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Introduction
Chapter 1. Basic Principles of Pharmaceutical Analysis

1.1 Pharmaceutical analysis criteria
1.2 Errors in Pharmaceutical Analysis
1.4 Sources and causes of poor quality of medicinal substances
1.5 General requirements for purity tests
1.6 Methods of pharmaceutical analysis and their classification

Chapter 2. Physical Methods of Analysis

2.1 Verification of physical properties or measurement of physical constants of drug substances
2.2 Setting the pH of the medium
2.3 Determination of clarity and turbidity of solutions
2.4 Estimation of chemical constants

Chapter 3. Chemical Methods of Analysis

3.1 Features of chemical methods of analysis
3.2 Gravimetric (weight) method
3.3 Titrimetric (volumetric) methods
3.4 Gasometric analysis
3.5 Quantitative elemental analysis

Chapter 4. Physical and chemical methods of analysis

4.1 Features of physicochemical methods of analysis
4.2 Optical methods
4.3 Absorption methods
4.4 Methods based on emission of radiation
4.5 Methods based on the use of a magnetic field
4.6 Electrochemical methods
4.7 Separation methods
4.8 Thermal methods of analysis

Chapter 5

5.1 Biological quality control of medicines
5.2 Microbiological control of medicinal products

conclusions
List of used literature

Introduction

Pharmaceutical analysis is the science of chemical characterization and measurement of biologically active substances at all stages of production: from the control of raw materials to the assessment of the quality of the resulting medicinal substance, the study of its stability, the establishment of expiration dates and the standardization of the finished dosage form. Pharmaceutical analysis has its own specific features that distinguish it from other types of analysis. These features lie in the fact that substances of various chemical nature are subjected to analysis: inorganic, organoelement, radioactive, organic compounds from simple aliphatic to complex natural biologically active substances. The range of concentrations of analytes is extremely wide. The objects of pharmaceutical analysis are not only individual medicinal substances, but also mixtures containing a different number of components. The number of medicines is increasing every year. This necessitates the development of new methods of analysis.

Methods of pharmaceutical analysis need to be systematically improved due to the continuous increase in the requirements for the quality of drugs, and the requirements for both the degree of purity of medicinal substances and the quantitative content are growing. Therefore, it is necessary to widely use not only chemical, but also more sensitive physical and chemical methods for assessing the quality of drugs.

The requirements for pharmaceutical analysis are high. It should be sufficiently specific and sensitive, accurate in relation to the standards stipulated by GF XI, VFS, FS and other scientific and technical documentation, carried out in short periods of time using the minimum quantities of tested drugs and reagents.

Pharmaceutical analysis, depending on the tasks, includes various forms of drug quality control: pharmacopoeial analysis, step-by-step control of the production of medicines, analysis of individual dosage forms, express analysis in a pharmacy and biopharmaceutical analysis.

Pharmacopoeial analysis is an integral part of pharmaceutical analysis. It is a set of methods for studying drugs and dosage forms set forth in the State Pharmacopoeia or other regulatory and technical documentation (VFS, FS). Based on the results obtained during the pharmacopoeial analysis, a conclusion is made on the compliance of the medicinal product with the requirements of the Global Fund or other regulatory and technical documentation. In case of deviation from these requirements, the drug is not allowed to be used.

The conclusion about the quality of the medicinal product can only be made on the basis of the analysis of the sample (sample). The procedure for its selection is indicated either in a private article or in a general article of the Global Fund XI (issue 2). Sampling is carried out only from undamaged sealed and packed in accordance with the requirements of the NTD packaging units. At the same time, the requirements for precautionary measures for working with poisonous and narcotic drugs, as well as for toxicity, flammability, explosiveness, hygroscopicity and other properties of drugs, must be strictly observed. To test for compliance with the requirements of the NTD, multi-stage sampling is carried out. The number of steps is determined by the type of packaging. At the last stage (after control by appearance), a sample is taken in the amount necessary for four complete physical and chemical analyzes (if the sample is taken for controlling organizations, then for six such analyzes).

From the "angro" packaging, point samples are taken, taken in equal quantities from the top, middle and bottom layers of each packaging unit. After establishing homogeneity, all these samples are mixed. Loose and viscous drugs are taken with a sampler made of an inert material. Liquid medicinal products are thoroughly mixed before sampling. If this is difficult to do, then point samples are taken from different layers. The selection of samples of finished medicinal products is carried out in accordance with the requirements of private articles or control instructions approved by the Ministry of Health of the Russian Federation.

Performing a pharmacopoeial analysis allows you to establish the authenticity of the drug, its purity, to determine the quantitative content of the pharmacologically active substance or ingredients that make up the dosage form. While each of these stages has a specific purpose, they cannot be viewed in isolation. They are interrelated and complement each other. For example, melting point, solubility, pH of an aqueous solution, etc. are criteria for both authenticity and purity of a medicinal substance.

Chapter 1. Basic Principles of Pharmaceutical Analysis

1.1 Pharmaceutical analysis criteria

At various stages of pharmaceutical analysis, depending on the tasks set, criteria such as selectivity, sensitivity, accuracy, time spent on the analysis, and the amount of the analyzed drug (dosage form) are important.

The selectivity of the method is very important when analyzing mixtures of substances, since it makes it possible to obtain the true values of each of the components. Only selective methods of analysis make it possible to determine the content of the main component in the presence of decomposition products and other impurities.

Requirements for the accuracy and sensitivity of pharmaceutical analysis depend on the object and purpose of the study. When testing the degree of purity of the drug, methods are used that are highly sensitive, allowing you to set the minimum content of impurities.

When performing step-by-step production control, as well as when conducting express analysis in a pharmacy, an important role is played by the time factor spent on the analysis. For this, methods are chosen that allow the analysis to be carried out in the shortest time intervals and at the same time with sufficient accuracy.

In the quantitative determination of a medicinal substance, a method is used that is distinguished by selectivity and high accuracy. The sensitivity of the method is neglected, given the possibility of performing an analysis with a large sample of the drug.

A measure of the sensitivity of a reaction is the limit of detection. It means the lowest content at which the presence of the determined component can be detected by this method with a given confidence level. The term "limit of detection" was introduced instead of such a concept as "discovered minimum", it is also used instead of the term "sensitivity". The sensitivity of qualitative reactions is influenced by such factors as the volumes of solutions of reacting components, concentrations of reagents, pH of the medium, temperature, duration experience.This should be taken into account when developing methods for qualitative pharmaceutical analysis.To establish the sensitivity of reactions, the absorbance index (specific or molar), established by the spectrophotometric method, is increasingly used.In chemical analysis, the sensitivity is set by the value of the limit of detection of a given reaction.Physicochemical methods are distinguished by high sensitivity The most highly sensitive are radiochemical and mass spectral methods, which make it possible to determine 10 -8 -10 -9% of the analyte, polarographic and fluorimetric 10 -6 -10 -9%, sensitivity of spectrophotometric methods is 10 -3 -10 -6% , potentiometric 10 -2%.

The term "analysis accuracy" simultaneously includes two concepts: reproducibility and correctness of the obtained results. Reproducibility characterizes the scatter of the results of an analysis compared to the mean. Correctness reflects the difference between the actual and found content of the substance. The accuracy of the analysis for each method is different and depends on many factors: the calibration of measuring instruments, the accuracy of weighing or measuring, the experience of the analyst, etc. The accuracy of the analysis result cannot be higher than the accuracy of the least accurate measurement.

So, when calculating the results of titrimetric determinations, the least accurate figure is the number of milliliters of titrant used for titration. In modern burettes, depending on their accuracy class, the maximum measurement error is about ±0.02 ml. The leakage error is also ±0.02 ml. If, with the indicated total measurement and leakage error of ±0.04 ml, 20 ml of titrant is consumed for titration, then the relative error will be 0.2%. With a decrease in the sample and the number of milliliters of titrant, the accuracy decreases accordingly. Thus, titrimetric determination can be performed with a relative error of ±(0.2--0.3)%.

The accuracy of titrimetric determinations can be improved by using microburettes, the use of which significantly reduces errors from inaccurate measurement, leakage and temperature effects. An error is also allowed when taking a sample.

The weighing of the sample when performing the analysis of the medicinal substance is carried out with an accuracy of ± 0.2 mg. When taking a sample of 0.5 g of the drug, which is usual for pharmacopoeial analysis, and weighing accuracy of ± 0.2 mg, the relative error will be 0.4%. When analyzing dosage forms, performing express analysis, such accuracy when weighing is not required, therefore, a sample is taken with an accuracy of ± (0.001--0.01) g, i.e. with a limiting relative error of 0.1--1%. This can also be attributed to the accuracy of weighing the sample for colorimetric analysis, the accuracy of the results of which is ±5%.

1.2 Mistakes during Pharmaceutical Analysis

When performing a quantitative determination by any chemical or physico-chemical method, three groups of errors can be made: gross (misses), systematic (certain) and random (uncertain).

Gross errors are the result of a miscalculation of the observer when performing any of the determination operations or incorrectly performed calculations. Results with gross errors are discarded as poor quality.

Systematic errors reflect the correctness of the results of the analysis. They distort the measurement results, usually in one direction (positive or negative) by some constant value. The reason for systematic errors in the analysis may be, for example, the hygroscopicity of the drug when weighing its sample; imperfection of measuring and physico-chemical instruments; experience of the analyst, etc. Systematic errors can be partially eliminated by making corrections, instrument calibration, etc. However, it is always necessary to ensure that the systematic error is commensurate with the error of the instrument and does not exceed the random error.

Random errors reflect the reproducibility of the results of the analysis. They are called by uncontrolled variables. The arithmetic mean of random errors tends to zero when a large number of experiments are performed under the same conditions. Therefore, for calculations, it is necessary to use not the results of single measurements, but the average of several parallel determinations.

The correctness of the results of the determinations is expressed by the absolute error and the relative error.

The absolute error is the difference between the result obtained and the true value. This error is expressed in the same units as the determined value (grams, milliliters, percent).

The relative error of the determination is equal to the ratio of the absolute error to the true value of the quantity being determined. The relative error is usually expressed as a percentage (by multiplying the resulting value by 100). Relative errors in determinations by physicochemical methods include both the accuracy of performing preparatory operations (weighing, measuring, dissolving) and the accuracy of performing measurements on the device (instrumental error).

The values of relative errors depend on the method used to perform the analysis and whether the analyzed object is an individual substance or a multicomponent mixture. Individual substances can be determined by analyzing the spectrophotometric method in the UV and visible regions with a relative error of ±(2--3)%, IR spectrophotometry ±(5--12)%, gas-liquid chromatography ±(3--3 ,5)%; polarography ±(2--3)%; potentiometry ±(0.3--1)%.

When analyzing multicomponent mixtures, the relative error of determination by these methods increases by about a factor of two. The combination of chromatography with other methods, in particular the use of chromato-optical and chromatoelectrochemical methods, makes it possible to analyze multicomponent mixtures with a relative error of ±(3--7)%.

