Chemical methods for the analysis of dosage forms. Methods for the analysis of drugs. Definition of "heavy" metals

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Introduction

Description of the drug

List of references

Introduction

Among the tasks of pharmaceutical chemistry, such as the modeling of new drugs, drugs and their synthesis, the study of pharmacokinetics, etc., a special place is occupied by the analysis of the quality of drugs. The State Pharmacopoeia is the collection of mandatory national standards and regulations that regulate the quality of drugs.

Pharmacopoeial analysis of medicinal products includes quality assessment based on a variety of indicators. In particular, the authenticity of the medicinal product is established, its purity is analyzed, a quantitative determination is carried out. Initially, exclusively chemical methods were used for such an analysis; authenticity reactions, impurity reactions and quantification titrations.

Over time, not only the level of technical development of the pharmaceutical industry has increased, but also the requirements for the quality of medicines have changed. In recent years, there has been a tendency towards a transition to the expanded use of physical and physicochemical methods of analysis. In particular, infrared and ultraviolet spectrophotometry, nuclear magnetic resonance spectroscopy, etc. are widely used. Chromatography methods (high-performance liquid, gas-liquid, thin-layer), electrophoresis, etc. are widely used.

The study of all these methods and their improvement is one of the most important tasks of pharmaceutical chemistry today.

quality medicinal pharmacopoeial spectral

Qualitative and quantitative analysis methods

The analysis of a substance can be carried out in order to establish its qualitative or quantitative composition. In accordance with this, a distinction is made between qualitative and quantitative analysis.

Qualitative analysis makes it possible to establish what chemical elements the analyte consists of and what ions, groups of atoms or molecules are included in its composition. When studying the composition of an unknown substance, a qualitative analysis always precedes a quantitative one, since the choice of a method for the quantitative determination of the constituent parts of an analyte depends on the data obtained during its qualitative analysis.

Qualitative chemical analysis is mostly based on the transformation of the analyte into some new compound "possessing characteristic properties: color, a certain physical state, crystalline or amorphous structure, specific smell, etc. The chemical transformation that occurs during this process is called a qualitative analytical reaction , and the substances causing this transformation are called reagents (reagents).

For example, to open Fe +++ ions in a solution, the solution to be analyzed is first acidified with hydrochloric acid, and then a solution of potassium hexacyanoferrate (II) K4 is added. In the presence of Fe +++, a blue precipitate of iron hexacyanoferrate (II) Fe43 precipitates. (Prussian blue):

Another example of a qualitative chemical analysis is the detection of ammonium salts by heating the analyte with an aqueous solution of sodium hydroxide. Ammonium ions in the presence of OH ions form ammonia, which is recognized by the smell or by the blue discoloration of wet red litmus paper:

In the above examples, solutions of potassium hexacyanoferrate (II) and sodium hydroxide are, respectively, reagents for Fe +++ and NH4 + ions.

When analyzing a mixture of several substances that are close in chemical properties, they are preliminarily separated and only then characteristic reactions to individual substances (or ions) are carried out, therefore, a qualitative analysis covers not only individual reactions for detecting ions, but also methods for their separation.

Quantitative analysis allows you to establish quantitative ratios of the constituent parts of a given compound or mixture of substances. In contrast to qualitative analysis, quantitative analysis makes it possible to determine the content of individual components of the analyte or the total content of the analyte in the test product.

Methods of qualitative and quantitative analysis, which make it possible to determine the content of individual elements in an analyte, are called elemental analysis; functional groups - functional analysis; individual chemical compounds characterized by a certain molecular weight - molecular analysis.

A set of various chemical, physical and physicochemical methods of separation and determination of individual structural (phase) components of heterogeneous ones! systems that differ in properties and physical structure and are bounded from each other by interfaces is called phase analysis.

Methods for researching the quality of medicines

In accordance with GF XI, the methods of research of medicines are divided into physical, physicochemical and chemical.

Physical methods. They include methods for determining the melting point, solidification, density (for liquid substances), refractive index (refractometry), optical rotation (polarimetry), etc.

Physical and chemical methods. They can be divided into 3 main groups: electrochemical (polarography, potentiometry), chromatographic and spectral (UV and IR spectrophotometry and photocolorimetry).

Polarography is a method for studying electrochemical processes based on establishing the dependence of the current strength on the voltage applied to the system under study. The electrolysis of the investigated solutions is carried out in an electrolyzer, one of the electrodes of which is a dropping mercury electrode, and the auxiliary one is a mercury electrode with a large surface, the potential of which practically does not change when a current of low density passes. The resulting polarographic curve (polarogram) has the form of a wave. The dimness of the wave is associated with the concentration of the reactants. The method is used for the quantitative determination of many organic compounds.

Potentiometry is a method for determining pH and potentiometric titration.

Chromatography is a process of separation of mixtures of substances that occurs when they move in a flow of a mobile phase along a stationary sorbent. Separation occurs due to the difference in one or another physicochemical properties of the substances to be separated, leading to their unequal interaction with the substance of the stationary phase, therefore, to a difference in the retention time of the sorbent layer.

According to the mechanism underlying the separation, one distinguishes between adsorption, distribution and ion-exchange chromatography. According to the method of separation and the equipment used, chromatography on columns, on paper in a thin layer of sorbent, gas and liquid chromatography, high-performance liquid chromatography (HPLC), etc. is distinguished.

Spectral methods are based on the selective absorption of electromagnetic radiation by the analyte. There are spectrophotometric methods based on the absorption of monochromatic radiation in the UV and IR ranges by a substance, colorimetric and photocolorimetric methods based on the absorption of nonmonochromatic radiation of the visible part of the spectrum by a substance.

Chemical methods. Based on the use of chemical reactions for drug identification. For inorganic drugs, reactions are used for cations and anions, for organic drugs, for functional groups, while only those reactions are used that are accompanied by a visual external effect: a change in the color of the solution, the release of gases, precipitation, etc.

Using chemical methods, the numerical indicators of oils and esters (acid number, iodine number, saponification number) are determined, characterizing their good quality.

Chemical methods for the quantitative analysis of medicinal substances include the gravimetric (weight) method, titrimetric (volumetric) methods, including acid-base titration in aqueous and non-aqueous media, gasometric analysis and quantitative elemental analysis.

