DEVELOPMENT OF TECHNOLOGY OF TABLETS CONTAINING IRON

ABSTRACT

The composition and rational technology of tablets with anti-anemic action were determined and substantiated. The choice of excipients for tablet cores was carried out on the basis of studying the technological properties of compressible masses for tableting, and the physicomechanical properties of model tablets. It was found that the optimal solution for granulation is an alcohol solution of polyvinylpyrrolidone, which made it possible to obtain tablet cores of necessary strength.

АННОТАЦИЯ

Определен состав и обоснована рациональная технология таблеток антианемического действия. Выбор вспомогательных веществ для таблеток-ядер проведен на основе изучения технологических свойств прессуемых масс для таблетирования, и физико-механический свойств модельных таблеток. Установлено, что оптимальным для грануляции, является спиртовой раствор поливинилпирролидона, который позволил получить таблетки-ядра необходимой прочности.

Keywords: iron deficiency, iron sulfate, folic acid, vitamin B₁₂, tablet, flowability, bulk density, compressibility, angle of repose, residual moisture, pushing pressure of model tablets from the matrix, compression ratio, core-tablet, fractional composition.

Ключевые слова: дефицита железа, железо сульфат, фолиевая кислота, витамина В₁₂, таблетка, сыпучесть, насыпная плотность, прессуемость, угол естественного откоса, остаточная влажность, давление выталкивания модельных таблеток из матрицы, коэффициент сжатия, таблетка-ядро, фракционный состав.

Introduction. Iron deficiency is the main and most common nutritional disorder in the world. Iron deficiency, which affects many children and women in developing countries, is the only malnutrition that is also highly prevalent in industrialized countries. More people suffer from iron deficiency than from any other health condition, which is a public health problem commensurate with an epidemic. Less noticeable in its manifestations than, for example, protein-energy malnutrition, iron deficiency leads to severe consequences - poor health, premature death and loss of income. Iron deficiency and anemia reduce the productivity of individuals and entire populations, lead to serious economic consequences and create obstacles to national development. Overall, the most vulnerable, poorest and least educated people are disproportionately affected by iron deficiency, and it is they who will benefit the most from reduced levels. Iron deficiency anemia is a syndrome that is characterized by a decrease in the amount of hemoglobin and/or red blood cells in the blood due to a lack of the microelement iron in the body. This type of anemia is the most common among all, and according to statistics, it accounts for about 78% in the structure of such diseases. According to WHO, about 1.8 billion people worldwide suffer from anemia. A hidden lack of iron (sideropenia) can be found in 3.6 billion people. According to WHO statistics, there are more than 2 billion people in the world suffering from anemia, most of them women and children [1, 2]. This problem is also very relevant for Uzbekistan. Most of the drugs used to treat anemia are imported from abroad.

The development of a complex anti-anemic domestic preparation containing iron sulfate, folic acid, vitamin B₁₂ for the treatment of iron deficiency conditions is one of the urgent tasks of pharmaceutical science and practical healthcare. Folic acid is a water-soluble vitamin essential for the growth and development of the circulatory and immune systems. Folic acid deficiency can cause megaloblastic anemia in adults, and taking folic acid during pregnancy reduces the risk of fetal neural tube defects. Vitamin B₁₂ is the common name for two chemical variants of the cobalamin molecule - cyanocobalamin and hydroxycobalamin, which have vitamin activity. It dissolves well in water, practically does not break down during prolonged heat treatment. The main benefit of Cobalamin is to help the development of red blood cells, it is necessary for the normal process of cell division (hematopoiesis) and the formation of DNA. It affects the state of rapidly renewing tissues - blood, immune system, skin and mucous membranes of the gastrointestinal tract. It also brings invaluable benefits in the formation of nerve fibers and has a positive effect on metabolism, the movement of lipids and carbohydrates in the body. Prevents anemia. In children, it promotes growth and improves appetite. Increases energy. Maintains the nervous system in a healthy state. Reduces irritability. Improves concentration, memory and balance. Iron makes up only 0.0065% of the body weight of a person weighing 60 kg - about 2.1 g (35 mg/kg of body weight), but the biological significance of iron in the body is very high. This trace element is a universal component of a living cell, participating in many metabolic processes, body growth, as well as in the processes of tissue respiration. Iron easily enters into contact with atmospheric oxygen and participates in its transportation to all cells of the body, supporting their vital activity. In addition, iron is part of myoglobin, a protein that stores oxygen in muscles, and is also found in more than 70 different enzymes. Therefore, with iron deficiency, the protective and adaptive forces of the body and metabolism are disrupted. A decrease in the amount of iron in the body (in the blood, bone marrow and depot), which disrupts the formation of hemoglobin, as well as proteins containing iron (myoglobin, iron-containing tissue enzymes) leads to iron deficiency anemia. The absorption of iron by the cells of the mucous membrane of the gastrointestinal tract from salt compounds mainly occurs in a divalent form, since apoferritin in enterocytes, which prevents excessive intake of iron into the body, can only bind to Fe²⁺ ions. Therefore, preparations based on various iron (II) salts (sulfate, fumarate, gluconate, succinate, glutamate, lactate, etc.) have greater bioavailability and are generally more preferable than preparations containing iron (III) salts. In addition, they are the cheapest drugs compared to other iron preparations [2, 3]. The purpose of this work is to develop the optimal composition and technology of an antianemic drug in the form of tablets.