The accuracy of biological methods is much lower than that of chemical and physicochemical methods. The relative error of biological determinations reaches 20-30 and even 50%. To improve accuracy, SP XI introduced a statistical analysis of the results of biological tests.

The relative determination error can be reduced by increasing the number of parallel measurements. However, these possibilities have a certain limit. It is advisable to reduce the random measurement error by increasing the number of experiments until it becomes less than the systematic one. Typically, 3-6 parallel measurements are performed in pharmaceutical analysis. When statistically processing the results of determinations, in order to obtain reliable results, at least seven parallel measurements are performed.

1.3 General principles for testing the identity of medicinal substances

Authenticity testing is a confirmation of the identity of the analyzed medicinal substance (dosage form), carried out on the basis of the requirements of the Pharmacopoeia or other regulatory and technical documentation (NTD). Tests are performed by physical, chemical and physico-chemical methods. An indispensable condition for an objective test of the authenticity of a medicinal substance is the identification of those ions and functional groups included in the structure of molecules that determine pharmacological activity. With the help of physical and chemical constants (specific rotation, pH of the medium, refractive index, UV and IR spectrum), other properties of molecules that affect the pharmacological effect are also confirmed. Chemical reactions used in pharmaceutical analysis are accompanied by the formation of colored compounds, the release of gaseous or water-insoluble compounds. The latter can be identified by their melting point.

1.4 Sources and causes of poor quality of medicinal substances

The main sources of technological and specific impurities are equipment, raw materials, solvents and other substances that are used in the preparation of medicines. The material from which the equipment is made (metal, glass) can serve as a source of impurities of heavy metals and arsenic. With poor cleaning, the preparations may contain impurities of solvents, fibers of fabrics or filter paper, sand, asbestos, etc., as well as acid or alkali residues.

The quality of synthesized medicinal substances can be influenced by various factors.

Technological factors are the first group of factors that influence the process of drug synthesis. The degree of purity of the starting materials, temperature, pressure, pH of the medium, solvents used in the synthesis process and for purification, drying mode and temperature, which fluctuates even within small limits - all these factors can lead to the appearance of impurities that accumulate from one to another stage. In this case, the formation of products of side reactions or decomposition products, the processes of interaction of the initial and intermediate synthesis products with the formation of such substances, from which it is difficult then to separate the final product, can occur. In the process of synthesis, the formation of various tautomeric forms is also possible both in solutions and in the crystalline state. For example, many organic compounds can exist in amide, imide, and other tautomeric forms. And quite often, depending on the conditions of preparation, purification and storage, the medicinal substance can be a mixture of two tautomers or other isomers, including optical ones, differing in pharmacological activity.

The second group of factors is the formation of various crystalline modifications, or polymorphism. About 65% of medicinal substances belonging to the number of barbiturates, steroids, antibiotics, alkaloids, etc., form 1-5 or more different modifications. The rest give during crystallization stable polymorphic and pseudopolymorphic modifications. They differ not only in physicochemical properties (melting point, density, solubility) and pharmacological action, but they have different values of free surface energy and, consequently, unequal resistance to the action of air oxygen, light, moisture. This is caused by changes in the energy levels of molecules, which affects the spectral, thermal properties, solubility and absorption of drugs. The formation of polymorphic modifications depends on the crystallization conditions, the solvent used, and the temperature. The transformation of one polymorphic form into another occurs during storage, drying, grinding.

In medicinal substances obtained from plant and animal raw materials, the main impurities are associated natural compounds (alkaloids, enzymes, proteins, hormones, etc.). Many of them are very similar in chemical structure and physicochemical properties to the main extraction product. Therefore, cleaning it is very difficult.

The dustiness of industrial premises of chemical-pharmaceutical enterprises can have a great influence on the contamination with impurities of some drugs by others. In the working area of these premises, provided that one or more preparations (dosage forms) are received, all of them can be contained in the form of aerosols in the air. In this case, the so-called "cross-contamination" occurs.

The World Health Organization (WHO) in 1976 developed special rules for the organization of production and quality control of medicines, which provide for the conditions for preventing "cross-contamination".

Not only the technological process, but also storage conditions are important for the quality of drugs. The good quality of preparations is affected by excessive moisture, which can lead to hydrolysis. As a result of hydrolysis, basic salts, saponification products and other substances with a different pharmacological action are formed. When storing crystalline preparations (sodium arsenate, copper sulfate, etc.), on the contrary, it is necessary to observe conditions that exclude the loss of crystallization water.

When storing and transporting drugs, it is necessary to take into account the effect of light and oxygen in the air. Under the influence of these factors, decomposition of, for example, substances such as bleach, silver nitrate, iodides, bromides, etc. can occur. Of great importance is the quality of the container used to store medicines, as well as the material from which it is made. The latter can also be a source of impurities.

Thus, impurities contained in medicinal substances can be divided into two groups: technological impurities, i.e. introduced by the feedstock or formed during the production process, and impurities acquired during storage or transportation, under the influence of various factors (heat, light, atmospheric oxygen, etc.).

The content of these and other impurities must be strictly controlled to exclude the presence of toxic compounds or the presence of indifferent substances in medicinal products in such quantities that interfere with their use for specific purposes. In other words, the medicinal substance must have a sufficient degree of purity, and therefore, meet the requirements of a certain specification.

A drug substance is pure if further purification does not change its pharmacological activity, chemical stability, physical properties and bioavailability.

In recent years, due to the deterioration of the environmental situation, medicinal plant raw materials are also tested for the presence of impurities of heavy metals. The importance of such tests is due to the fact that when conducting studies of 60 different samples of plant materials, the content of 14 metals was established in them, including such toxic ones as lead, cadmium, nickel, tin, antimony and even thallium. Their content in most cases significantly exceeds the established maximum allowable concentrations for vegetables and fruits.

The pharmacopoeial test for the determination of heavy metal impurities is one of the widely used in all national pharmacopoeias of the world, which recommend it for the study of not only individual medicinal substances, but also oils, extracts, and a number of injectable dosage forms. In the opinion of the WHO Expert Committee, such tests should be carried out on medicinal products having single doses of at least 0.5 g.

1.5 General requirements for purity tests

Evaluation of the degree of purity of a medicinal product is one of the important steps in pharmaceutical analysis. All drugs, regardless of the method of preparation, are tested for purity. At the same time, the content of impurities is determined. They can be divided into two groups: impurities that affect the pharmacological action of the drug, and impurities that indicate the degree of purification of the substance. The latter do not affect the pharmacological effect, but their presence in large quantities reduces the concentration and, accordingly, reduces the activity of the drug. Therefore, pharmacopoeias set certain limits for these impurities in drugs.

Thus, the main criterion for the good quality of a medicinal product is the presence of acceptable limits for physiologically inactive impurities and the absence of toxic impurities. The concept of absence is conditional and is associated with the sensitivity of the test method.

The general requirements for purity tests are the sensitivity, specificity and reproducibility of the reaction used, as well as the suitability of its use for establishing acceptable limits for impurities.

For purity tests, select reactions with a sensitivity that allows you to determine the acceptable limits of impurities in a given medicinal product. These limits are established by preliminary biological testing, taking into account the possible toxic effects of the impurity.

There are two ways to determine the maximum content of impurities in the test preparation (reference and non-reference). One of them is based on comparison with a reference solution (standard). At the same time, under the same conditions, a color or turbidity is observed that occurs under the action of any reagent. The second way is to set a limit on the content of impurities based on the absence of a positive reaction. In this case, chemical reactions are used, the sensitivity of which is lower than the detection limit of admissible impurities.

To speed up the performance of tests for purity, their unification and achieving the same accuracy of analysis in domestic pharmacopoeias, a system of standards was used. A reference is a sample containing a certain amount of an impurity to be discovered. The determination of the presence of impurities is carried out by the colorimetric or nephelometric method, comparing the results of reactions in the standard solution and in the drug solution after adding the same amounts of the corresponding reagents. The accuracy achieved in this case is quite sufficient to establish whether more or less impurities are contained in the test preparation than is permissible.

When performing tests for purity, it is necessary to strictly follow the general guidelines provided for by pharmacopoeias. Water and reagents used should not contain ions, the presence of which is established; test tubes should be of the same diameter and colorless; samples must be weighed to the nearest 0.001 g; reagents should be added simultaneously and in equal amounts to both the reference and the test solution; the resulting opalescence is observed in transmitted light against a dark background, and the color is observed in reflected light against a white background. If the absence of an impurity is established, then all reagents are added to the test solution, except for the main one; then the resulting solution is divided into two equal parts and the main reagent is added to one of them. When compared, there should be no noticeable differences between both parts of the solution.

It should be borne in mind that the sequence and rate of addition of the reagent will affect the results of the purity tests. Sometimes it is also necessary to observe the time interval during which the result of the reaction should be monitored.

The source of impurities in the production of finished dosage forms can be poorly purified fillers, solvents and other excipients. Therefore, the degree of purity of these substances must be carefully controlled before they are used in production.

1.6 Methods of pharmaceutical analysis and their classification

Pharmaceutical analysis uses a variety of research methods: physical, physico-chemical, chemical, biological. The use of physical and physico-chemical methods requires appropriate instruments and instruments, therefore, these methods are also called instrumental, or instrumental.

The use of physical methods is based on the measurement of physical constants, for example, transparency or degree of turbidity, color, humidity, melting, solidification and boiling points, etc.

With the help of physicochemical methods, the physical constants of the analyzed system are measured, which change as a result of chemical reactions. This group of methods includes optical, electrochemical, chromatographic.

Chemical methods of analysis are based on the performance of chemical reactions.

Biological control of medicinal substances is carried out on animals, individual isolated organs, groups of cells, on certain strains of microorganisms. Establish the strength of the pharmacological effect or toxicity.

Methods used in pharmaceutical analysis should be sensitive, specific, selective, fast and suitable for rapid analysis in a pharmacy setting.

Chapter 2. Physical Methods of Analysis

2.1 Verification of physical properties or measurement of physical constants of medicinal substances

The authenticity of the medicinal substance is confirmed; state of aggregation (solid, liquid, gas); color, smell; the shape of the crystals or the type of amorphous substance; hygroscopicity or degree of weathering in air; resistance to light, air oxygen; volatility, mobility, flammability (of liquids). The color of a medicinal substance is one of the characteristic properties that allows its preliminary identification.

Determination of the degree of whiteness of powdered medicines is a physical method, first included in the Global Fund XI. The degree of whiteness (hue) of solid medicinal substances can be assessed by various instrumental methods based on the spectral characteristics of the light reflected from the sample. To do this, measure the reflection coefficients when the sample is illuminated with white light obtained from a special source with a spectral distribution or passed through filters with a maximum transmission of 614 nm (red) or 459 nm (blue). You can also measure the reflectance of light passed through a green filter (522 nm). The reflection coefficient is the ratio of the magnitude of the reflected light flux to the magnitude of the incident light flux. It allows you to determine the presence or absence of a color shade in medicinal substances by the degree of whiteness and degree of brightness. For white or white substances with a grayish tint, the degree of whiteness is theoretically equal to 1. Substances in which it is 0.95--1.00, and the degree of brightness< 0,85, имеют сероватый оттенок.