Gravimetric method. From inorganic medicinal substances, this method can be used to determine sulfates, converting them into insoluble barium salts, and silicates, having previously calcined them to silicon dioxide. It is possible to use gravimetry for the analysis of preparations of quinine salts, alkaloids, some vitamins, etc.

Titrimetric methods. These are the most widespread methods in pharma- macevtic analysis, which are notable for their low labor intensity and sufficiently high accuracy. Titrimetric methods can be subdivided into precipitation titration, acid - base, redox, compleximetry, and nitritometry. With their help, a quantitative assessment is made by determining the individual elements or functional groups contained in the drug molecule.

Precipitation titration (argentometry, mercurimetry, mercurometry, etc.).

Acid-base titration (titration in an aqueous medium, acidimetry - using acid as a titrant, alkalimetry - using alkali for titration, titration in mixed solvents, non-aqueous titration, etc.).

Redox titration (iodometry, iodochlorometry, bromatometry, permanganatometry, etc.).

Compleximetry. The method is based on the formation of strong, water-soluble complexes of metal cations with Trilon B or other complexones. The interaction takes place in a stoichiometric ratio of 1: 1 regardless of the cation charge.

Nitritometry. The method is based on the reactions of primary and secondary aromatic amines with sodium nitrite, which are used as a titrant. Primary aromatic amines form a diazo compound with sodium nitrite in an acidic medium, while secondary aromatic amines form nitroso compounds under these conditions.

Gasometric analysis. Has limited use in pharmaceutical analysis. The objects of this analysis are two gaseous drugs: oxygen and cyclopropane. The essence of gasometric determination lies in the interaction of gases with absorption solutions.

Quantitative elemental analysis. This analysis is used for the quantitative determination of organic and organoelement compounds containing nitrogen, halogens, sulfur, as well as arsenic, bismuth, mercury, antimony, and other elements.

Biological methods of quality control of medicinal substances. Biological assessment of drug quality is carried out according to their pharmacological activity or toxicity. Biological microbiological methods are used in cases where it is impossible to draw a conclusion about the good quality of drugs using physical, chemical and physicochemical methods. Biological tests are carried out on animals (cats, dogs, pigeons, rabbits, frogs, etc.), individual isolated organs (uterine horn, part of the skin) and cell groups (blood cells, strains of microorganisms, etc.). Biological activity is established, as a rule, by comparing the action of the test and standard samples.

Medicines that are not sterilized during the production process are tested for microbiological purity (tablets, capsules, granules, solutions, extracts, ointments, etc.). These tests are aimed at determining the composition and amount of microflora present in the DF. At the same time, compliance with the norms limiting microbial contamination (contamination) is established. The test includes the quantitative determination of viable bacteria and fungi, the identification of certain types of microorganisms, intestinal flora and staphylococci. The test is carried out under aseptic conditions in accordance with the requirements of the State Pharmacopoeia XI (v. 2, p. 193) by a two-layer agar method in Petri dishes.

The sterility test is based on the proof of the absence of viable microorganisms of any kind in the drug and is one of the most important indicators of drug safety. All drugs for parenteral administration, eye drops, ointments, etc. are subjected to these tests. To control sterility, use the bioglycolic and liquid Sabouraud medium, using the method of direct inoculation on nutrient media. If the drug has a pronounced antimicrobial effect or is poured into containers of more than 100 ml, then the membrane filtration method is used (GF, v. 2, p. 187).

Acidum acetylsalicylicum

Acetylsalicylic acid, or aspirin, is the salicylic ester of acetic acid.

Description. Colorless crystals or odorless white crystalline powder, slightly acidic taste. In humid air, it gradually hydrolyzes to form acetic and salicylic acids. We will slightly dissolve in water, we will easily dissolve in alcohol, we will dissolve in chloroform, ether, in solutions of caustic and carbonic alkalis.

To liquefy the mass, chlorobenzene is added, the reaction mixture is poured into water, the released acetylsalicylic acid is filtered off and recrystallized from benzene, chloroform, isopropyl alcohol or other organic solvents.

In the finished preparation of acetylsalicylic acid, residues of unbound salicylic acid may be present. The amount of salicylic acid as an impurity is regulated and a limit for the content of salicylic acid in acetylsalicylic acid is established by the State Pharmacopoeias of different countries.

The State Pharmacopoeia of the USSR, the tenth edition of 1968, establishes the permissible limit for the content of salicylic acid in acetylsalicylic acid, not more than 0.05% in the preparation.

Acetylsalicylic acid during hydrolysis in the body breaks down into salicylic and acetic acids.

Acetylsalicylic acid, as an ester formed by acetic acid and phenolic acid (instead of alcohol), is very easily hydrolyzed. Even when standing in humid air, it hydrolyzes into acetic and salicylic acids. In this regard, pharmacists often have to check whether the acetylsalicylic acid has hydrolyzed. For this, the reaction with FeCl3 is very convenient: acetylsalicylic acid does not stain with FeCl3, while salicylic acid resulting from hydrolysis gives a violet color.

Clinical and pharmacological group: NSAIDs

Pharmacological act

Acetylsalicylic acid belongs to the group of acid-forming NSAIDs with analgesic, antipyretic and anti-inflammatory properties. The mechanism of its action is the irreversible inactivation of cyclooxygenase enzymes, which play an important role in the synthesis of prostaglandins. Acetylsalicylic acid in doses ranging from 0.3 g to 1 g is used to relieve pain and conditions associated with mild fever, such as colds and flu, to reduce fever and relieve pain in joints and muscles.

It is also used to treat acute and chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, osteoarthritis.

Acetylsalicylic acid inhibits platelet aggregation by blocking the synthesis of thromboxane A2 and is used for most vascular diseases in doses of 75-300 mg per day.

Indications

rheumatism;

rheumatoid arthritis;

infectious and allergic myocarditis;

fever with infectious and inflammatory diseases;

pain syndrome of weak and moderate intensity of various origins (including neuralgia, myalgia, headache);

prevention of thrombosis and embolism;

primary and secondary prevention of myocardial infarction;

prevention of cerebrovascular accidents by ischemic type;

in gradually increasing doses for prolonged "aspirin" desensitization and the formation of persistent NSAID tolerance in patients with "aspirin" asthma and "aspirin triad".