Materials and research methods. The optimal dosage of iron sulfate, folic acid and vitamin B₁₂ in tablets, ascertained as a result of pharmacological studies, is 112.6 mg for iron sulfate, 0.8 mg folic acid, 0.01 mg cyanocobalamin, which implies the introduction of excipients into the tablet. When choosing methods for manufacturing tablets, as well as when selecting excipients, the physicochemical and technological properties of the substance are of great importance: flowability, expressed in terms of the mass flow rate of the powder from the vibrating funnel, and the angle of repose, bulk density, shape and size of particles, compressibility, the density of the substance [4, 6] of the tablet dosage form, the technological characteristics of the mixture of the substance iron sulfate, folic acid, vitamin B₁₂ were determined. Technological parameters of mixtures of the substance: fractional composition, bulk volume, flowability, compressibility were determined according to the methods given in the literature [5] on devices from Erweka (Germany). The moisture content of the substance was determined by drying on an MB35 Ohaus halogen moisture analyzer. To determine the resistance of tablets to crushing, a sample weighing 0.5 g was pressed into a tablet with a diameter of 11 mm in a hydraulic press at a pressure of 120 MPa, and then the strength of the resulting tablet was determined on an Erweka TVT device (Germany). The force of ejection of tablets from the matrix was determined by ejecting the obtained pressing by the lower punch with registration of the extrusion pressure on the pressure gauge of the press [5, 6].

Results and discussion. The study of the technological properties of the mixture of the substance showed poor flowability (3.0*10^-3 kg/s), a high compaction coefficient (3.5), and an increased residual moisture content of 5.5%. The pressure of expulsion of model tablets from the matrix when lubricated with stearic acid was high and amounted to 8.5 MPa.

Table 1.

Physico-chemical and technological properties of mixtures of the substance iron sulfate, folic acid and vitamin B₁₂

Thus, according to the unsatisfactory results of the studied technological parameters of the substance mixtures, the need to use excipients (Sharipov’s) was assumed. Taking into account the physicochemical and technological properties of mixtures of the substance in the development of the composition and technology, the possibility of using such fillers as sucrose, lactose, MCC, potato starch, corn starch, calcium stearate, representing local raw materials, has been studied. The role of binders was performed by purified water, 55-67% sugar syrup, ethyl alcohol of various concentrations -30, 40, 50, 70, 96%, 4-15% starch solutions, 10-20% PVP solution in 50% ethyl alcohol [8]. Experimental samples of tablets were prepared with the addition of excipients in various ratios and combinations according to 35 prescriptions. Table 2 shows the compositions of 8 tablets formulations, which differ from each other both in type and in the amount of excipients used. Initially, we studied the possibility of obtaining tablets by direct compression, which, as is well known, has a number of advantages. The direct pressing method makes it possible to achieve high labor productivity, significantly reduce the time of the technological cycle by eliminating a number of operations and stages, eliminate the use of several items of equipment, reduce production areas, and reduce energy and labor costs. An analysis of the obtained technological parameters showed the need to add excipients that improve flowability, reduce the force of ejection of tablets from the matrix channel, and reduce the absorption of moisture from the air. Tablets obtained by direct compression did not meet the requirements of SP XII in terms of abrasion strength (85%), fracture strength (30 N), average weight and deviations from the average weight (0.3 + 15%). Therefore, to achieve the goal, the wet granulation method was used. Granulation - directed coarsening of particles, i.e. the process of converting a powdered material into grains of a certain size is carried out in order to compact the powder and obtain uniform grains-granules with good flowability and a high bulk density. When using purified water, ethyl alcohol of various concentrations as a binding component, the model tablets turned out to be very loose, brittle and easily crumbled, the granules had a large proportion of small fractions, and the flowability also had the lowest index and amounted to 3.4 kg/s *10^-3, when using 2%, 5%, 7% solutions of methylcellulose (MC), hydroxypropyl methylcellulose (OPMC), 5%, 7%, 10% starch solutions as a binding component, the disintegration time of the resulting model tablets exceeded the regulated ones and amounted to 25-30 minutes, with moistening the mass with a 10% alcohol solution of PVP, the granulate after drying turned out to be strong, the pressed mass had the best flow characteristics (9.5-10.4 kg /s *10^-3), the fractional composition was uniform than in other pressed masses, the obtained model tablets had a qualitative appearance, sufficient mechanical strength (85-95 N), disintegration (6-8 min). Therefore, in subsequent studies, a 10% alcohol solution of PVP was chosen as a binding agent. 8 tablet mixtures were obtained, differing in the nature and amount of excipients (Table 2). As technological indicators of the pressed mass, the fractional composition, bulk density, flowability, angle of repose, porosity, compaction coefficient, compressibility coefficient, and residual moisture were studied. The determination of the above parameters was carried out according to the methods of SP XII. The results are shown in table 3.