A more accurate assessment of the whiteness of medicinal substances can be carried out using reflection spectrophotometers, for example, SF-18, manufactured by LOMO (Leningrad Optical and Mechanical Association). The intensity of color or grayish shades is set by absolute reflection coefficients. Whiteness and brightness values are characteristics of the quality of whites and whites with hints of medicinal substances. Their permissible limits are regulated in private articles.

More objective is the establishment of various physical constants: melting (decomposition) temperature, solidification or boiling point, density, viscosity. An important indicator of authenticity is the solubility of the medicinal product in water, solutions of acids, alkalis, organic solvents (ether, chloroform, acetone, benzene, ethyl and methyl alcohol, oils, etc.).

The constant characterizing the homogeneity of solids is the melting point. It is used in pharmaceutical analysis to establish the identity and purity of most drug solids. It is known that this is the temperature at which the solid is in equilibrium with the liquid phase when the vapor phase is saturated. The melting point is a constant value for an individual substance. The presence of even a small amount of impurities changes (as a rule, reduces) the melting point of a substance, which makes it possible to judge the degree of its purity. The identity of the compound under study can be confirmed by a mixed melting test, since a mixture of two substances having the same melting points melts at the same temperature.

To establish the melting point, SP XI recommends a capillary method that allows you to confirm the authenticity and approximately the degree of purity of the medicinal product. Since a certain content of impurities is allowed in medicinal preparations (normalized by FS or VFS), the melting point may not always be clearly expressed. Therefore, most pharmacopoeias, including SP XI, under the melting point mean the temperature range at which the process of melting of the test drug occurs from the appearance of the first drops of liquid to the complete transition of the substance into a liquid state. Some organic compounds decompose when heated. This process occurs at the decomposition temperature and depends on a number of factors, in particular on the heating rate.

The intervals of melting temperatures given in private articles of the State Pharmacopoeia (FS, VFS) indicate that the interval between the beginning and end of the melting of the medicinal substance should not exceed 2°C. If it exceeds 2°C, then the private article should indicate by what amount. If the transition of a substance from a solid to a liquid state is fuzzy, then instead of the melting temperature interval, the temperature is set at which only the beginning or only the end of melting occurs. This temperature value should fit into the interval given in the private article of the Global Fund (FS, VFS).

Description of the device and methods for determining the melting point is given in the SP XI, issue 1 (p. 16). Depending on the physical properties, various methods are used. One of them is recommended for solids that are easily powdered, and the other two are for substances that do not grind into powder (fats, wax, paraffin, petroleum jelly, etc.). It should be borne in mind that the accuracy of establishing the temperature interval at which the melting of the test substance occurs can be affected by the conditions of sample preparation, the rate of rise and accuracy of temperature measurement, and the experience of the analyst.

In GF XI, no. 1 (p. 18), the conditions for determining the melting point are specified and a new device with a measurement range of 20 to 360°C (PTP) with electric heating is recommended. It is distinguished by the presence of a glass block-heater, which is heated by coiled constantan wire, an optical device and a control panel with a nomogram. The capillaries for this device should be 20 cm long. The PTP device provides a higher accuracy in determining the melting point. If discrepancies are obtained in determining the melting point (indicated in a private article), then the results of its determination on each of the devices used should be given.

The solidification point is understood as the highest, remaining for a short time, constant temperature at which the transition of a substance from a liquid to a solid state occurs. In GF XI, no. 1 (p. 20) describes the design of the device and the method for determining the solidification temperature. Compared to GF X, an addition has been made to it regarding substances capable of supercooling.

The boiling point, or more precisely, the temperature limits of distillation, is the interval between the initial and final boiling points at normal pressure of 760 mmHg. (101.3 kPa). The temperature at which the first 5 drops of liquid were distilled into the receiver is called the initial boiling point, and the temperature at which 95% of the liquid passed into the receiver is called the final boiling point. The indicated temperature limits can be set by the macromethod and the micromethod. In addition to the device recommended by GF XI, vol. 1 (p. 18), to determine the melting point (MTP), a device for determining the temperature limits of distillation (TPP) of liquids, manufactured by the Klin plant "Laborpribor" (SP XI, issue 1, p. 23), can be used. This instrument provides more accurate and reproducible results.

Keep in mind that the boiling point depends on atmospheric pressure. The boiling point is set only for a relatively small number of liquid drugs: cyclopropane, chloroethyl, ether, halothane, chloroform, trichlorethylene, ethanol.

When determining the density, the mass of a substance of a certain volume is taken. The density is set using a pycnometer or hydrometer according to the methods described in SP XI, vol. 1 (p. 24--26), strictly observing the temperature regime, since the density depends on temperature. This is usually achieved by thermostating the pycnometer at 20°C. Certain intervals of density values confirm the authenticity of ethyl alcohol, glycerin, vaseline oil, vaseline, solid paraffin, halogen derivatives of hydrocarbons (chloroethyl, halothane, chloroform), formaldehyde solution, ether for anesthesia, amyl nitrite, etc. GF XI, vol. 1 (p. 26) recommends establishing the alcohol content in preparations of ethyl alcohol 95, 90, 70 and 40% by density, and in dosage forms either by distillation with subsequent determination of density, or by the boiling point of water-alcohol solutions (including tinctures).

Distillation is carried out by boiling certain amounts of alcohol-water mixtures (tinctures) in flasks hermetically connected to the receiver. The latter is a volumetric flask with a capacity of 50 ml. Collect 48 ml of distillate, bring its temperature to 20°C and add water to the mark. The distillation density is set with a pycnometer.

When determining alcohol (in tinctures) by boiling point, use the device described in SP XI, vol. 1 (p. 27). The thermometer readings are taken 5 minutes after the start of boiling, when the boiling point stabilizes (deviations are not more than ±0.1°C). The result obtained is converted to normal atmospheric pressure. The alcohol concentration is calculated using the tables available in GF XI, vol. 1 (p.28).

Viscosity (internal friction) is a physical constant that confirms the authenticity of liquid medicinal substances. There are dynamic (absolute), kinematic, relative, specific, reduced and characteristic viscosity. Each of them has its own units of measurement.

To assess the quality of liquid preparations having a viscous consistency, for example, glycerin, petrolatum, oils, the relative viscosity is usually determined. It is the ratio of the viscosity of the investigated liquid to the viscosity of water, taken as a unit. To measure kinematic viscosity, various modifications of viscometers such as Ostwald and Ubbelohde are used. The kinematic viscosity is usually expressed in m 2 * s -1 . Knowing the density of the liquid under study, one can then calculate the dynamic viscosity, which is expressed in Pa * s. Dynamic viscosity can also be determined using rotational viscometers of various modifications such as "Polymer RPE-1 I" or microrheometers of the VIR series. Geppler-type viscometers are based on measuring the speed of a ball falling in a liquid. They allow you to set the dynamic viscosity. All instruments must be temperature controlled, as viscosity is highly dependent on the temperature of the fluid being tested.

Solubility in GF XI is considered not as a physical constant, but as a property that can serve as an approximate characteristic of the test preparation. Along with the melting point, the solubility of a substance at constant temperature and pressure is one of the parameters by which the authenticity and purity of almost all medicinal substances are established.

The method for determining solubility according to SP XI is based on the fact that a sample of a pre-ground (if necessary) drug is added to a measured volume of the solvent and continuously mixed for 10 minutes at (20±2)°C. A drug is considered dissolved if no particles of the substance are observed in the solution in transmitted light. If the dissolution of the drug takes more than 10 minutes, then it is classified as slowly soluble. Their mixture with the solvent is heated on a water bath to 30°C and complete dissolution is observed after cooling to (20±2)°C and vigorous shaking for 1--2 minutes. More detailed instructions on the conditions for the dissolution of slowly soluble drugs, as well as drugs that form cloudy solutions, are given in private articles. Solubility rates in various solvents are indicated in private articles. They stipulate cases when solubility confirms the degree of purity of the medicinal substance.

In GF XI, no. 1 (p. 149) includes the phase solubility method, which makes it possible to quantify the degree of purity of a medicinal substance by accurately measuring solubility values. This method is based on the Gibbs phase rule, which establishes the relationship between the number of phases and the number of components under equilibrium conditions. The essence of establishing phase solubility lies in the successive addition of an increasing mass of the drug to a constant volume of the solvent. To achieve a state of equilibrium, the mixture is subjected to prolonged shaking at a constant temperature, and then, using diagrams, the content of the dissolved medicinal substance is determined, i.e. establish whether the test preparation is an individual substance or a mixture. The phase solubility method is characterized by objectivity, does not require expensive equipment, knowledge of the nature and structure of impurities. This makes it possible to use it for qualitative and quantitative analyses, as well as for studying the stability and obtaining purified drug samples (up to a purity of 99.5%). An important advantage of the method is the ability to distinguish between optical isomers and polymorphic forms of drugs. The method is applicable to all kinds of compounds that form true solutions.

2.2 Setting the pH of the medium

Important information about the degree of purity of the medicinal product is given by the pH value of its solution. This value can be used to judge the presence of impurities of acidic or alkaline products.

The principle of detecting impurities of free acids (inorganic and organic), free alkalis, i.e. acidity and alkalinity, is to neutralize these substances in a solution of the drug or in an aqueous extract. Neutralization is performed in the presence of indicators (phenolphthalein, methyl red, thymolphthalein, bromophenol blue, etc.). The acidity or alkalinity is judged either by the color of the indicator, or by its change, or the amount of titrated alkali or acid solution used for neutralization is determined.

The reaction of the medium (pH) is a characteristic of the chemical properties of a substance. This is an important parameter that should be set when performing technological and analytical operations. The degree of acidity or basicity of solutions must be taken into account when performing drug purity and quantitation tests. The shelf life of medicinal substances, as well as the severity of their use, depend on the pH values of solutions.

The pH value approximately (up to 0.3 units) can be determined using indicator paper or a universal indicator. Of the many ways to establish the pH value of the environment, GF XI recommends colorimetric and potentiometric methods.

The colorimetric method is very simple to implement. It is based on the property of indicators to change their color at certain ranges of pH values. To perform the tests, buffer solutions with a constant concentration of hydrogen ions are used, differing from each other by a pH value of 0.2. To a series of such solutions and to the test solution add the same amount (2-3 drops) of the indicator. According to the coincidence of color with one of the buffer solutions, the pH value of the medium of the test solution is judged.

