Development of quality control methods for a finished iodine-containing medicinal product in the study of the discipline "Chemistry of medicinal products"

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Rivne State University for the Humanities, Rivne, Ukraine

Development of quality control methods for a finished iodine-containing medicinal product in the study of the discipline "Chemistry of medicinal products"

Sachuk R.M.

Abstract

The paper highlights the main issues related to the development of methods of quality control of input materials (methods of control of input raw materials), active and auxiliary substances of raw materials, quality control of the ready-to-use veterinary medicinal product "Iodozol", when studying the discipline "Chemistry of medicinal products" by students of higher education. The main questions that may arise for students when developing appropriate specifications for ready-made medicinal products are analyzed. The study was based on the study of the materials of the registration dossier for the veterinary medicine "Iodozol" (solution for intrauterine use, aerosol), obtained from the author's own experience. The article presents the main aspects of the development of quality control methods for the veterinary preparation "Iodozol", an integral stage of which is, in fact, the development of methods for controlling the active and auxiliary substances of the medicine.

The analysis and introduction of theoretically based quality control methods for the veterinary medicinal product "Iodozol" into pedagogical activities will allow students to systematize the acquired knowledge, practical skills and their use in future professional activities.

Key words: iodine, medicinal product, pharmaceutical development, quality control methods, specification.

Розробка методик контролю якості на готовий йодовмісний лікарський засіб при вивченні дисципліни «Хімія лікарських препаратів»

Сачук Р.М.

Рівненський державний гуманітарний університет, м. Рівне, Україна;

Резюме

student veterinary pedagogical activity

У статті висвітлено основні питання щодо розробки методик контролю якості вхідних матеріалів (методи контролю вхідної сировини), діючих і допоміжних речовин сировини, контролю якості на готовий ветеринарний лікарські засіб «Йодозол», при вивченні здобувачами вищої освіти дисципліни «Хімія лікарських препаратів». Проаналізовано основні питання, які можуть виникнути у студентів при розробці відповідних специфікацій на готові лікарські препарати. Дослідження базувалося на вивченні матеріалів реєстраційного досьє на ветеринарний лікарський засіб «Йодозол» (розчин для внутрішньоматкового застосування, аерозоль), отриманого із власного досвіду автора. У статті наведені основні аспекти щодо розробки методики контролю якості на ветеринарний лікарський засіб «Йодозол», невід'ємним етапом якої є, власне, розробка методів контролю діючої та допоміжних речовин на лікарський засіб. Аналіз та введення у педагогічну діяльність теоретично обґрунтованих методик контролю якості на ветеринарний лікарський засіб «Йодозол» дозволять студентам систематизувати отримані знання, практичні навички і їх використання у майбутній професійній діяльності.

Ключові слова: методики контролю якості, специфікація, йод, фармацевтична розробка, лікарський засіб.

Iodine is a unique medicinal substance in the pharmaceutical aspect. It is the main active ingredient for a large number of drugs widely used in medicine and veterinary medicine, as it determines the high biological activity and versatile pharmacological effect of these drugs.

Iodine has a wide range of antimicrobial, fungicidal, anthelmintic, antiviral and antiprotozoal effects, which are the most important characteristics of medicinal antiseptic preparations. In this regard, in the last few decades, the trace element iodine has attracted the attention of scientists as a promising means for synthesizing new antibacterial drugs, followed by their widespread use in practical veterinary medicine (Kraydashenko et al., 2015).

It is known that the quality of a medicinal product is established at the stage of pharmaceutical development, which consists in a comprehensive study on the development of a finished medicinal product, which convincingly demonstrates that the proposed qualitative and quantitative composition, the selected preparation form, production technology and primary packaging ensure the creation of a high-quality product (Panagopoulou and Georgarakis, 1990; Sachuk et al., 2022; 2023; Zarivna, 2023).

A ready-to-use preparation is a dosed drug in the form and condition intended for use, which has undergone all stages of production, including final packaging (Liapunov et al., 2011; Berest et al., 2017).

The quality control of the ready-to-use medicinal product is carried out at the following stages: registration - through examination and approval of quality control methods and text for labeling, verification of production compliance with GMP requirements; import - by quality control of each imported series; circulation - through scheduled and unscheduled inspections of importers, distributors and veterinary pharmacies.