Instructions by application and dosage

For adults, a single dose varies from 40 mg to 1 g, daily - from 150 mg to 8 g; frequency of application - 2-6 times a day. It is preferable to drink it with milk or alkaline mineral waters.

Side act

nausea, vomiting;

anorexia;

epigastric pain;

the occurrence of erosive and ulcerative lesions;

bleeding from the gastrointestinal tract;

dizziness;

headache;

reversible visual impairment;

noise in ears;

thrombocytopenia, anemia;

hemorrhagic syndrome;

lengthening of bleeding time;

impaired renal function;

acute renal failure;

skin rash;

quincke's edema;

bronchospasm;

"aspirin triad" (combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid and pyrazolone drugs);

reye's (Raynaud's) syndrome;

increased symptoms of chronic heart failure.

Contraindications

erosive and ulcerative lesions of the gastrointestinal tract in the acute phase;

gastrointestinal bleeding;

"aspirin triad";

a history of indications of urticaria, rhinitis caused by taking acetylsalicylic acid and other NSAIDs;

hemophilia;

hemorrhagic diathesis;

hypoprothrombinemia;

dissecting aortic aneurysm;

portal hypertension;

vitamin K deficiency;

hepatic and / or renal failure;

deficiency of glucose-6-phosphate dehydrogenase;

reye's syndrome;

children's age (up to 15 years - the risk of developing Reye's syndrome in children with hyperthermia against the background of viral diseases);

1st and 3rd trimesters of pregnancy;

lactation period;

hypersensitivity to acetylsalicylic acid and other salicylates.

Special directions

It is used with caution in patients with liver and kidney diseases, with bronchial asthma, erosive and ulcerative lesions and bleeding from the gastrointestinal tract in history, with increased bleeding or while conducting anticoagulant therapy, decompensated chronic heart failure.

Acetylsalicylic acid, even in small doses, reduces the excretion of uric acid from the body, which can cause an acute attack of gout in predisposed patients. Long-term therapy and / or the use of acetylsalicylic acid in high doses requires medical supervision and regular monitoring of hemoglobin levels.

The use of acetylsalicylic acid as an anti-inflammatory agent in a daily dose of 5-8 grams is limited due to the high likelihood of side effects from the gastrointestinal tract.

Before surgery, to reduce bleeding during surgery and in the postoperative period, you should stop taking salicylates for 5-7 days.

During prolonged therapy, it is necessary to carry out a general blood test and a study of feces for occult blood.

The use of acetylsalicylic acid in pediatrics is contraindicated, since in the case of a viral infection in children under the influence of acetylsalicylic acid, the risk of developing Reye's syndrome increases. The symptoms of Reye's syndrome are prolonged vomiting, acute encephalopathy, and enlarged liver.

The duration of treatment (without consulting a doctor) should not exceed 7 days when prescribed as an analgesic and more than 3 days as an antipyretic.

During the period of treatment, the patient should refrain from drinking alcohol.

The form release, composition and packaging

Tablets 1 tab.

acetylsalicylic acid 325 mg

30 - containers (1) - packs.

50 - containers (1) - packs.

12 - blisters (1) - packs.

Pharmacopoeia monograph. experimental part

Description. Colorless crystals or white crystalline powder; odorless or weak odor, slightly acidic taste. The drug is stable in dry air, in humid air it gradually hydrolyzes to form acetic and salicylic acids.

Solubility. We will slightly dissolve in water, we will easily dissolve in alcohol, we will dissolve in chloroform, ether, in solutions of caustic and carbonic alkalis.

Authenticity. 0 , 5 g of the preparation are boiled for 3 minutes with 5 ml of sodium hydroxide solution, then cooled and acidified with diluted sulfuric acid; a white crystalline precipitate is formed. The solution is poured into another test tube and 2 ml of alcohol and 2 ml of concentrated sulfuric acid are added to it; the solution smells like ethyl acetate. 1-2 drops of ferric chloride solution are added to the sediment; a violet color appears.

0.2 g of the drug is placed in a porcelain cup, add 0.5 ml of concentrated sulfuric acid, mix and add 1-2 drops of water; there is a smell of acetic acid. Then add 1-2 drops of formalin; a pink color appears.

Melting point 133-138 ° (temperature rise rate 4-6 ° per minute).

Chlorides. 1.5 g of the preparation is shaken with 30 ml of water and filtered. 10 ml of filtrate must withstand the chloride test (not more than 0.004% in the preparation).

Sulfates... 10 ml of the same filtrate must withstand the sulfate test (not more than 0.02% in the preparation).

Organic impurities... 0.5 g of the drug is dissolved in 5 ml of concentrated sulfuric acid; the color of the solution should not be more intense than the standard No. 5a.

Free salicylic acid... Dissolve 0.3 g of the drug in 5 ml of alcohol and add 25 ml of water (test solution). 15 ml of this solution are placed in one cylinder, and 5 ml of the same solution in the other. 0.5 ml of 0.01% aqueous salicylic acid solution, 2 ml of alcohol and make up to 15 ml with water (standard solution). Then, 1 ml of an acidic 0.2% solution of iron ammonium alum is added to both cylinders.

The color of the test solution should not be more intense than the reference solution (no more than 0.05% in the preparation).

Sulfate ash and heavy metals... Sulphated ash from 0.5 g of the preparation should not exceed 0.1% and must withstand the test for heavy metals (no more than 0.001% in the preparation).

Quantitative definition. About 0.5 g of the drug (accurately weighed) is dissolved in 10 ml of phenolphthalein neutralized (5-6 drops) and alcohol cooled to 8-10 °. The solution is titrated with the same indicator 0.1 N. caustic soda solution until pink color.

1 ml 0.1 N. caustic soda solution corresponds to 0.01802 g of C9H8O4 of which the preparation must contain at least 99.5%.

Storage. In a well-sealed container.

Antirheumatic, anti-inflammatory, analgesic, antipyretic agent.

Pharmaceutical chemistry is a science that, based on the general laws of chemical sciences, explores the methods of obtaining, structure, physical and chemical properties of medicinal substances, the relationship between their chemical structure and action on the body; methods of drug quality control and changes occurring during their storage.