In GF XI, no. 1 (p. 116) provides detailed information on the preparation of standard buffer solutions for various pH ranges: from 1.2 to 11.4. As reagents for this purpose, combinations of various ratios of solutions of potassium chloride, potassium hydrophthalate, monosubstituted potassium phosphate, boric acid, sodium tetraborate with hydrochloric acid or sodium hydroxide solution are used. Purified water used for the preparation of buffer solutions should have a pH of 5.8--7.0 and be free from carbon dioxide impurities.

The potentiometric method should be attributed to physicochemical (electrochemical) methods. The potentiometric determination of pH is based on the measurement of the electromotive force of an element composed of a standard electrode (with a known potential value) and an indicator electrode, the potential of which depends on the pH of the test solution. To establish the pH of the medium, potentiometers or pH meters of various brands are used. Their adjustment is carried out using buffer solutions. The potentiometric method for determining pH differs from the colorimetric method in higher accuracy. It has fewer limitations and can be used to determine pH in colored solutions, as well as in the presence of oxidizing and reducing agents.

In GF XI, no. 1 (p. 113) includes a table that lists the solutions of substances used as standard buffer solutions for testing pH meters. The data given in the table make it possible to establish the temperature dependence of the pH of these solutions.

2.3 Determination of transparency and turbidity of solutions

Transparency and degree of turbidity of the liquid according to SP X (p. 757) and SP XI, vol. 1 (p. 198) is established by comparing the test tubes of the test liquid with the same solvent or with standards in a vertical arrangement. A liquid is considered transparent if, when it is illuminated with an opaque electric lamp (power 40 W), on a black background, the presence of undissolved particles, except for single fibers, is not observed. According to GF X, standards are a suspension obtained from certain amounts of white clay. Standards for determining the degree of turbidity according to SP XI are suspensions in water from mixtures of certain amounts of hydrazine sulfate and hexamethylenetetramine. First prepare a 1% solution of hydrazine sulfate and a 10% solution of hexamethylenetetramine. By mixing equal volumes of these solutions, a reference standard is obtained.

In the general article of SP XI, there is a table that indicates the amounts of the main standard required for the preparation of standard solutions I, II, III, IV. It also shows the scheme for viewing the transparency and degree of turbidity of liquids.

Coloring of liquids according to GF XI, vol. 1 (p. 194) is determined by comparing the test solutions with an equal amount of one of the seven standards in daylight reflected light on a matte white background. For the preparation of standards, four basic solutions are used, obtained by mixing in various ratios of the initial solutions of cobalt chloride, potassium dichromate, copper (II) sulfate and iron (III) chloride. Sulfuric acid solution (0.1 mol/l) is used as a solvent for the preparation of stock solutions and standards.

Liquids are considered colorless if they do not differ in color from water, and solutions - from the corresponding solvent.

Adsorption capacity and dispersion are also indicators of the purity of some drugs.

Very often, a test based on their interaction with concentrated sulfuric acid is used to detect impurities of organic substances. The latter can act as an oxidizing or dehydrating agent.

As a result of such reactions, colored products are formed. The intensity of the resulting color should not exceed the corresponding color standard.

To establish the purity of drugs, the definition of ash is widely used (GF XI, issue 2, p. 24). By calcining a sample of the preparation in a porcelain (platinum) crucible, the total ash is established. Then, after adding diluted hydrochloric acid, the ash insoluble in hydrochloric acid is determined. In addition, sulfate ash obtained after heating and calcining a sample of the preparation treated with concentrated sulfuric acid is also determined.

One of the indicators of the purity of organic drugs is the content of the residue after calcination.

When establishing the purity of some drugs, they also check the presence of reducing substances (by discoloration of the potassium permanganate solution), coloring substances (colorlessness of the aqueous extract). Water-soluble salts (in insoluble preparations), substances insoluble in ethanol, and impurities insoluble in water (according to the turbidity standard) are also detected.

2.4 Estimation of chemical constants

To assess the purity of oils, fats, waxes, and some esters, chemical constants such as acid number, saponification number, ester number, iodine number are used (SP XI, issue 1, pp. 191, 192, 193).

Acid number - the mass of potassium hydroxide (mg), which is necessary to neutralize the free acids contained in 1 g of the test substance.

Saponification number - the mass of potassium hydroxide (mg), which is necessary to neutralize free acids and acids formed during the complete hydrolysis of esters contained in 1 g of the test substance.

The ester number is the mass of potassium hydroxide (mg) that is needed to neutralize the acids formed during the hydrolysis of esters contained in 1 g of the test substance (i.e., the difference between the saponification number and the acid number).

The iodine number is the mass of iodine (g) that binds 100 g of the test substance.

SP XI provides methods for establishing these constants and methods for calculating them.

Chapter 3. Chemical Methods of Analysis

3.1 Features of chemical methods of analysis

These methods are used to authenticate medicinal substances, test them for purity, and quantify them.

For identification purposes, reactions are used that are accompanied by an external effect, such as a change in the color of the solution, the release of gaseous products, precipitation or dissolution of precipitates. The identification of inorganic medicinal substances consists in the detection, by means of chemical reactions, of the cations and anions that make up the molecules. The chemical reactions used to identify organic medicinal substances are based on the use of functional analysis.

The purity of medicinal substances is established by means of sensitive and specific reactions, suitable for determining the permissible limits for the content of impurities.

Chemical methods have proved to be the most reliable and effective, they make it possible to perform the analysis quickly and with high reliability. In case of doubt in the results of the analysis, the last word remains with the chemical methods.

Quantitative methods of chemical analysis are divided into gravimetric, titrimetric, gasometric analysis and quantitative elemental analysis.

3.2 Gravimetric (weight) method

The gravimetric method is based on the weighing of the precipitated substance in the form of a poorly soluble compound or the distillation of organic solvents after the extraction of the medicinal substance. The method is accurate but lengthy, as it involves such operations as filtering, washing, drying (or calcining) to constant weight.

Sulphates can be determined gravimetrically from inorganic medicinal substances by converting them into insoluble barium salts, and silicates by preliminary calcination to silicon dioxide.

Methods for gravimetric analysis of preparations of quinine salts recommended by the Global Fund are based on the precipitation of the base of this alkaloid under the action of sodium hydroxide solution. Bigumal is determined in the same way. Benzylpenicillin preparations are precipitated as N-ethylpiperidine salt of benzylpenicillin; progesterone - in the form of hydrazone. It is possible to use gravimetry to determine alkaloids (by weighing free bases or picrates, picrolonates, silicotungstates, tetraphenylborates), as well as to determine some vitamins that are precipitated in the form of water-insoluble hydrolysis products (vikasol, rutin) or in the form of silicotungstate (thiamine bromide ). There are also gravimetric techniques based on the precipitation of acidic forms of barbiturates from sodium salts.

Metamizole (analgin) for many decades has been an emergency drug in our country, and not a remedy for the treatment of chronic diseases. That is how he should remain.

Analgin was synthesized in 1920 in search of an easily soluble form of amidopyrine. This is the third main direction in the development of painkillers. Analgin, according to statistics, is one of the most beloved drugs, and most importantly, it is available to everyone. Although in fact he is very few years old - only about 80. Experts developed Analgin specifically to deal with severe pain. Indeed, he saved a lot of people from torment. It was used as an affordable pain reliever, since there was no wide range of painkillers at that time. Of course, narcotic analgesics were used, but the medicine of that time already had sufficient data on, and this group of drugs was used only in appropriate cases. The drug Analgin is very popular in medical practice. Already one name says about what Analgin helps from and in what cases it is used. After all, in translation it means "absence of pain." Analgin belongs to the group of non-narcotic analgesics, i.e. drugs that can reduce pain without affecting the psyche.

In clinical practice, analgin (metamisole sodium) was first introduced in Germany in 1922. Analgin became indispensable for hospitals in Germany during the Second World War. For many years it remained a very popular drug, but this popularity had a downside: its widespread and almost uncontrolled use as an over-the-counter drug led in the 70s. of the last century to deaths from agranulocytosis (an immune blood disease) and shock. This has resulted in analgin being banned in a number of countries while remaining available over the counter in others. The risk of serious side effects when using combined preparations containing metamizole is higher than when taking "pure" analgin. Therefore, in most countries, such funds have been withdrawn from circulation.

Trade name: a nalgin.
International name: Metamizole sodium (Metamizole sodium).
Group affiliation: Analgesic non-narcotic agent.
Dosage form: capsules, solution for intravenous and intramuscular administration, rectal suppositories [for children], tablets, tablets [for children].

Chemical composition and physico-chemical properties of analgin

Analgin. analginum.

Metamizole sodium.Metamizolum natricum

Chemical Name: 1-phenyl-2,3-dimethyl-4-methyl-aminopyrazolone-5-N-methane - sodium sulfate

Gross formula: C 13 H 18 N 3 NaO 5 S

Fig.1

Appearance: colorless needle-shaped crystals of a bitter taste, odorless.

Paracetamol

In 1877 Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University in the reduction of p-nitrophenol with tin in glacial acetic acid, but it was not until 1887 that clinical pharmacologist Joseph von Mering tested paracetamol on patients. In 1893, von Mehring published an article reporting the clinical results of paracetamol and phenacetin, another aniline derivative. Von Mering argued that, unlike phenacetin, paracetamol has some ability to cause methemoglobinemia. Paracetamol was then quickly abandoned in favor of phenacetin. Bayer began selling phenacetin as a leading pharmaceutical company at the time. Introduced to medicine by Heinrich Dreser in 1899, phenacetin has been popular for many decades, especially in the widely advertised over-the-counter "headache potion" typically containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes barbiturates.

Tradename:Paracetamol

International name:paracetamol

Group affiliation: analgesic non-narcotic agent.

Dosage form:pills

Chemical composition and physico-chemical properties of paracetamol

Paracetamol. paracetamolum.

Gross - formula:C 8 H 9 NO 2 ,

Chemical Name: N-(4-Hydroxyphenyl)acetamide.

Appearance: white or white with cream or pink tint Fig.2 crystalline powder. Easilyoensh679k969soluble in alcohol, insoluble in water.

Aspirin (acetysalicylic acid)

Aspirin was first synthesized in 1869. This is one of the most famous and widely used drugs. It turned out that the history of aspirin is typical of many other drugs. As early as 400 BC, the Greek physician Hippocrates recommended that patients chew willow bark to relieve pain. He, of course, could not know about the chemical composition of the painkillers, but they were derivatives of acetylsalicylic acid (chemists found out only two millennia later). In 1890, F. Hoffman, who worked for the German company Bayer, developed a method for the synthesis of acetylsalicylic acid, the basis of aspirin. Aspirin was introduced to the market in 1899, and from 1915 began to be sold without prescriptions. The mechanism of analgesic action was discovered only in the 1970s. In recent years, aspirin has become a tool for the prevention of cardiovascular disease.

Tradename : Aspirin.

international name : acetylsalicylic acid.

Group affiliation : non-steroidal anti-inflammatory drug.

Dosage form: pills.