Table 2.

Investigated model compositions of granulates for obtaining tablets-cores, prepared by wet granulation

To obtain model compositions of tablets in laboratory conditions, the required amount of the substance of iron sulfate, folic acid, vitamin B₁₂ and excipients was weighed according to the relevant prescriptions. Tablet mixtures were moistened with a solution of a binder, the mass plasticity required for granulation was ascertained experimentally. The moistened compressible mass was dried in an oven at a temperature not exceeding 30°C to an optimal residual moisture content of 2.8–3.0%, then wiped through a stainless steel sieve with a hole diameter of 1.5 mm. Magnesium granules were dusted with stearate and aerosil, previously crushed and screened through a nylon sieve with a hole diameter of 100 μm. Then the granulate was pressed with a manual hydraulic press on a press tool with a diameter of 9 mm, biconcave shape at a pressing pressure of 120 MPa, while fixing the ejection pressure on the pressure gauge and recalculating in MPa. To assess the compressibility, a powder weighing 0.5 g was pressed on a manual hydraulic press into a model tablet 11 mm in diameter at a pressure of 120 MPa (40 atm). The crushing load was determined on a spring dynamometer. The compressibility (mechanical compressive strength) of the mass was expressed in Newtons. The technological properties of the pressed masses were determined according to the data given in the literature [5].

Table 3.

The results of determining the technological properties of compressible masses for tablet cores

According to Table 3, it can be noted that the auxiliary substances used improved the technological properties of the substance - flowability, bulk density, angle of repose, compression ratio, etc., had more positive values for the pressed mass than for the substance, which indicates the correct selection of auxiliary substances and the course of the technological process. The results of the study of the physical and mechanical properties of the obtained tablets showed that the tablets of all formulations meet the requirements of SP XII in terms of strength. It was noted that the use of sucrose and lactose caused the granulate to adhere to the surface of the press tool. Positive indicators of the pressed mass were noted when using starch, MCC and PVP solution (Plasdone S-630) as a binding agent. A great influence on the quality of the tablets has an external friction when pushing the tablets out of the matrix channel. The greater the friction of the tablet on the matrix, the more inhomogeneously the residual stress, density, and strength are distributed in it, which leads to delamination of the tablets during their ejection from the matrix. To obtain high-quality tablets, the ejection pressure should be no more than 10% of the pressing pressure [7]. When using composition No. 8, the extrusion pressure did not rise above 2.5 MPa, i.e. was only 2% compared to other formulations. An analysis of the technological characteristics of tablet mixtures of model compositions and the quality of the obtained tablets (Table 3) showed that all compositions have good flowability, bulk weight, and meet the requirements for disintegration and mechanical abrasion resistance.

Conclusion: the best ratio of flowability, bulk density, ejection pressure from the matrix, mechanical strength, abrasion resistance, disintegration has a mixture of model composition No. 8. Composition No. 8 meets all the physical and mechanical requirements for SP XII imposed on tablets [4], and has relatively small sizes and average weight of tablets, and this does not make it difficult for patients to swallow tablets. Based on the above results, composition No. 8 was chosen for further research.

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