As for quality control methods, where a list of detailed requirements is indicated, which must be met by products or materials used or obtained (according to GMP requirements), that is, this is a document that describes in detail the methods of complete chemical, biological and pharmaco-technological quality control of drugs (Bezuhlyi et al., 2013; Nemchenko et al.,2017; Zarivna, 2023). Therefore, the future specialist, when studying the discipline "Chemistry of medicinal preparations" with the specialty "Secondary education, chemistry", must learn to select, in accordance with the dosage form, alternative methods of analysis, taking into account the structure and properties of the active pharmaceutical ingredient in order to be able to develop draft specifications for ready medicinal product and be guided by them in their practical activities to confirm the quality of the medicinal product.

The purpose of the study is to highlight the main issues related to the development of quality control methods for ready-made iodine-containing medicinal products when studying the discipline "Chemistry of Medicinal Products".

Materials and methods

The development and testing of quality control methods for the ready-made iodine-containing veterinary medicinal product was carried out on the basis of the laboratory for quality control, safety and registration of veterinary medicinal products and feed additives of "DEVIE" LLC.

The development and testing of the methods was carried out using the following equipment, dishes and reagents: analytical scales with a weighing accuracy of 0.0001 g; ultrasonic bath UZU-01 or similar; sodium hydroxide, n.d.a.; hydrochloric acid, n.d.a.; silver nitrate, n.d.a.; potassium iodide, n.d.a.; sodium thiosulfite, n.d.a.; membrane filters with a pore size of 0.2-0.5 ^m; argentum nitrate, CC; sodium eosin, PFA; potato starch, CC; acetic acid, PFA; sodium thiosulfate, CC; loop microbiological, platinum; gas burner; water is purified according to SPU 2.0, and laboratory dishes were prepared according to DSTU ISO 4787.

Results

The educational discipline "Chemistry of medicinal preparations" belongs to the professionally oriented training of specialists in the specialty "Secondary education, chemistry". The discipline "Chemistry of medicinal preparations" belongs to the list of selective educational disciplines at the "bachelor" level of education, which are offered as part of the cycle of professional training of students under the educational program "Secondary Education (Chemistry)" in the third year of study at the Rivne State Humanitarian University. It provides students with the formation of research-oriented professional competence and is aimed at studying theoretical and practical issues of the chemistry of medicinal products with the aim of mastering the methods of identification, quantitative determination, and quality control of medicinal products. In practical classes for students of higher education, the theoretical foundations of the pharmaceutical quality system are laid, which provides for the quality control of medicinal products at the stage of pharmaceutical development (Derzhavna Farmakopeia Ukrainy, 2014; 2015; European Pharmacopoeia, 2009), research, storage, and consumption, in accordance with current control methods quality and requirements, in accordance with good practices: GMP/GLP, GCP, GPP, GDP (Rahman et al, 1990; European Pharmacopoeia, 2009), which is ensured by the use of various tests, such as: physical, physico-chemical, chemical, the theoretical foundations of which were studied by students at previous courses of study of chemical disciplines. Students get acquainted with the state policy in the field of standardization of pharmaceuticals, the prerequisite of which is, in fact, the development of projects of quality control methods. For this, they study the basics of the State Pharmacopoeia of Ukraine (Derzhavna Farmakopeia Ukrainy, 2014; 2015; Bezuhly et al, 2013; Kraidashenko et al, 2105; Zarivna, 2023), technological instructions for the production of the drug, proper practices, laws, standards, codes of established practice, on the basis of which the main and additional parameters of the quality of ready-to-use medicines are selected. After that, the qualitative composition and quantitative content of active pharmaceutical ingredients are confirmed by an alternative method of analysis, as a result of which quality markers and appropriate acceptance criteria are selected (WHO Good Practices for Pharmaceutical Quality Control Laboratories, 2009; Derzhavna Farmakopeia Ukrainy (SPU), 2014).

On the example of one veterinary medicinal product, we will consider the input material control algorithm (input raw material control methods), quality certificates of active and auxiliary substances in the production of the drug "Iodozol" (solution for intrauterine use, aerosol).

Given that 1 ml of the drug contains the active substance: iodine - 5 mg and potassium iodide - 10 mg, and auxiliary substances - propylene glycol.

Let's consider each of the components of the drug separately.

Iodine is crystalline.

Appearance. Light-black plates with a metallic luster of crystals with a characteristic smell. Volatile at normal temperature, ignites when heated, forming violet vapors.

Solubility. It is poorly soluble in water, easily soluble in an aqueous solution of iodides, soluble in 10 parts of 95% alcohol, ether and chloroform. Solutions in chloroform are purple.

Authenticity. A solution of the drug in water, when 1 drop of starch solution is added, forms a blue color. When boiling, the color disappears and appears immediately after cooling.

Transparency and color of the solution. 1 g of the ground drug should completely dissolve in 25 ml of 10% sodium thiosulfate solution, forming a transparent and colorless solution.