The main methods of researching medicinal substances in pharmaceutical chemistry are analysis and synthesis - dialectically closely related processes that complement each other. Analysis and synthesis are powerful tools for understanding the essence of phenomena occurring in nature.

The problems facing pharmaceutical chemistry are solved using classical physical, chemical and physicochemical methods, which are used both for the synthesis and for the analysis of medicinal substances.

To learn pharmaceutical chemistry, a future pharmacist must have deep knowledge in the field of general theoretical chemical and biomedical disciplines, physics, mathematics. Strong knowledge in the field of philosophy is also required, for pharmaceutical chemistry, like other chemical sciences, is concerned with the study of the chemical form of motion of matter.

Pharmaceutical chemistry occupies a central place among other special pharmaceutical disciplines - pharmacognosy, drug technology, pharmacology, organization and economics of pharmacy, toxicological chemistry, and is a kind of connecting link between them.

At the same time, pharmaceutical chemistry occupies an intermediate position between the complex of medico-biological and chemical sciences. The object of drug use is the body of a sick person. Specialists working in the field of clinical medical sciences (therapy, surgery, obstetrics and gynecology, etc.), as well as theoretical medical disciplines: anatomy, physiology, etc., are engaged in the study of the processes occurring in the body of a sick person, and its treatment. in medicine, drugs require the joint work of a doctor and a pharmacist in treating a patient.

As an applied science, pharmaceutical chemistry is based on the theory and laws of chemical sciences such as inorganic, organic, analytical, physical, colloidal chemistry. In close connection with inorganic and organic chemistry, pharmaceutical chemistry is engaged in the study of methods for the synthesis of medicinal substances. Since their effect on the body depends on both chemical structure and physicochemical properties, pharmaceutical chemistry uses the laws of physical chemistry.

When developing methods for controlling the quality of drugs and dosage forms in pharmaceutical chemistry, analytical chemistry methods are used. However, pharmaceutical analysis has its own specific features and includes three mandatory stages: the identification of the drug, control of its purity (setting the permissible limits for impurities) and the quantitative determination of the drug substance.

The development of pharmaceutical chemistry is impossible without the widespread use of the laws of such exact sciences as physics and mathematics, since without them it is impossible to learn the physical methods of researching medicinal substances and various calculation methods used in pharmaceutical analysis.

A variety of research methods are used in pharmaceutical analysis: physical, physicochemical, chemical, biological. The use of physical and physicochemical methods requires appropriate devices 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, moisture, melting point, solidification and boiling point, etc.

Physicochemical methods are used to measure the physical constants of the analyzed system, which change as a result of chemical reactions. This group of methods includes optical, electrochemical, chromatographic.

Chemical analysis methods 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. Determine the strength of the pharmacological effect or toxicity.

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

List of references

1. Pharmaceutical chemistry: Textbook. allowance / Ed. L.P. Arzamastseva. M .: GEOTAR-MED, 2004.

2. Pharmaceutical analysis of drugs / Under the general editorship of V.A.

3. Shapovalova. Kharkov: IMP "Rubicon", 1995.

4. Melent'eva G.A., Antonova L.A. Pharmaceutical chemistry. Moscow: Medicine, 1985.

5. Arzamastsev A.P. Pharmacopoeial analysis. M .: Medicine, 1971.

6. Belikov V.G. Pharmaceutical chemistry. In 2 parts. Part 1. General pharmaceutical chemistry: Textbook. for pharmacies. in-tov and fak. honey. in-tov. M .: Higher. shk., 1993.

7. State Pharmacopoeia of the Russian Federation, X edition - under. ed. Yurgel N.V. Moscow: "Scientific Center for Expertise of Medicinal Products". 2008.

8. International Pharmacopoeia, Third Edition, V.2. World Health Organization. Geneva. 1983, 364 p.

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Introduction

Pharmaceutical analysis is the science of chemical characterization and measurement of biologically active substances at all stages of production: from raw material control to assessing the quality of the resulting medicinal substance, studying its stability, establishing shelf life and standardizing the finished dosage form. Pharmaceutical analysis has its own specific features that distinguish it from other types of analysis. These features consist in the fact that the analysis is carried out on substances of various chemical nature: inorganic, organoelement, radioactive, organic compounds from simple aliphatic to complex natural biologically active substances. Extremely wide range of analyte concentrations. The objects of pharmaceutical analysis are not only individual medicinal substances, but also mixtures containing different numbers of components. The number of medicines is increasing every year. This necessitates the development of new methods of analysis.

Methods of pharmaceutical analysis require systematic improvement in connection with the continuous increase in requirements for the quality of drugs, and the requirements for both the purity of drugs and the quantitative content are growing. Therefore, it is necessary to widely use not only chemical, but also more sensitive physicochemical methods for assessing the quality of drugs.

There are high demands on pharmaceutical analysis. It should be sufficiently specific and sensitive, accurate in relation to the standards stipulated by GF XI, VFS, FS and other NTD, performed in short periods of time using minimal amounts of tested drugs and reagents.

Pharmaceutical analysis, depending on the tasks set, includes various forms of drug quality control: pharmacopoeial analysis, stepwise control of drug production, 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 researching medicinal products 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 State Pharmacopoeia or other regulatory and technical documentation. If you deviate from these requirements, the drug is not allowed for use.

The conclusion about the quality of the medicinal product can be made only 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 GF XI (issue 2). Sampling is carried out only from undamaged, sealed and packed packaging units in accordance with the requirements of NTD. At the same time, the requirements for precautions 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 NTD requirements, multistage 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 required for four complete physicochemical analyzes (if the sample is taken for regulatory organizations, then for six such analyzes).

Spot samples are taken from the Angro packaging, taken in equal amounts from the upper, middle and lower layers of each packaging unit. After establishing homogeneity, all these samples are mixed. Bulk and viscous drugs are taken with a sampler made of an inert material. Mix liquid drugs thoroughly before sampling. If it is difficult to do this, 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 makes it possible to establish the authenticity of a medicinal product, its purity, and to determine the quantitative content of a 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 interconnected and complement each other. So, for example, melting point, solubility, pH of the aqueous solution, etc. are criteria for both the authenticity and the purity of a medicinal substance.