Chemical composition and physico-chemical properties of aspirin

Acetylsalicylic acid.Acidum acetylsalicylicum

Gross - formula: WITH 9 H 8 ABOUT 4

Chemical Name: 2-acetoxy-benzoic acid.

Appearance :hpure substance is a white crystalline powder, almost withoutdictionaryodor, sour taste.

Dibazol

Dibazol was created in the Soviet Union in the middle of the last century. For the first time this substance was noted in 1946 as the most physiologically active benzimidazole salt. In the course of experiments conducted on laboratory animals, the ability of a new substance to improve the transmission of nerve impulses in the spinal cord was noticed. This ability was confirmed during clinical trials, and in the early 1950s the drug was introduced into clinical practice for the treatment of diseases of the spinal cord, in particular, poliomyelitis. Currently in use as a means to strengthen the immune system, improve metabolism and increase stamina.

Tradename: Dibazol.

international name : Dibazol. 2nd: Benzylbenzimidazole hydrochloride.

Group affiliation : a drug of the group of peripheral vasodilators.

Dosage form : solution for intravenous and intramuscular administration, rectal suppositories [for children], tablets.

Chemical composition and physico-chemical properties: Dibazol

It is highly soluble in water, but poorly soluble in alcohol.

Gross formula :C 14 H 12 N 2 .

chemical name : 2-(Phenylmethyl)-1H-benzimidazole.

Appearance : benzimidazole derivative,

Figure 4 is white, white-yellow or

light gray crystalline powder.

Analgin.

Pharmacological properties:

Analgin belongs to the group of non-steroidal anti-inflammatory drugs, the effectiveness of which is due to the activity of metamizole sodium, which:

Blocks the passage of pain impulses through the bundles of Gaulle and Burdakh;

Significantly increases heat transfer, which makes it expedient to use Analgin at high temperatures;

Promotes an increase in the threshold of excitability of the thalamic centers of pain sensitivity;

It has a mild anti-inflammatory effect;

Promotes some antispasmodic effect.

The activity of Analgin develops approximately 20 minutes after ingestion, reaching a maximum after 2 hours.

Indications for use

According to instructions,Analgin is used to eliminate the pain syndrome provoked by diseases such as:

Arthralgia;

Intestinal, biliary and renal colic;

Burns and injuries;

Shingles;

Neuralgia;

decompression sickness;

myalgia;

Algodysmenorrhea, etc.

Effective is the use of Analgin to eliminate toothache and headache, as well as postoperative pain syndrome. In addition, the drug is used for febrile syndrome caused by insect bites, infectious and inflammatory diseases or post-transfusion complications.

To eliminate the inflammatory process and reduce the temperature, Analgin is rarely used, since there are more effective means for this.

Paracetamol

Pharmacological properties:

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. It binds to plasma proteins by 15%. Paracetamol crosses the blood-brain barrier. Less than 1% of the dose of paracetamol taken by a nursing mother passes into breast milk. Paracetamol is metabolized in the liver and excreted in the urine, mainly in the form of glucuronides and sulfonated conjugates, less than 5% is excreted unchanged in the urine.

Indications for use

for rapid relief of headache, including migraine pain;

toothache;

neuralgia;

muscular and rheumatic pain;

as well as with algomenorrhea, pain in injuries, burns;

to reduce fever with colds and flu.

Aspirin

Pharmacological properties:

Acetylsalicylic acid (ASA) has analgesic, antipyretic and anti-inflammatory effects due to the inhibition of cyclooxygenase enzymes involved in the synthesis of prostaglandins.

ASA in the dose range of 0.3 to 1.0 g is used to reduce fever in diseases such as colds andand to relieve joint and muscle pain.
ASA inhibits platelet aggregation by blocking the synthesis of thromboxane A 2 in platelets.

Indications for use

for symptomatic relief of headache;

toothache;

sore throat;

pain in muscles and joints;

back pain;

elevated body temperature with colds and other infectious and inflammatory diseases (in adults and children over 15 years old)

Dibazol

Pharmacological properties

Vasodilating agent; has a hypotensive, vasodilating effect, stimulates the function of the spinal cord, has a moderate immunostimulating activity. It has a direct antispasmodic effect on the smooth muscles of blood vessels and internal organs. Facilitates synaptic transmission in the spinal cord. It causes an expansion (short) of the cerebral vessels and is therefore especially indicated in forms of arterial hypertension caused by chronic hypoxia of the brain due to local circulatory disorders (sclerosis of the cerebral arteries). In the liver, dibazol undergoes metabolic transformations by methylation and carboxyethylation with the formation of two metabolites. It is mainly excreted by the kidneys, and to a lesser extent - through the intestines.

Indications for use

Various conditions accompanied by arterial hypertension, incl. and hypertension, hypertensive crises;

Spasm of smooth muscles of internal organs (intestinal, hepatic, renal colic);

Residual effects of poliomyelitis, facial paralysis, polyneuritis;

Prevention of viral infectious diseases;

Increasing the body's resistance to external adverse effects.

1) It is revealed that the doctrine of medicines is one of the most ancient medical disciplines. Drug therapy in its most primitive form already existed in primitive human society. The first medicines were mostly of plant origin. The emergence of scientific pharmacology dates back to the 19th century, when individual active principles were isolated from plants for the first time in their pure form, the first synthetic compounds were obtained, and when, thanks to the development of experimental methods, it became possible to experimentally study the pharmacological properties of medicinal substances.

2) It has been established that drugs can be classified according to the following principles:

– therapeutic use;

–pharmacological agents;

– chemical compounds.

3) The chemical composition and physical properties of analgin, paracetamol and aspirin preparations, which are indispensable in a home first-aid kit, are considered. It has been established that the medicinal substances of these preparations are complex derivatives of aromatic hydrocarbons and amines.

4) The pharmacological properties of the studied drugs are shown, as well as indications for their use and physiological effects on the body. Most often, these medicinal substances are used as antipyretic and analgesic.

Chapter 2. Practical part. Study of the quality of medicines

2.1. The quality of medicines

In the definition of the World Health Organization, a falsified (counterfeit) medicinal product (FLS) means a product that is deliberately and unlawfully provided with a label that incorrectly indicates the authenticity of the drug and (or) the manufacturer.

The concepts of "counterfeit", "counterfeit" and "fake" legally have certain differences, but for an ordinary citizen they are identical. A fake is a drug produced with a change in its composition, while maintaining its appearance, and often accompanied by false information about its composition . A drug is considered counterfeit, the production and further sale of which is carried out under someone else's individual characteristics (trademark, name or place of origin) without the permission of the patent holder, which is a violation of intellectual property rights.

A counterfeit drug is often regarded as counterfeit and counterfeit. In the Russian Federation, a counterfeit drug is considered to be a drug that is recognized as such by Roszdravnadzor after a thorough check with the publication of relevant information on the website of Roszdravnadzor. From the date of publication, the circulation of FLS should be discontinued with withdrawal from the distribution network and placement in a quarantine zone separately from other drugs. Moving this FLS is a violation.

Counterfeit drugs are considered the fourth public health scourge after malaria, AIDS and smoking. For the most part, counterfeits do not match the quality, effectiveness or side effects of the original drugs, causing irreparable harm to the health of a sick person; are produced and distributed without the control of the relevant authorities, causing enormous financial harm to legitimate drug manufacturers and the state. Death from FLS is among the top ten causes of death.

Experts identify four main types of counterfeit drugs.

1st type - "dummy medicines". In these "medicines", as a rule, there are no main therapeutic components. Those who take them do not feel the difference, and even for a number of patients, the use of "pacifiers" can have a positive effect due to the placebo effect.

2nd type - “drugs-imitators”. Such “drugs” use active ingredients that are cheaper and less effective than in a genuine drug. The danger lies in the insufficient concentration of active substances that patients need.

3rd type - Altered drugs. These "drugs" contain the same active substance as the original product, but in larger or smaller quantities. Naturally, the use of such drugs is unsafe, because it can lead to increased side effects (especially with an overdose).

4th type - copy medicines. They are among the most common types of counterfeit drugs in Russia (up to 90% of the total number of counterfeits), which are usually produced by clandestine industries and, through one or another channel, fall into batches of legal drugs. These drugs contain the same active ingredients as legal drugs, but there are no guarantees of the quality of the underlying substances, compliance with the norms of technological processes of production, etc. Therefore, the risk of consequences of taking such drugs is increased.

Offenders are brought to administrative responsibility under Art. 14.1 of the Code of Administrative Offenses of the Russian Federation, or criminal liability for which, due to the absence of liability for falsification in the Criminal Code, comes under several offenses and is mainly qualified as fraud (Article 159 of the Criminal Code of the Russian Federation) and illegal use of a trademark (Article 180 Criminal Code of the Russian Federation).

The Federal Law "On Medicines" provides a legal basis for the seizure and destruction of FLS, both those produced in Russia and imported from abroad, and those in circulation on the domestic pharmaceutical market.

Part 9 of Article 20 establishes a ban on the import into Russia of medicines that are fakes, illegal copies or falsified medicines. The customs authorities are obliged to confiscate and destroy them if found.

Art. 31, establishes a ban on the sale of medicinal products that have become unusable, have an expired shelf life or are recognized as counterfeit. They are also subject to destruction. The Ministry of Health of Russia, by its order of December 15, 2002 No. 382, approved the Instruction on the procedure for the destruction of medicines that have become unusable, medicines with an expired shelf life and medicines that are fakes or illegal copies. But the instructions have not yet been amended in accordance with the additions to the Federal Law "On Medicines" of 2004 on counterfeit and substandard medicines, which now define and indicate the prohibition of their circulation and withdrawal from circulation, and also proposed by the state authorities to bring normative legal acts in line with this law.

Roszdravnadzor issued a letter No. 01I-92/06 dated 08.02.2006 “On the organization of the work of the territorial departments of Roszdravnadzor with information on substandard and falsified medicines”, which contradicts the legal norms of the Law on Medicines and nullifies the fight against counterfeiting. The law prescribes to withdraw from circulation and destroy counterfeit medicines, and Roszdravnadzor (paragraph 4, clause 10) suggests that territorial departments control the withdrawal from circulation and destruction of counterfeit medicines. By proposing 16 to exercise control only over the return to the owner or owner for further destruction, Roszdravnadzor allows the circulation of counterfeit medicines to continue and return them to the owner, that is, the counterfeiting criminal himself, which grossly violates the Law and the Instructions for destruction. At the same time, there are often references to the Federal Law of December 27, 2002 No. 184-FZ “On Technical Regulation”, in Art. 36-38 of which establishes the procedure for the return to the manufacturer or seller of products that do not meet the requirements of the technical regulation. However, it must be borne in mind that this procedure does not apply to counterfeit medicines that are produced without complying with the technical regulations, by whom and where.

