production of solid dosage forms. If this technology is not applicable, wet granulation technology can be used. As stated above, effervescent tablet powder is very susceptible to moisture, and the presence of even a small amount of water can cause a chemical reaction. Direct pressing is a cost-effective technology that saves production time and reduces the number of production cycles. From our point of view, this technology should be preferred. The direct pressing technology does not require special equipment and is suitable for water-sensitive materials.
When is direct compression technology not applicable?

• In the case where there is a large difference between the bulk densities of the materials used, which can lead to desegregation of the tableting powder;
• active substances having a fine particle size are used in a small dosage. In this case, there may be a problem associated with the uniformity of the composition, but this can be avoided by grinding part of the filler and pre-mixing it with the active substance;
• sticky or oxygen-sensitive substances require a filler with very good flow characteristics,water solubility and absorption, such as dextrates withtheir porous, round particles (see fig. 1). Givenexcipient used in technologydirect compression, suitable for complex formulations, notrequires additional binders or anti-binding agents substances.

Obviously, direct compression technology cannotbe applicable in every case, but should be the number one choice in the production of effervescent tablets.

Lubricants
Traditional internal lubrication of an effervescent tablet is problematic due to the lipophilicity of the lubricant. Insoluble particles appear on the surface of the water after disintegration in the form of a foamy thin layer. How to prevent such a phenomenon? One way to prevent this problem can be the use of water-soluble lubricants - adding the amino acid L-leucine directly to the tablet mass. Another way is to replace the lipophilic magnesium stearate with the more hydrophilic sodium stearyl fumarate. PRUV® as an internal lubricant.

Conclusion
The right choice of excipient and technology for the production of effervescent tablets will save time, reduce production costs and allow the use of various sweeteners and taste masking agents in production. We present to your attention some recipes for the production of effervescent tablets by direct compression.