Chapter 1. Basic principles of pharmaceutical analysis

1.1 Criteria for pharmaceutical analysis

At various stages of pharmaceutical analysis, depending on the tasks set, such criteria as selectivity, sensitivity, accuracy, time spent on the analysis, consumed 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 \u200b\u200bof each of the components. Only selective analytical methods allow determining 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 a preparation, techniques are used that are highly sensitive, allowing you to establish the minimum content of impurities.

When performing step-by-step production control, as well as when conducting express analysis in a pharmacy, an important factor is the time spent on the analysis. For this, methods are chosen that allow the analysis to be carried out in the shortest possible 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 analysis with a large sample of the preparation.

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

The term "analytical accuracy" includes two concepts at the same time: reproducibility and accuracy of the results obtained. Reproducibility refers to the dispersion of the test results 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 consumed 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 20 ml of titrant is consumed for titration with the indicated total error of measurement and leakage of ± 0.04 ml, then the relative error will be 0.2%. With a decrease in the weight 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 increased by using micro burettes, the use of which significantly reduces errors from inaccurate metering, leakage and temperature effects. An error is also allowed when taking a sample.

The weighing of the sample during 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 preparation, which is usual for pharmacopoeial analysis, and weighing accuracy ± 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, the sample is taken with an accuracy of ± (0.001-0.01) g, i.e. with a marginal relative error of 0.1-1%. This can be attributed to the accuracy of weighing the sample for colorimetric analysis, the accuracy of the results of which is ± 5%.

1.2 Errors Possible During Pharmaceutical Analysis

When performing a quantitative determination by any chemical or physicochemical method, three groups of errors can be made: gross (blunders), 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 analysis results. They distort the measurement results, usually in one direction (positive or negative) by some constant value. The reason for systematic errors in the analysis can be, for example, the hygroscopicity of the preparation when weighing its sample; imperfection of measuring and physical and chemical devices; the 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 instrument error and does not exceed the random error.

Random errors reflect the reproducibility of the analysis results. 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 determination is equal to the ratio of the absolute error to the true value of the determined value. Express the relative error, usually as a percentage (multiplying the resulting value by 100). The relative errors of determinations by physicochemical methods include both the accuracy of the preparatory operations (weighing, measuring, dissolving), and the accuracy of measurements on the device (instrumental error).

The values \u200b\u200bof the relative errors depend on the method used for the analysis and what the analyzed object is - an individual substance or a multicomponent mixture. Individual substances can be determined by spectrophotometric analysis 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 two times. The combination of chromatography with other methods, in particular, the use of chromatographic and electrochemical chromatographic methods, allows the analysis of multicomponent mixtures with a relative error of ± (3-7)%.

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

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 systematic. Typically, in pharmaceutical analysis, 3-6 parallel measurements are performed. When statistical processing of the determination results, in order to obtain reliable results, at least seven parallel measurements are performed.

1.3 General principles of testing the authenticity of medicinal substances

Authenticity test 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). The tests are performed by physical, chemical and physicochemical 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 the 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 influence 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. In case of poor cleaning, the preparations may contain solvent impurities, fibers of fabrics or filter paper, sand, asbestos, etc., as well as residues of acids or alkalis.

Various factors can influence the quality of synthesized medicinal substances.

Technological factors are the first group of factors influencing the synthesis of a medicinal substance. The degree of purity of the starting materials, temperature regime, pressure, pH of the medium, solvents used in the synthesis process and for purification, drying regime and temperature, fluctuating even within small limits - all these factors can lead to the appearance of impurities that accumulate from one to another. stages. 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 substances from which it is difficult to separate the final product can then occur. During the 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. Moreover, often, depending on the conditions of production, purification and storage, a drug 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 related to the number of barbiturates, steroids, antibiotics, alkaloids, etc., form 1-5 or more different modifications. The rest give stable polymorphic and pseudopolymorphic modifications upon crystallization. They differ not only in their physicochemical properties (melting point, density, solubility) and pharmacological action, but they have different values \u200b\u200bof free surface energy, and therefore, unequal resistance to the action of oxygen in air, light, moisture. It is caused by changes in the energy levels of the 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.

Dustiness of industrial premises of chemical and pharmaceutical enterprises can have a great influence on the contamination of some drugs by impurities with others. In the working area of \u200b\u200bthese premises, subject to the receipt of one or several drugs (dosage forms), all of them can be contained in the form of aerosols in the air. This is what is known as "cross contamination".

In 1976, the World Health Organization (WHO) 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 the storage conditions are important for the quality of medicines. The good quality of drugs is influenced by excessive moisture, which can lead to hydrolysis. As a result of hydrolysis, basic salts, saponification products and other substances with a different character of pharmacological action are formed. When storing crystalline hydrate preparations (sodium arsenate, copper sulfate, etc.), on the contrary, it is necessary to comply with the conditions excluding 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 can occur, for example, of substances such as bleach, silver nitrate, iodides, bromides, etc. The quality of the container used for storing medicinal products, as well as the material from which it is made, is of great importance. The latter can also be a source of impurities.

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

The content of those and other impurities should be strictly controlled in order to exclude the presence of toxic compounds or the presence of indifferent substances in medicines 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 medicinal substance is pure if further purification does not change its pharmacological activity, chemical stability, physical properties, and bioavailability.

In recent years, in connection with the deterioration of the ecological situation, medicinal plant raw materials are also tested for the presence of impurities of heavy metals. The importance of carrying out such tests is due to the fact that during the study of 60 different samples of plant raw materials, the content of 14 metals in them was established, including such toxic ones as lead, cadmium, nickel, tin, antimony and even thallium. In most cases, their content significantly exceeds the established MAC for vegetables and fruits.

The pharmacopoeial test for the determination of heavy metal impurities is one of the most 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 trials should be carried out on medicinal products with single doses of at least 0.5 g.