From January 1, 2008, in accordance with Art. 2 of the Federal Law of December 18, 2006 No. 231-FZ “On the Enactment of Part Four of the Civil Code of the Russian Federation”, new legislation on the protection of intellectual property came into force, the objects of which include means of individualization, including trademarks, with through which drug manufacturers protect the rights to their products. The fourth part of the Civil Code of the Russian Federation (part 4 of article 1252) defines counterfeit material carriers of the results of intellectual activity and means of individualization

The pharmaceutical industry in Russia today needs a total scientific and technical re-equipment, as its fixed assets are worn out. It is necessary to introduce new standards, including GOST R 52249-2004, without which the production of high-quality medicines is not possible.

2.2. The quality of medicines.

For the analysis of drugs, we used methods for determining the presence of amino groups in them (lignin test), phenolic hydroxyl, heterocycles, carboxyl group, and others. (We took the methods from methodological developments for students in medical colleges and on the Internet).

Reactions with the drug analgin.

Determination of the solubility of analgin.

1 .Dissolved 0.5 tablets of analgin (0.25 g) in 5 ml of water, and the second half of the tablet in 5 ml of ethyl alcohol.

Fig.5 Weighing the preparation Fig.6 Grinding the preparation

Conclusion: analgin is well dissolved in water, but practically does not dissolve in alcohol.

Determining the presence of a CH group 2 SO 3 Na .

Heated 0.25 g of the drug (half a tablet) in 8 ml of dilute hydrochloric acid.

Fig.7 Heating the preparation

Found: first smell of sulfur dioxide, then formaldehyde.

Conclusion: this reaction makes it possible to prove that analgin contains a formaldehyde sulfonate group.

Determining the properties of a chameleon

1 ml of the resulting analgin solution was added 3-4 drops of a 10% solution of iron chloride (III). When analgin interacts with Fe 3+ oxidation products are formed

painted in blue, which then turns into dark green, and then orange, i.e. exhibits the properties of a chameleon. This means that the drug is of high quality.

For comparison, we took preparations with different expiration dates and identified, using the above method, the quality of the preparations.

Fig. 8 The appearance of the property of a chameleon

Fig.9 Comparison of drug samples

Conclusion: the reaction with the drug of a later production date proceeds according to the chameleon principle, which indicates its quality. But the drug of earlier production did not show this property, it follows that this drug cannot be used for its intended purpose.

4. The reaction of analgin with hydroperite. ("Smoke bomb")

the reaction proceeds immediately in two places: at the sulfo group and the methylaminyl group. Accordingly, hydrogen sulfide, as well as water and oxygen, can be formed at the sulfo group.

-SO3 + 2H2O2 = H2S + H2O + 3O2.

The resulting water leads to partial hydrolysis at the C - N bond and methylamine is split off, and water and oxygen are also formed:

-N(CH3) + H2O2 = H2NCH3 + H2O +1/2 O2

And finally it becomes clear what kind of smoke is obtained in this reaction:

Hydrogen sulfide reacts with methylamine to form methylammonium hydrosulfide:

H2NCH3 + H2S = HS.

And the suspension of its small crystals in the air creates a visual sensation of "smoke".

Rice. 10 Reaction of analgin with hydroperite

Reactions with the drug paracetamol.

Determination of acetic acid

Fig.11 Heating a solution of paracetamol with hydrochloric acid Fig.12 Cooling the mixture

Conclusion: the smell of acetic acid that appears means that this drug is really paracetamol.

Determination of the phenol derivative of paracetamol.

A few drops of 10% ferric chloride solution were added to 1 ml of paracetamol solution (III).

Fig. 13 The appearance of blue coloration

Observed: blue color indicates the presence of a phenol derivative in the composition of the substance.

0.05 g of the substance was boiled with 2 ml of dilute hydrochloric acid for 1 minute and 1 drop of potassium dichromate solution was added.

Fig.14 Boiling with hydrochloric acid Fig.15 Oxidation with potassium dichromate

Observed: the appearance of a blue-violet color,does not turn red.

Conclusion: in the course of the reactions, the qualitative composition of the paracetamol preparation was proved, and it was found that it is a derivative of aniline.

Reactions with aspirin.

For the experiment, we used aspirin tablets manufactured by the Pharmstandard-Tomskhimfarm pharmaceutical production factory. Valid until May 2016.

Determination of the solubility of aspirin in ethanol.

0.1 g of drugs were added to test tubes and 10 ml of ethanol were added. At the same time, partial solubility of aspirin was observed. Test tubes with substances were heated on an alcohol lamp. The solubility of drugs in water and ethanol was compared.

Conclusion: The results of the experiment showed that aspirin is more soluble in ethanol than in water, but precipitates in the form of needle crystals. That's whyThe use of aspirin in conjunction with ethanol is unacceptable. It should be concluded that the use of alcohol-containing drugs in conjunction with aspirin, and even more so with alcohol, is inadmissible.

Determination of a phenol derivative in aspirin.

0.5 g of acetylsalicylic acid, 5 ml of sodium hydroxide solution were mixed in a beaker and the mixture was boiled for 3 minutes. The reaction mixture was cooled and acidified with dilute sulfuric acid until a white crystalline precipitate formed. The precipitate was filtered off, part of it was transferred into a test tube, 1 ml of distilled water was added to it, and 2-3 drops of ferric chloride solution were added.

Hydrolysis of the ester bond leads to the formation of a phenol derivative, which with ferric chloride (3) gives a violet color.

Fig.16 Boiling a mixture of aspirin Fig.17 Oxidation with a solution Fig.18 Qualitative reaction

with sodium hydroxide of sulfuric acid for a phenol derivative

Conclusion: hydrolysis of aspirin produces a phenol derivative, which gives a violet color.

A phenol derivative is a substance that is very dangerous for human health, which affects the appearance of side effects on the human body when taking acetylsalicylic acid. Therefore, it is necessary to strictly follow the instructions for use (this fact was mentioned back in the 19th century).

2.3. Conclusions to chapter 2

1) It is established that a huge number of medicinal substances are currently being created, but also a lot of fakes. The topic of the quality of medicines will always be relevant, since our health depends on the consumption of these substances. The quality of medicines is determined by GOST R 52249 - 09. In the definition of the World Health Organization, a counterfeit (counterfeit) drug (FLS) means a product that is intentionally and unlawfully provided with a label that incorrectly indicates the authenticity of the drug and (or) manufacturer.

2) For the analysis of drugs, we used methods for determining the presence of amino groups in them (lignin test) phenolic hydroxyl, heterocycles, carboxyl group and others. (We took the methods from the teaching aid for students of chemical and biological specialties).

3) In the course of the experiment, the qualitative composition of analgin, dibazol, paracetamol, aspirin preparations and the quantitative composition of analgin were proved. The results and more detailed conclusions are given in the text of the work in Chapter 2.

Conclusion

The purpose of this study was to get acquainted with the properties of some medicinal substances and to establish their quality using chemical analysis.

I conducted an analysis of literary sources in order to establish the composition of the studied medicinal substances that make up analgin, paracetamol, aspirin, their classification, chemical, physical and pharmaceutical properties. We have selected a method suitable for establishing the quality of selected drugs in an analytical laboratory. Studies of the quality of drugs were carried out according to the chosen method of qualitative analysis.

Based on the work done, it was found that all medicinal substances correspond to the quality of GOST.

Of course, it is impossible to consider the whole variety of drugs, their effect on the body, the features of the use and dosage forms of these drugs, which are ordinary chemicals. A more detailed acquaintance with the world of drugs awaits those who will continue to be engaged in pharmacology and medicine.

I would also like to add that despite the rapid development of the pharmacological industry, scientists have not yet been able to create a single drug without side effects. Each of us should remember this: because, having felt unwell, we first of all go to the doctor, then to the pharmacy, and the treatment process begins, which is often expressed in unsystematic medication.

Therefore, in conclusion, I would like to give recommendations on the use of drugs:

Medicines must be stored properly, in a special place, away from light and heat sources, according to the temperature regime, which must be indicated by the manufacturer (in the refrigerator or at room temperature).

Medicines must be kept out of the reach of children.

An unknown medicine should not remain in the medicine cabinet. Each jar, box or sachet must be signed.

Medicines should not be used if they have expired.

Do not take drugs prescribed to another person: well tolerated by some, they can cause drug-induced illness (allergies) in others.

Strictly follow the rules for taking the drug: the time of admission (before or after meals), dosage and the interval between doses.

Take only those medicines that your doctor has prescribed for you.

Do not rush to start with medicines: sometimes it is enough to get enough sleep, rest, breathe fresh air.

Observing even these few and simple recommendations for the use of medicines, you can save the main thing - health!

Bibliographic list.

1) Alikberova L.Yu. Entertaining chemistry: A book for students, teachers and parents. – M.: AST-PRESS, 2002.

2) Artemenko A.I. The use of organic compounds. – M.: Bustard, 2005.

3) Mashkovsky M.D. Medicines. M.: Medicine, 2001.

4) Pichugina G.V. Chemistry and everyday life of a person. M.: Bustard, 2004.

5) Vidal's Handbook: Medicines in Russia: A Handbook.- M.: Astra-PharmService.- 2001.- 1536 p.

6) Tutelyan V.A. Vitamins: 99 questions and answers. - M. - 2000. - 47 p.

7) Encyclopedia for children, volume 17. Chemistry. - M. Avanta+, 200.-640s.

8) Register of Medicinal Products of Russia "Encyclopedia of Medicines". - 9th edition - LLC M; 2001.

9) Mashkovsky M.D. Medicines of the 20th century. M.: New wave, 1998, 320 p.;

10) Dyson G., May P. Chemistry of synthetic medicinal substances. Moscow: Mir, 1964, 660 p.

11) Encyclopedia of drugs 9 edition 2002. Medicines M.D. Mashkovsky 14th edition.

12) http:// www. consultpharma. en/ index. php/ en/ documents/ production/710- gostr-52249-2009- part1? showall=1

The widespread introduction of the principles of evidence-based medicine into clinical practice is largely due to the economic aspect. The correct distribution of funds depends on how convincing the scientific data on the clinical and cost-effectiveness of methods of diagnosis, treatment and prevention are. In clinical practice, specific decisions should be made not so much on the basis of personal experience or expert opinion, but on the basis of rigorously proven scientific data. Attention should be paid not only to the futility, but also to the lack of evidence-based evidence of the benefits of using various methods of treatment and prevention. Currently, this provision is of particular relevance, since clinical trials are financed mainly by manufacturers of medical goods and services.

The concept of "evidence-based medicine", or "evidence-based medicine", was proposed by Canadian scientists from Mac Master University in Toronto in 1990. Evidence-based medicine is not a new science, but rather a new approach, direction or technology for collecting, analyzing, summarizing and interpreting scientific information. The need for evidence-based medicine has arisen primarily in connection with the increase in the volume of scientific information, in particular in the field of clinical pharmacology. Every year, more and more new drugs are introduced into clinical practice. They are actively studied in numerous clinical studies, the results of which are often ambiguous, and sometimes even directly opposite. To use the information received, it must not only be carefully analyzed, but also summarized.