Iodized cyanide. 0.75 g of the drug is dissolved in 30 ml of water and filtered. 10 ml of filtrate is decolorized with a dilute solution of sulfuric acid, add 1 drop of ferrous sulfate solution, 1 drop of chloride solution, 1 drop of oxidized iron chloride solution and 0.5 ml of caustic sodium solution. The mixture is easily heated and acidified with dilute hydrochloric acid; no blue color should appear.

Halogens. To the second 10 ml of filtrate, dilute sulfuric acid solution is added drop by drop to decolorize iodine. 1 ml of concentrated ammonia solution and 4 ml of silver nitrate solution, shake vigorously and filter. The filtrate is diluted with water to 25 ml. 10 ml of purified filtrate after acidification with 1.0-1.5 ml of nitric acid must withstand the test for chlorides (no more than 0.02% in the preparation).

Quantitative definition. About 0.2 g of the ground drug is added to an accurately weighed flask with a ground stopper containing 10 ml of potassium iodide solution and weighed again. The resulting solution is diluted with water to 20 ml and titrated to 0.1 n. sodium thiosulfite solution until the color disappears (starch indicator).

ml. 0.1 n. of sodium thiosulfite solution corresponds to 0.01269 g of iodine, which should be at least 99.5% in the preparation.

Potassium iodide.

Appearance. Colorless, white cubic crystals or white fine-crystalline powder without odor, salty-bitter taste. At high humidity, it becomes raw.

Solubility. Soluble in 0.75 parts of water, 12 parts of alcohol and 2.5 parts of glycerin.

Transparency and color of the solution. 1 g of the drug is dissolved in 10 ml of freshly boiled water and cooled water. The solution should be clear and colorless.

Alkalinity. Add 0.2 ml of 0.02 N to the resulting solution. hydrochloric acid solution; the solution should not turn pink from the addition of 1 drop of phenolphthalein solution.

Sulfates. 3 g of the drug is dissolved in 30 ml of water. 10 ml of this solution must pass the sulfate test (no more than 0.01% in the preparation).

Quantitative definition. About 0.3 g of the drug (exact weight), pre-dried at 110 0C for 4 hours, dissolve in 30 ml of water, add to 30 ml of water, add 1.5 ml of diluted acetic acid, 5 drops of 0.1% solution of sodium eosinate and titrate 0.1 n. silver nitrate solution until the color of the precipitate changes from yellow to pink.

1 ml of silver nitrate solution corresponds to 0.01660 g of CI, which should be at least 99.5% in the dried preparation.

Determіnation the identity of iodine. Preparation of starch solution: 1 g of starch (exact measurement) and 5 ml of purified water are added to a porcelain mortar, the resulting mixture is ground until a homogeneous mass is obtained and slowly poured with constant stirring into 90 ml of boiling purified water. The resulting suspension is boiled for 2-3 minutes until obtaining barely opalescent liquid.

Conducting research. The contents of the bottle are poured into a measuring cup with a capacity of 200 ml through an adapter with a tip. Add 0.5 ml of the drug to a measuring cup with a volume of 50 ml, add 20 ml of purified water and 0.5 ml of starch solution. In the presence of iodine, a blue color is formed.

Determining the identity of potassium iodide.

Conducting research. The contents of the bottle are poured into a measuring cup with a capacity of 200 ml through an adapter with a tip. Wait 4 hours until the foam disappears and the repellent evaporates. A drop of the drug on a platinum wire is introduced into the colorless zone of fire. A light purple color should appear.

Let's consider in more detail the quality control of the ready-to-use veterinary medicinal product "Iodozol".

Determination of the content of iodine and potassium iodide in the preparation. Preparation of starch solution. 1 g of starch (precisely weighed) and 5 ml of purified water are added to a porcelain mortar, the resulting mixture is ground until a homogeneous mass is obtained and slowly poured with constant stirring to 90 ml of boiling water purified by P. The resulting suspension is boiled for 2-3 minutes until obtaining a slightly opalescent liquid.

Preparation of 0.1 N solution of silver nitrate. Place 1.6887 g (exact weight) of argentum nitrate in a 100 ml volumetric flask, add 90 ml of purified P water, stir until the weight is dissolved, and make up to the mark with P purified water.

Preparation of indicator 1% sodium eosinate. Place 0.25 g (precise measure) of the sodium eosinate indicator in a 25 ml volumetric flask, add 20 ml of P-purified water, stir until the measure dissolves, and make up to the mark with P-purified water.

Preparation of diluted acetic acid. Place 31.3 ml of glacial acetic acid in a 100 ml volumetric flask and make up to the mark with purified water.