1.5 General requirements for tests for cleanliness

Assessment of the purity of a medicinal product is one of the important stages of pharmaceutical analysis. All drugs, regardless of the preparation method, are tested for purity. In this case, the content of impurities is established. Their

8-09-2015, 20:00

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In modern pharmaceutical analysis, non-aqueous solvents have become widely used. If earlier the main solvent in the analysis was water, now they simultaneously use various non-aqueous solvents (glacial or anhydrous acetic acid, acetic anhydride, dimethylformamide, dioxane, etc.), which make it possible to change the strength of the basicity and acidity of the analyzed substances. Received the development of a micro-method, in particular, a drop analysis method, convenient for use in intra-pharmaceutical quality control of drugs.

In recent years, such research methods have been widely developed, in which a combination of various methods is used in the analysis of medicinal substances. For example, gas chromatography-mass spectrometry is a combination of chromatography and mass spectrometry. Physics, quantum chemistry, and mathematics are increasingly penetrating into modern pharmaceutical analysis.

The analysis of any medicinal substance or raw material must begin with an external examination, while paying attention to the color, smell, crystal shape, container, packaging, glass color. After external examination of the object of analysis, an average sample is taken for analysis in accordance with the requirements of GF X (p. 853).

Research methods of medicinal substances are subdivided into physical, chemical, physicochemical, biological.

Physical methods of analysis provide for the study of the physical properties of a substance without resorting to chemical reactions. These include: determination of solubility, transparency

or the degree of turbidity, color; determination of density (for liquid substances), humidity, melting point, solidification, boiling. Corresponding techniques are described in GF X. (Pp. 756-776).

Chemical research methods are based on chemical reactions. These include: determination of ash content, reaction of the medium (pH), characteristic numerical indicators of oils and fats (acid number, iodine number, saponification number, etc.).

For the purpose of identifying medicinal substances, only those reactions are used that are accompanied by a visual external effect, for example, a change in the color of the solution, the release of gases, the precipitation or dissolution of precipitates, etc.

Chemical methods of research also include weight and volumetric methods of quantitative analysis adopted in analytical chemistry (method of neutralization, precipitation, redox methods, etc.). In recent years, such chemical research methods as titration in non-aqueous media and complexometry have entered into pharmaceutical analysis.

Qualitative and quantitative analysis of organic medicinal substances, as a rule, is carried out according to the nature of the functional groups in their molecules.

Physicochemical methods are used to study physical phenomena that occur as a result of chemical reactions. For example, in the colorimetric method, the intensity of the color is measured depending on the concentration of the substance, in the conductometric analysis - the measurement of the conductivity of solutions, etc.

Physicochemical methods include: optical (refractometry, polarimetry, emission and fluorescence methods of analysis, photometry, including photocolorimetry and spectrophotometry, nephelometry, turbodimetry), electrochemical (potentiometric and polarographic methods), chromatographic methods.

At present, classical (titrimetric) methods of analysis are widely used for the quantitative determination of medicinal substances in regulatory documents (GF CHYY), but in this case, the determination is not carried out according to the pharmacologically active part of the molecule.

Nitrometry is a method of titrimetric analysis in which a solution of sodium nitrite is used as a titration reagent.

It is used for the quantitative determination of compounds containing a primary or secondary aromatic amino group, for the determination of hydrazines, as well as aromatic nitro compounds after preliminary reduction of the nitro group to the amino group. An exact weighed portion of the drug sample specified in the monograph is dissolved in a mixture of 10 ml of water and 10 ml of hydrochloric acid diluted with 8.3%. Add water to a total volume of 80 ml, 1 g of potassium bromide and titrate with 0.1 M sodium nitrite solution with constant stirring. At the beginning of the titration, add sodium nitrite solution at a rate of 2 ml / min, and at the end (0.5 ml to the equivalent amount) - 0.05 ml / min.

Titration is carried out at a solution temperature of 15-20 ° C, however, in some cases, cooling to 0-5 ° C is required.

The equivalence point is determined by electrometric methods (potentiometric titration, amperometric titration) or using internal indicators.

In potentiometric titration, a platinum electrode is used as an indicator electrode, while a silver chloride or saturated calomel electrode is used as reference electrodes.

A potential difference of 0.3-0.4 V is applied to the electrodes, unless otherwise specified in the monograph.

Tropeolin 00 (4 drops of solution), tropeolin 00 mixed with methylene blue (4 drops of tropeolin 00 solution and 2 drops of methylene blue solution), neutral red (2 drops at the beginning and 2 drops at the end of titration) are used as internal indicators.

Titration with tropeolin 00 is carried out until the color changes from red to yellow, with a mixture of tropeolin 00 with methylene blue - from red-violet to blue, with neutral red - from red-violet to blue. Exposure at the end of the neutral red titration is increased to 2 min. A control experiment is carried out in parallel.

Using nitrometry, they determine: chloramphenicol, novocaine hydrochloride, paracetamol, sulfadimethoxine. The determination is based on the aromatic amino group.

Arbidol, articaine hydrochloride, atenolol, acyclovir, diazolin, diphenhydramine, droperidol, drotaverine hydrochloride, isoniazid, ketamine hydrochloride, clotrimazole, clonidine hydrochloride, methazoline, codeine caffeinated water, caffeinated water , papaverine hydrochloride, pyridoxine hydrochloride, piroxicam, fenpiverinium bromide, chloropyramine hydrochloride, verapamil hydrochloride, haloperidol, gliclazide, diazepam, itraconazole, clemastine fumarate, meloxicam, meldonium, sodium thiorminium hydrochloride ... Using this method, more than half of the medicinal substances included in the GF CHYY are quantified. The disadvantage of this method is that the decomposition products of drugs, which have basic properties, can also be titrated with perchloric acid along with undecomposed drugs.

The quantitative determination of analgin according to GF CHYY is carried out by the iodometric method. About 0.15 g (accurately weighed) of the substance is placed in a dry flask, 20 ml of alcohol 96%, 5 ml of 0.01 M hydrochloric acid solution are added and immediately titrated with 0.1 M iodine solution with stirring until a yellow color appears that does not disappear into for 30 s. ... The method is based on the oxidation of sulfur plus 4 to sulfur plus 6. The disadvantage of the method is that the determination is not carried out according to the pharmacologically active part of the molecule (1-phenyl-2,3-dimethyl-4-methylamino pyrazolone-5).