For the rational use of new drugs, achieving their maximum therapeutic effect and preventing their adverse reactions, it is necessary to obtain a comprehensive description of the drug, data on all its therapeutic and possible negative properties already at the testing stage. One of the main ways to obtain new drugs is the screening of biologically active substances. It should be noted that this way of searching for and creating new drugs is very time consuming - on average, one drug worthy of attention falls on 5-10 thousand investigated compounds. Through screening and random observations, valuable drugs were found that entered medical practice. However, randomness cannot be the main principle in the selection of new drugs. As science developed, it became quite obvious that the creation of drugs should be based on the identification of biologically active substances involved in vital processes, the study of pathophysiological and pathochemical processes underlying the development of various diseases, as well as an in-depth study of the mechanisms of pharmacological action. Achievements in the biomedical sciences make it possible to increasingly carry out directed synthesis of substances with improved properties and certain pharmacological activity.

Preclinical study of the biological activity of substances is usually divided into pharmacological and toxicological. Such a division is conditional, since these studies are interdependent and are based on the same principles. The results of the study of acute toxicity of medicinal compounds provide information for subsequent pharmacological studies, which, in turn, determine the intensity and duration of the study of chronic toxicity of the substance.

The purpose of pharmacological studies is to determine the therapeutic activity of the drug, as well as its effect on the main anatomical and physiological systems of the body. In the process of studying the pharmacodynamics of a substance, not only its specific activity is established, but also possible side reactions associated with the pharmacological effect. The effect of an investigational drug on sick and healthy organisms may differ, therefore, pharmacological tests should be carried out on models of the relevant diseases or pathological conditions.

In toxicological studies, the nature and severity of the possible damaging effects of drugs on experimental animals are established. There are three stages in toxicological studies:

study of acute toxicity of a substance with a single injection;

determination of chronic toxicity of the compound, which includes repeated use of the drug for 1 year, and sometimes more;

determination of the specific toxicity of the drug - oncogenicity, mutagenicity, embryotoxicity, including teratogenic effects, sensitizing properties, as well as the ability to cause drug dependence.

The study of the damaging effect of the study drug on the body of experimental animals allows us to determine which organs and tissues are most sensitive to this substance and what should be paid special attention to in clinical trials.

The purpose of clinical trials is to evaluate the therapeutic or prophylactic efficacy and tolerability of a new pharmacological agent, to establish the most rational doses and regimens for its use, as well as to compare it with existing drugs. When evaluating the results of clinical trials, the following characteristics should be taken into account: the presence of a control group, clear criteria for inclusion and exclusion of patients, inclusion of patients in studies before choosing a treatment, random (blind) choice of treatment, an adequate method of randomization, blind control, blind evaluation of treatment outcomes, information about complications and side effects, information about the quality of life of patients, information about the number of patients who dropped out of the study, adequate statistical analysis indicating the names of the texts and programs used, statistical power, information about the size of the identified effect.

Clinical trial programs for different groups of drugs can vary significantly. However, some significant provisions must always be reflected. The goals and objectives of the test should be clearly stated; determine the criteria for selecting patients; indicate the method of distribution of patients into the main and control groups and the number of patients in each group; the method of establishing effective doses of the drug, the duration of the study; control method (open, blind, double, etc.), comparator drug and placebo, methods for quantitative analysis of the effect of study drugs (indicators subject to registration); methods of static data processing.

When evaluating publications on treatment methods, it should be remembered that the exclusion criteria for patients from the study are specified quite often, and the inclusion criteria are less common. If it is not clear on which patients the drug was studied, then it is difficult to assess the information content of the data obtained. Most of the research is carried out in specialized university hospitals or research centers, where patients, of course, differ from patients in district clinics. Therefore, after the initial tests, more and more research is being carried out. First - multicenter, when due to the involvement of different hospitals and the outpatient features of each of them are smoothed out. Then open. With each stage, the confidence that the research results will be applicable to any hospital increases.

The issue of establishing the dose and regimen of the study drug is very important and difficult. There are only the most general recommendations, mainly to start with a low dose, which is gradually increased until the desired or side effect is obtained. When developing rational doses and regimens for the study drug, it is desirable to establish the breadth of its therapeutic action, the range between the minimum and maximum safe therapeutic doses. The duration of use of the study drug should not exceed the duration of toxicological tests on animals.

In the process of clinical trials of new drugs, 4 interrelated phases (stages) are distinguished.

The phase of the first clinical trials is called “sighting”, or “clinico-pharmacological”. Its purpose is to establish the tolerability of the study drug and whether it has a therapeutic effect.

In phase II, clinical trials are carried out on 100-200 patients. A necessary condition is the presence of a control group that does not differ significantly in composition and size from the main group. Patients in the experimental group (main) and control should be the same in terms of gender, age, initial background treatment (it is desirable to stop it 2-4 weeks before the start of the study). The groups are randomly formed using tables of random numbers, in which each digit or each combination of digits has an equal selection probability. Randomization, or random distribution, is the main way to ensure the comparability of comparison groups.

In clinical trials, new drugs are tried to be compared with placebo, which allows you to evaluate the real effectiveness of therapy, for example, its effect on life expectancy of patients compared with no treatment. The need for a double-blind method is determined by the fact that if doctors know what treatment the patient is receiving (active drug or placebo), then they can involuntarily wishful thinking.

A necessary condition for conducting adequate clinical trials is randomization. From consideration, it is necessary to immediately exclude articles about studies in which the distribution of patients into comparison groups was not random, or the method of distribution was unsatisfactory (for example, patients were divided according to the days of the week of admission to the hospital) or there is no information about it at all. Even less informative are studies with historical control (when previously obtained data or the results of studies conducted in other medical institutions are used for comparison). In the international literature, randomization is reported in 9/10 articles on pharmacotherapy, but only 1/3 of the articles specify the method of randomization. If the quality of randomization is in doubt, then the experimental and control groups are most likely not comparable, and other sources of information should be sought.

Of great importance is the clinical significance and statistical significance of the results of treatment. The results of a clinical trial or a population study are presented in the form of information about the frequency of outcomes and the statistical significance of differences between groups of patients. Does the author present statistically significant but small differences as clinically significant? Statistically significant is what actually exists with a high probability. It is clinically significant that, by its size (for example, the magnitude of the reduction in mortality) convinces the physician of the need to change his practice in favor of a new method of treatment.

Methods, criteria for evaluating the effectiveness of the drug, the time of measurement of the relevant indicators should be agreed before the start of the test. Evaluation criteria are clinical, laboratory, morphological and instrumental. Often, the effectiveness of an investigational drug is judged by reducing the dose of other drugs. For each group of drugs there are mandatory and additional (optional) criteria.

The purpose of phase III clinical trials is to obtain additional information about the effectiveness and side effects of a pharmacological agent, clarify the features of the drug's action and determine relatively rare adverse reactions. The features of the drug in patients with circulatory disorders, kidney and liver function are being studied, interaction with other drugs is being evaluated. The results of treatment are recorded in individual registration cards. At the end of the study, the results are summarized, processed statistically and presented in the form of a report. Corresponding indicators obtained for the same period of time in the main and control groups are compared statically. For each indicator, the average difference is calculated for the studied period of time (compared to the baseline before treatment) and the reliability of the noted dynamics within each group is assessed. Then, the average differences in the values of specific indicators of the control and experimental groups are compared to assess the difference in the effect of the study agent and the placebo or comparator drug. A report on the results of clinical trials of a new drug is drawn up in accordance with the requirements of the Pharmacological Committee and submitted to the committee with specific recommendations. A recommendation for clinical use is considered justified if the new product:

More effective than known drugs of similar action;

It has better tolerance than known drugs (with the same tolerance);

Effective in cases where treatment with known drugs is unsuccessful;

More cost-effective, has a simple method of treatment or a more convenient dosage form;

In combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.

After the approval of the use of a new drug in veterinary practice and its introduction, phase IV studies begin - the effect of the drug is studied in various situations in practice.

Introduction

Chapter 1. Basic Principles of Pharmaceutical Analysis

1.1 Pharmaceutical analysis criteria

1.2 Errors in Pharmaceutical Analysis

1.3 General principles for testing the identity of medicinal substances

1.4 Sources and causes of poor quality of medicinal substances

1.5 General requirements for purity tests

1.6 Methods of pharmaceutical analysis and their classification

Chapter 2. Physical Methods of Analysis

2.1 Verification of physical properties or measurement of physical constants of drug substances

2.2 Setting the pH of the medium

2.3 Determination of clarity and turbidity of solutions

2.4 Estimation of chemical constants

Chapter 3. Chemical Methods of Analysis

3.1 Features of chemical methods of analysis

3.2 Gravimetric (weight) method

3.3 Titrimetric (volumetric) methods

3.4 Gasometric analysis

3.5 Quantitative elemental analysis

Chapter 4. Physical and chemical methods of analysis

4.1 Features of physicochemical methods of analysis

4.2 Optical methods

4.3 Absorption methods

4.4 Methods based on emission of radiation

4.5 Methods based on the use of a magnetic field

4.6 Electrochemical methods

4.7 Separation methods

4.8 Thermal methods of analysis

Chapter 5

5.1 Biological quality control of medicines

5.2 Microbiological control of medicinal products

List of used literature

Introduction

Chapter 1. Basic Principles of Pharmaceutical Analysis

1.1 Pharmaceutical analysis criteria

At various stages of pharmaceutical analysis, depending on the tasks set, criteria such as selectivity, sensitivity, accuracy, time spent on the analysis, and the amount of the analyzed drug (dosage form) are important.

The selectivity of the method is very important when analyzing mixtures of substances, since it makes it possible to obtain the true values of each of the components. Only selective methods of analysis make it possible to determine the content of the main component in the presence of decomposition products and other impurities.

Requirements for the accuracy and sensitivity of pharmaceutical analysis depend on the object and purpose of the study. When testing the degree of purity of the drug, methods are used that are highly sensitive, allowing you to set the minimum content of impurities.

When performing step-by-step production control, as well as when conducting express analysis in a pharmacy, an important role is played by the time factor spent on the analysis. For this, methods are chosen that allow the analysis to be carried out in the shortest time intervals and at the same time with sufficient accuracy.

In the quantitative determination of a medicinal substance, a method is used that is distinguished by selectivity and high accuracy. The sensitivity of the method is neglected, given the possibility of performing an analysis with a large sample of the drug.