Conducting research to determine the quantitative content of iodine in the drug. In a 250 ml conical flask with a ground glass stopper (on an ice bath), add 9 ml (exact volume) of the solution for research, add 20 ml of cooled water, a few drops of starch solution (the solution turns blue) and titrate to 0.1 n with sodium thiosulfate until the color changes to colorless.

1 ml of sodium thiosulfate corresponds to 0.01269 g of iodine.

The content of iodine in the preparation, mg/ml, is determined by formula (1):

V1 - volume of 0.1 N sodium thiosulfate solution used for titration of an aliquot of the drug, ml;

0.01269 - the mass of iodine corresponding to 1 ml of 0.1 N sodium thiosulfate solution, g;

K1 is the correction factor for 0.1 N sodium thiosulfate solution;

100 - dilution of the drug, ml;

9 - an aliquot of the drug taken for research, ml.

Conducting research to determine the quantitative content of potassium iodide in the preparation. Add 20 ml of diluted acetic acid, 0.5 ml of 1 % sodium eosin solution to the previous solution and titrate with 0.1 M argentum nitrate solution until the color changes from yellow to pink. The difference between the number of milliliters of argentum nitrate and the number of milliliters of sodium thiosulfate is used to calculate the potassium iodide content.

ml of 0.1 M argentum nitrate corresponds to 0.01660 g of CI.

The content of potassium iodide in the preparation, mg/ml, is determined by formula (2):

Vi - volume of 0.1 M sodium thiosulfate solution used for titration of an aliquot of the drug, ml;

V2 - volume of 0.1 N argentum nitrate solution used for titration of an aliquot of the drug, ml;

K1 is the correction factor for 0.1 N sodium thiosulfate solution;

K2 is the correction factor for 0.1 M argentum nitrate solution;

0.0166 is the mass of potassium iodide, in grams, corresponding to 1 ml of 0.1 N AgNO3 solution

9 - an aliquot of pr equipment, taken for research, ml.

The quality indicators of the drug were compared with the characteristics and standards specified in the table 1.

Table 1. Indicators of quality control of "lodozol" VLZ

Taking into account the above, the student must be able to analyze methods, target elements, respectively, because these knowledge and skills are a prerequisite for creating a high-quality and safe veterinary medicinal product. Quality control methods include full chemical and pharmaco-technological quality control of the drug, therefore, in order to develop quality control methods for ready-to-use medicinal products, students must clearly select alternative methods for determining the qualitative composition and quantitative content of active substances in the drug, taking into account the structure, physical and chemical properties active pharmaceutical ingredients, etc.

In addition, they must be able to confirm their benign quality by appearance, solubility, pH in accordance with the requirements of current regulatory documentation, in particular the State Pharmacopoeia of Ukraine. Also, they should be able to carry out the proposed reactions for identification of active pharmaceutical ingredients by cationic and anionic composition, use chemical methods of analysis to identify medicinal products of an organic nature by analytical and functional groups, taking into account the requirements of the SPU.

In addition, students must select the pharmaco-technological indicators of the quality of the medicinal product depending on the type of dosage form, according to the edition of the SPU. The State Pharmacopoeia of Ukraine establishes general requirements for certain methods of analysis, as well as acceptance criteria, which, in appropriate cases, are part of the evaluation of the active pharmaceutical ingredient and medicinal product, respectively. Therefore, knowing its requirements regarding the quality indicators of ready-to-use medicines, methods of analysis, etc., a higher education student will not only learn to develop projects of appropriate quality control methods for preparations, but also will be able to apply them in their practical activities to confirm the assessment of the quality of a medicinal preparation.

Conclusions

Summarizing the above, "Medicinal chemistry" is a discipline that forms a system of knowledge and skills that will definitely enable a future specialist in the field of pedagogy to fully and qualitatively fulfill his professional duties in the field of medicinal chemistry and become competitive on the labor market. During the teaching of this discipline, the theoretical foundations of the study of the quality of medicinal products by students are laid, which involves quality control of medicinal products at the stage of development, research, storage and consumption, in accordance with existing quality control methods and requirements in the GMP/GLP, GCP, GPP, GDP, which is ensured by the use of various tests. Analysis and introduction of theoretically grounded modern provisions, new techniques and methods into pedagogical activity will allow students to systematize the acquired knowledge, practical skills and use them in future professional activities.

The next stage of the research will be the presentation of the theoretical foundations of new methods of analysis and their application in practice, which will allow students to conduct quality control of preparations for therapeutic application at the highest level and fully provide them with the appropriate level of training in the field of secondary education "Chemistry" and competitiveness in the international labor market.

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