The method of alkalimetry is used to determine acetylsalicylic acid, glutamic acid, doxazosin mesylate, methyluracil, naproxen, nicotinic acid, pitofenone hydrochloride, theophylline, furosemide - the equivalence point is established using an indicator. Bromhexine hydrochloride, lidocaine hydrochloride, lisinopril, ranitidine hydrochloride - with a potentiometric ending. The standardization of these substances is carried out mainly according to HCl, which is not a pharmacologically active substance.

HPLC method GF CHYY recommends using for the determination of guaifenesin, carbamazepine, ketorolac, riboxin, simvastatin, ondansetron hydrochloride. The determination is carried out according to the pharmacologically active part of the drug molecule.

Hydrocortisone acetate, spironolactone, furazolidone are determined spectrophotometrically. The method is not selective enough, since the decomposition products and the test substance can have the same maximum of light absorption.

At the present stage of development of pharmaceutical chemistry, physicochemical methods of analysis have a number of advantages over classical ones, since they are based on the use of both physical and chemical properties of medicinal substances and in most cases are characterized by rapidity, selectivity, high sensitivity, the possibility of unification and automation.

The GLC method is universal, highly sensitive, and reliable. This method for the qualitative and quantitative determination of Dimexide 50% ointment was used by M.V. Gavrilin, E.V. Kompantseva and others.

A.G. Witenberg, in the course of studying chlorinated tap water, found that the content of impurities of volatile halogenated hydrocarbons does not remain constant, but increases when water is in the water supply system. This indicates the incompleteness of the chemical transformations of the humic substance after the chlorination of water. The existing certified methods based on vapor-phase gas chromatographic analysis do not take into account this feature, provide for the determination of only free halogenated hydrocarbons. A comparative assessment of the official methods was carried out, and sources of errors exceeding the permissible values \u200b\u200bwere identified. The ways to optimize all stages of analysis are proposed to create methods that provide a minimum of error and reliable information on the content of volatile halogenated hydrocarbons in tap and waste waters.

Gas chromatography was used to determine amphetamines, barbiturates, benzodiazepines, and opiates in urine by high-temperature solid-phase microextraction of medicinal substances.

Ion chromatography was used by Siang De-Wen to determine anionites in drinking water. The method turned out to be simple, fast, and accurate (all anions are detected simultaneously with a standard deviation of ≥3%, regeneration 99.7% and 102%). The analysis lasted 15 minutes.

A number of authors have calculated: the differences in the gas chromatographic retention indices of the chlorination products of aliphatic ketones and the initial carbonyl compounds are constant. Their numerical values \u200b\u200bdepend on the number and position of chlorine atoms in the molecule. A variant of additive schemes for assessing retention indices for the identification of chlorine derivatives of carbonyl compounds was developed. I.G. Zenkevich established the order of chromatographic elution of diastomeric b-b "-dichloro-K-alkanes (K? 2).

I.V. Gruzdiev and co-authors studied 2- and 4-chloroaniline, 2,4- and 2,6-dichloroaniline, 2,4,5- and 2,4,6-trichloroaniline, and unsubstituted aniline, developed methods for determining their micro amounts in drinking water, including the preparation of bromine derivatives, liquid extraction with toluene, as well as for the determination of diphenhydramine hydrochloride and its base in the presence of decomposition products.

V.G. Amelin and others have applied gas chromatography with a time-of-flight mass spectrometric detector to identify and determine pesticides and polycyclic aromatic hydrocarbons (46 ingredients) in water and food.

Potapova T.V., Shcheglova N.V. When studying equilibrium reactions of formation of cyclohexadiaminetetraacetate, ethylenediaminetetraacetate, diethylenetriaminepentaacetate complexes of some metals, the method of ion exchange chromatography was used.

Using analytical systems (liquid chromatography, mass spectrometry), Sony Weihua and a number of authors have established that pharmaceutical preparations were almost completely destroyed in processes involving OH radicals of active electrolytes.

A.A. Vitaliev and others have studied the conditions for isolating ketorolac and diclofenac from biological fluids. A method of extraction with organic solvents at different pH was proposed. TLC was used to identify the analytes.

The use of planar chromatography on the example of amino acids and amlodipine was demonstrated by Pakhomov V.P., Checha O.A. for the study and separation of optically active medicinal substances into individual stereoisomers with subsequent identification.

The method of capillary gas chromatography in combination with mass spectrophotometry showed that the extraction of steroids from blood was the most complete (~ 100%).

Using recirculating HPLC, scientists have isolated eight non-cytotoxic bacterial drug resistance modifications.

N.N. Dementyeva, T.A. Zavrazhskaya used gas chromatographic methods to analyze various drugs in injection solutions and eye drops.

Hyperacin and pseudohyperacin in pharmaceutical preparations with fluorescence detection were determined by liquid chromatography. Valproic acid in human serum was identified by the same method, the detection limit was 700 mmol / l. HPLC was used to determine disodium cromoglycate in pharmaceuticals. Using this method, it was possible to discover 98.2-100.8% of the analyte added to the sample.

M.E. Evgeniev and his co-workers established the effect of the nature and polarity of the eluent, the content of the aqueous phase in the aqueous-non-aqueous mixture and its pH on the mobility of 5,7-dinitrobenzofurazine derivatives of a number of aromatic amines under UV-HPLC conditions. The ZORBAX SB-C18 column developed a method for separating a mixture of six aromatic amines.

When developing methods for assessing the quality of novocaine, cyclometazidine, sydnocarb A.S. Kvach and co-authors applied HPLC and microcolumn adsorption chromatography methods in combination with a photometric analysis method that allows quantitative determination of novocaine in a substance and liquid dosage forms by the pharmacologically active part of the molecule.

I.A. Kolychev, Z.A. Temerdashev, N.A. Frolov developed an HPLC method for the determination of twelve phenolic compounds in plant materials by reversed-phase HPLC with UV detection and an eluent elution mode. The influence of various factors of separation of gallic, trans-ferulic, protocatechic, trans-caffeic acids, quercetin, rutin, dihydroquercetin and epicatechin was studied.

ON. Epstein used the HPLC method for the simultaneous determination of drugs in suspensions. A number of authors have used this method to determine the simultaneous content of paroxetine, risperidone and 9-hydroxyrepiredone in human plasma (with coulometric detection. Using HPLC with a UV detector in the column reload mode, a method for the determination of clotrimazole and mometasone furate in a wide concentration range is described.