A measure of the sensitivity of a reaction is the limit of detection. It means the lowest content at which the presence of the determined component can be detected by this method with a given confidence level. The term "limit of detection" was introduced instead of such a concept as "discovered minimum", it is also used instead of the term "sensitivity". The sensitivity of qualitative reactions is influenced by such factors as the volumes of solutions of reacting components, concentrations of reagents, pH of the medium, temperature, duration experience.This should be taken into account when developing methods for qualitative pharmaceutical analysis.To establish the sensitivity of reactions, the absorbance index (specific or molar), established by the spectrophotometric method, is increasingly used.In chemical analysis, the sensitivity is set by the value of the limit of detection of a given reaction.Physicochemical methods are distinguished by high sensitivity The most highly sensitive are radiochemical and mass spectral methods, which make it possible to determine 10-810-9% of the analyte, polarographic and fluorimetric methods 10-610-9%, sensitivity of spectrophotometric methods Yu-310-6%, potentiometric methods 10-2%.

So, when calculating the results of titrimetric determinations, the least accurate figure is the number of millimeters.

One of the most important tasks of pharmaceutical chemistry is the development and improvement of methods for assessing the quality of medicines.

To establish the purity of medicinal substances, various physical, physico-chemical, chemical methods of analysis or a combination of them are used.

The GF offers the following methods of drug quality control.

Physical and physico-chemical methods. These include: determination of melting and solidification temperatures, as well as temperature limits of distillation; determination of density, refractive indices (refractometry), optical rotation (polarimetry); spectrophotometry - ultraviolet, infrared; photocolorimetry, emission and atomic absorption spectrometry, fluorimetry, nuclear magnetic resonance spectroscopy, mass spectrometry; chromatography - adsorption, distribution, ion-exchange, gas, high-performance liquid; electrophoresis (frontal, zonal, capillary); electrometric methods (potentiometric determination of pH, potentiometric titration, amperometric titration, voltammetry).

In addition, it is possible to use methods that are alternative to pharmacopoeial methods, which sometimes have more advanced analytical characteristics (speed, accuracy of analysis, automation). In some cases, a pharmaceutical company purchases a device based on a method not yet included in the Pharmacopoeia (for example, the method of Raman spectroscopy - optical dichroism). Sometimes it is advisable to replace the chromatographic method with a spectrophotometric one when determining the authenticity or testing for purity. The pharmacopoeial method for determining heavy metal impurities by precipitating them in the form of sulfides or thioacetamides has a number of disadvantages. To determine heavy metal impurities, many manufacturers are implementing such physicochemical methods of analysis as atomic absorption spectrometry and inductively coupled plasma atomic emission spectrometry.

An important physical constant that characterizes the authenticity and degree of purity of drugs is the melting point. A pure substance has a distinct melting point, which changes in the presence of impurities. For medicinal substances containing a certain amount of admissible impurities, the GF regulates the melting temperature range within 2 °C. But in accordance with Raoult's law (AT = iK3C, where AT is the decrease in the crystallization temperature; K3 is the cryoscopic constant; C is the concentration) at i = 1 (non-electrolyte), the value of AG cannot be the same for all substances. This is connected not only with the content of impurities, but also with the nature of the drug itself, i.e., with the value of the cryoscopic constant K3, which reflects the molar decrease in the melting point of the drug. Thus, at the same AT = 2 °C for camphor (K3 = 40) and phenol (K3 = 7.3), the mass fractions of impurities are not equal and amount to 0.76 and 2.5%, respectively.

For substances that melt with decomposition, the temperature at which the substance decomposes and a sharp change in its appearance occurs is usually indicated.

In some private articles of GF X, it is recommended to determine the solidification point or boiling point (according to GF XI - “distillation temperature limits”) for a number of liquid drugs. The boiling point should be within the interval given in the private article.

A wider interval indicates the presence of impurities.

In many private articles of GF X, permissible values \u200b\u200bof density, less often viscosity, are given, confirming the authenticity and good quality of drugs.

Almost all private articles of SP X normalize such an indicator of the quality of drugs as solubility in various solvents. The presence of impurities in a drug can affect its solubility, decreasing or increasing it, depending on the nature of the impurity.

The purity criteria are also the color of the drug and / or the transparency of liquid dosage forms.

A certain criterion for the purity of drugs can be such physical constants as the refractive index of a light beam in a solution of the test substance (refractometry) and specific rotation, due to the ability of a number of substances or their solutions to rotate the polarization plane when plane polarized light passes through them (polarimetry). Methods for determining these constants are related to optical methods of analysis and are also used to establish the authenticity and quantitative analysis of drugs and their dosage forms.

An important criterion for the good quality of a number of drugs is their water content. A change in this indicator (especially during storage) can change the concentration of the active substance, and, consequently, the pharmacological activity and make the drug unsuitable for use.

Chemical methods. These include: qualitative tests for authenticity, solubility, determination of volatile substances and water, determination of nitrogen content in organic compounds, titrimetric methods (acid-base titration, titration in non-aqueous solvents, complexometry), nitritemetry, acid number, saponification number, ether number, iodine number, etc.

biological methods. Biological methods of drug quality control are very diverse. Among them are tests for toxicity, sterility, microbiological purity.

To conduct physical and chemical analysis of semi-products, drug substances and finished dosage forms, when checking their quality for compliance with the requirements of the FS, the control and analytical laboratory must be equipped with the following minimum set of equipment and instruments:

IR spectrophotometer (to determine authenticity);

spectrophotometer for spectrometry in the visible and UV region (determination of authenticity, quantitative determination, dosing uniformity, solubility);

equipment for thin layer chromatography (TLC) (determination of authenticity, related impurities);

chromatograph for high performance liquid chromatography (HPLC) (authentication, quantitation, determination of related impurities, dosing uniformity, solubility);

gas-liquid chromatograph (GLC) (content of impurities, determination of dosing uniformity);

polarimeter (determination of authenticity, quantitative determination);

potentiometer (pH measurement, quantitative determination);

atomic absorption spectrophotometer (elemental analysis of heavy metals and non-metals);

K. Fischer titrator (determination of water content);

derivatograph (determination of weight loss upon drying).

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Introduction

Chapter 1. Basic Principles of Pharmaceutical Analysis

1.1 Pharmaceutical analysis criteria

At various stages of pharmaceutical analysis, depending on the tasks set, criteria such as selectivity, sensitivity, accuracy, time spent on the analysis, and the amount of the analyzed drug (dosage form) are important.

Requirements for the accuracy and sensitivity of pharmaceutical analysis depend on the object and purpose of the study. When testing the degree of purity of the drug, methods are used that are highly sensitive, allowing you to set the minimum content of impurities.

In the quantitative determination of a medicinal substance, a method is used that is distinguished by selectivity and high accuracy. The sensitivity of the method is neglected, given the possibility of performing an analysis with a large sample of the drug.

The accuracy of titrimetric determinations can be improved by using microburettes, the use of which significantly reduces errors from inaccurate measurement, leakage and temperature effects. An error is also allowed when taking a sample.

1.2 Mistakes during Pharmaceutical Analysis

When performing a quantitative determination by any chemical or physico-chemical method, three groups of errors can be made: gross (misses), systematic (certain) and random (uncertain).

Gross errors are the result of a miscalculation of the observer when performing any of the determination operations or incorrectly performed calculations. Results with gross errors are discarded as poor quality.

The correctness of the results of the determinations is expressed by the absolute error and the relative error.

The absolute error is the difference between the result obtained and the true value. This error is expressed in the same units as the determined value (grams, milliliters, percent).

The accuracy of biological methods is much lower than that of chemical and physicochemical methods. The relative error of biological determinations reaches 20-30 and even 50%. To improve accuracy, SP XI introduced a statistical analysis of the results of biological tests.

1.3 General principles for testing the identity of medicinal substances

1.4 Sources and causes of poor quality of medicinal substances

The quality of synthesized medicinal substances can be influenced by various factors.

The World Health Organization (WHO) in 1976 developed special rules for the organization of production and quality control of medicines, which provide for the conditions for preventing "cross-contamination".

A drug substance is pure if further purification does not change its pharmacological activity, chemical stability, physical properties and bioavailability.

1.5 General requirements for purity tests

1.6 Methods of pharmaceutical analysis and their classification

Pharmaceutical analysis uses a variety of research methods: physical, physico-chemical, chemical, biological. The use of physical and physico-chemical methods requires appropriate instruments and instruments, therefore, these methods are also called instrumental, or instrumental.

The use of physical methods is based on the measurement of physical constants, for example, transparency or degree of turbidity, color, humidity, melting, solidification and boiling points, etc.

With the help of physicochemical methods, the physical constants of the analyzed system are measured, which change as a result of chemical reactions. This group of methods includes optical, electrochemical, chromatographic.

Chapter 2. Physical Methods of Analysis

2.1 Verification of physical properties or measurement of physical constants of medicinal substances

2.2 Setting the pH of the medium

Important information about the degree of purity of the medicinal product is given by the pH value of its solution. This value can be used to judge the presence of impurities of acidic or alkaline products.

The pH value approximately (up to 0.3 units) can be determined using indicator paper or a universal indicator. Of the many ways to establish the pH value of the environment, GF XI recommends colorimetric and potentiometric methods.

In GF XI, no. 1 (p. 113) includes a table that lists the solutions of substances used as standard buffer solutions for testing pH meters. The data given in the table make it possible to establish the temperature dependence of the pH of these solutions.

2.3 Determination of transparency and turbidity of solutions

In the general article of SP XI, there is a table that indicates the amounts of the main standard required for the preparation of standard solutions I, II, III, IV. It also shows the scheme for viewing the transparency and degree of turbidity of liquids.

Liquids are considered colorless if they do not differ in color from water, and solutions - from the corresponding solvent.

Adsorption capacity and dispersion are also indicators of the purity of some drugs.

Very often, a test based on their interaction with concentrated sulfuric acid is used to detect impurities of organic substances. The latter can act as an oxidizing or dehydrating agent.

As a result of such reactions, colored products are formed. The intensity of the resulting color should not exceed the corresponding color standard.

One of the indicators of the purity of organic drugs is the content of the residue after calcination.

2.4 Estimation of chemical constants

To assess the purity of oils, fats, waxes, and some esters, chemical constants such as acid number, saponification number, ester number, iodine number are used (SP XI, issue 1, pp. 191, 192, 193).

Acid number - the mass of potassium hydroxide (mg), which is necessary to neutralize the free acids contained in 1 g of the test substance.

Saponification number - the mass of potassium hydroxide (mg), which is necessary to neutralize free acids and acids formed during the complete hydrolysis of esters contained in 1 g of the test substance.

The ester number is the mass of potassium hydroxide (mg) that is needed to neutralize the acids formed during the hydrolysis of esters contained in 1 g of the test substance (i.e., the difference between the saponification number and the acid number).

The iodine number is the mass of iodine (g) that binds 100 g of the test substance.

SP XI provides methods for establishing these constants and methods for calculating them.

Chapter 3. Chemical Methods of Analysis

3.1 Features of chemical methods of analysis

These methods are used to authenticate medicinal substances, test them for purity, and quantify them.

3.2 Gravimetric (weight) method

Sulphates can be determined gravimetrically from inorganic medicinal substances by converting them into insoluble barium salts, and silicates by preliminary calcination to silicon dioxide.

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