A.M. Martynov, E.V. Chuparina developed a non-destructive method of X-ray fluorescence analysis of ions in plants using a spectrometer. It was found that reducing the weight of a plant from 6 to 1 gram increases the sensitivity of the determination of elements. Using this technique, the elemental composition of violets used in medicine was determined.

A.S. Saushkina, V.A. Belikov performed spectrophotometry to identify chloramphenicol in dosage forms. A method for the quantitative determination of paracetamol and mefenamic acid in tablets is proposed using the UV spectrophotometry method. The optimal conditions for spectrophotometric analysis of metazide, ftivazid, isoniazid, chloramphenicol and synthomycin based on the study of UV spectra have been established. In the spectrophotometric determination of ketorolac, the relative error is ± 1.67%.

IN AND. Vershinin et al. Revealed deviations from the additivity of light-absorbing mixtures and predicted using statistical models obtained in the course of a full factorial experiment. Models relate variance and blend composition to optimize spectrophotometric analysis techniques.

J.A. Kormosh co-authored piroxicam based on the extraction of its ionic associate with a polymethine dye by the SPM method. The maximum extraction with toluene is achieved at pH \u003d 8.0-12.0 of the aqueous phase. To control the quality of medicinal products containing piroxicam, a method of extraction-spectrophotometric determination has been developed.

Extraction photometry is a promising method for studying a medicinal substance. This method is characterized by high sensitivity due to the formation of products of interaction with reagents, leading to the appearance of additional chromophores, an increase in conjugation, as well as due to the concentration of the reaction products in the organic phase. Sufficient accuracy, comparative ease of implementation and the possibility of determining the active substance by the pharmacologically active part of the molecule is another advantage of extraction photometry.

E.Yu. Zharskaya, D.F. Nokhrin, T.P. Churin used extraction photometry to determine verapamil hydrochloride, mezapam by the pharmacologically active part of the molecule based on the reaction with the salicylate copper complex (YY).

N.T. Bubo et al. Used bromcresol purple as a reagent for medicinal substances. Based on this reaction, extraction-photometric methods for the determination of fluoroacizine and acephene in tablets were developed.

G.I. Lukyanchikova and colleagues used extraction photometry in the analysis of aceclidine, oxylidine for the pharmacologically active part of the molecule based on the reaction with bromothymol blue. A number of authors used the extraction-photometric method for the quantitative determination of metamizil in 0.25% injection solution.

Studying the influence of the pH of the medium and temperature on the stability of aqueous solutions of spasmolitin, G.I. Oleshko developed an extraction-photometric method for its analysis for the pharmacologically active part of the molecule based on the complexation reaction with bromotallic acid.

A.A. Litvin et al. Developed an extraction-photometric method for the analysis of novocaine in injection solutions, ointments and studied the possibility of using it in the study of medicinal preparations containing novocaine during storage.

T.A. Smolyanyuk proposed a method for the extraction-photometric determination of diphenhydramine hydrochloride using tropeolin 000-1, which makes it possible to analyze it in the presence of impurities.

Photometry and turbidimetry are widely used in practical pharmacy. L.V. Kajonyan, I.A. Kondratenko was quantitatively determined by the photometric method according to the pharmacologically active part of the molecule of diphenhydramine hydrochloride and trimecaine. V.A. Popkov and others applied differential scanning colorimetry in pharmaceutical analysis for nicotinic acid, isoniazid, and ftivazid. A.I. Sichko used phototurbidimetry to quantify teturam. The disadvantage of photometric methods is that they do not always allow determining the active substance in the presence of degradation products.

The fluorometric method was also used for the quantitative determination of medicinal substances. V.M. Ivanov, O. A. Grigoriev, A.A. Khabarov used fluorescence analysis to control the quality of drugs containing furocoumarins of the psoralen group and folic acid. Column chromatography is also widely used. D.E. Bodrina, S.K. Eremin, B.N. Izotov used a microcolumn on a Melichrom liquid chromatograph to determine benzodiazepines in biological objects.

Recently, the chromatography-spectrophotometric method has become widespread for the quantitative determination of a substance by the pharmacologically active part of the molecule. It combines the high sensitivity of ultraviolet spectroscopy with the separation power of thin layer chromatography. S.A. Valevko, M.V. Mishustin developed a method for the chromatography-spectrophotometric determination of papaverine hydrochloride, and D.S. Lazaryan and E.V. Kompantsev used it to determine chlorpropamide in the presence of their decomposition products.

The spectrophotometric method does not always allow for objective control of the quantitative content of the active component. This is due to the fact that the decay products sometimes have an absorption maximum in the same spectral region as drugs.

Mass spectrometry, atomic absorption spectrophotometry, NMR, IR, and PMR spectroscopy open up great opportunities in the analysis of a drug and its conformations. To identify diphenhydramine hydrochloride, a chromatography-mass spectrometric method was used. It was found that the drug contains four impurities: benzophenone, 9-methylenefluorene, 9-fluorenyl dimethyl aminoethyl ether, and diphenyl methyl ether. The diphenhydramine content was 96.80%.

A method for the determination of atropine in belladonna extracts using mass spectrometry with chemical ionization at atmospheric pressure is described. Terbutamine was used as an internal standard. L.V. Adeishvili et al. Investigated the spectra of diphenhydramine hydrochloride and mebedrol and suggested using them for drug identification.

V.S. Kartashov used the NMR method to identify drugs, derivatives of quinoline and isoquinoline. The characteristic signals in the NMR spectra of drugs allow their reliable identification using a personal computer.

PMR spectroscopy with high magnetic field strength was used to quantify propranolol.

T.S. Chmilenko, E.A. Galimbievskaya, F.A. Chmilenko showed that when phenol red interacts with polyhexamethylene guanidinium chloride, an ion associate and several forms of aggregates are formed, the composition of which has been established by spectrophotometric, turbidimetric, refractometric and conductometric methods. Redistribution of absorption bands occurs, extreme points are observed, which correspond to the regions of maximum accumulation of the formed aggregates. A method for determining PHMG in the disinfectant "Biopag-D" using extreme points has been developed.