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Introduction

Description of the drug

Bibliography

Introduction

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

Pharmacopoeial analysis of medicines includes quality assessment based on many indicators. In particular, the authenticity of the drug is established, its purity is analyzed, and quantitative determination is carried out. Initially, exclusively chemical methods were used for such analysis; authenticity reactions, impurity reactions and titrations for quantitative determination.

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, spectral methods such as 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

Methods of qualitative and quantitative analysis

Analysis of a substance can be carried out 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 analyzed substance 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 quantitative determination of the constituent parts of the analyzed substance depends on the data obtained from its qualitative analysis.

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

For example, to discover Fe +++ ions in a solution, the analyzed solution 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 (II) hexacyanoferrate Fe43 precipitates. (Prussian blue):

Another example of 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 its smell or by the blueness of wet red litmus paper:

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

When analyzing a mixture of several substances with similar chemical properties, they are first separated and only then are characteristic reactions carried out on individual substances (or ions), so qualitative analysis covers not only individual reactions for detecting ions, but also methods for their separation.

Quantitative analysis makes it possible to establish quantitative relationships between 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 product under study.

Methods of qualitative and quantitative analysis that make it possible to determine the content of individual elements in the analyzed substance 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 for separating and determining individual structural (phase) components of heterogeneous! systems that differ in properties and physical structure and are limited from each other by interfaces are called phase analysis.

Methods for studying the quality of medicines

In accordance with the State Fund XI, methods for studying drugs are divided into physical, physicochemical and chemical.

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

Physico-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 on the voltage applied to the system under study. Electrolysis of the solutions under study 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. Wave exhaustion is related to the concentration of reacting substances. The method is used for the quantitative determination of many organic compounds.

Potentiometry is a method for determining pH and potentiometric titration.

Chromatography is the process of separating mixtures of substances that occur when they move in a mobile phase flow along a stationary sorbent. Separation occurs due to the difference in certain physicochemical properties of the substances being separated, leading to their unequal interaction with the stationary phase substance, and, consequently, to a difference in the retention time of the sorbent layer.

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

Spectral methods are based on the selective absorption of electromagnetic radiation by the analyzed substance. 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 non-monochromatic radiation in the visible part of the spectrum by a substance.

Chemical methods. Based on the use of chemical reactions to identify drugs. For inorganic drugs, reactions on cations and anions are used, for organic drugs - on functional groups, and only those reactions are used that are accompanied by a visible 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 (volume) methods, including acid-base titration in aqueous and non-aqueous media, gasometric analysis and quantitative elemental analysis.

Gravimetric method. Of inorganic medicinal substances, this method can be used to determine sulfates, converting them into insoluble barium salts, and silicates, pre-calcining them to silicon dioxide. It is possible to use gravimetry to analyze preparations of quinine salts, alkaloids, some vitamins, etc.

Titrimetric methods. This is the most common method in pharmaceutical analysis, characterized by low labor intensity and fairly high accuracy. Titrimetric methods can be divided into precipitation titration, acid-base, redox, compleximetry and nitritometry. With their help, quantitative assessment is carried out by determining 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 - the use of acid as a titrant, alkalimetry - the use of 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 occurs in a stoichiometric ratio of 1:1, regardless of the charge of the cation.

Nitritometry. The method is based on the reactions of primary and secondary aromatic amines with sodium nitrite, which is used as a titrant. Primary aromatic amines form a diazo compound with sodium nitrite in an acidic environment, and 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 the gasometric definition 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 for quality control of medicinal substances. Biological assessment of drug quality is carried out based on their pharmacological activity or toxicity. Biological microbiological methods are used in cases where using physical, chemical and physicochemical methods it is impossible to make a conclusion about the good quality of the drug. Biological tests are carried out on animals (cats, dogs, pigeons, rabbits, frogs, etc.), individual isolated organs (uterine horn, part of the skin) and groups of cells (blood cells, strains of microorganisms, etc.). Biological activity is determined, as a rule, by comparing the effects of test subjects and standard samples.

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

The sterility test is based on 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 subject to these tests. To control sterility, bioglycol and liquid Sabouraud medium are used using the direct inoculation method on nutrient media. If the drug has a pronounced antimicrobial effect or is bottled in 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 a salicylic ester of acetic acid.

Description. Colorless crystals or white crystalline powder, odorless, slightly acidic taste. In humid air it gradually hydrolyzes to form acetic and salicylic acids. Slightly soluble in water, easily soluble in alcohol, soluble in chloroform, ether, and 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 and recrystallized from benzene, chloroform, isopropyl alcohol or other organic solvents.

The finished acetylsalicylic acid preparation may contain residues of unbound salicylic acid. The amount of salicylic acid as an impurity is regulated and the limit for the content of salicylic acid in acetylsalicylic acid is set by State Pharmacopoeias of different countries.

The State Pharmacopoeia of the USSR, tenth edition of 1968, sets the permissible limit for the content of salicylic acid in acetylsalicylic acid of no more than 0.05% in the preparation.

Acetylsalicylic acid, when hydrolyzed 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. Already when standing in humid air, it hydrolyzes into acetic and salicylic acids. In this regard, pharmacists often have to check whether acetylsalicylic acid has been hydrolyzed. For this purpose, the reaction with FeCl3 is very convenient: acetylsalicylic acid does not give color with FeCl3, while salicylic acid, formed as a result of hydrolysis, gives a violet color.

Clinical-pharmacological group: NSAIDs

Pharmacological action

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 of 0.3 g to 1 g is used to relieve pain and conditions that are accompanied by 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, and 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-allergic myocarditis;

fever in 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 ischemic cerebrovascular accidents;

in gradually increasing doses for long-term “aspirin” desensitization and the formation of stable tolerance to NSAIDs in patients with “aspirin” asthma and the “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 use - 2-6 times a day. It is preferable to drink milk or alkaline mineral waters.

Side effects action

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;

prolongation of bleeding time;

renal dysfunction;

acute renal failure;

skin rash;

Quincke's edema;

bronchospasm;

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

Reye's syndrome (Raynaud's);

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;

liver and/or kidney failure;

deficiency of glucose-6-phosphate dehydrogenase;

Reye's syndrome;

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

1st and 3rd trimesters of pregnancy;

lactation period;

hypersensitivity to acetylsalicylic acid and other salicylates.

Special instructions

Use with caution in patients with liver and kidney diseases, bronchial asthma, erosive and ulcerative lesions and bleeding from the gastrointestinal tract in history, with increased bleeding or while carrying out 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. When carrying out long-term therapy and/or using acetylsalicylic acid in high doses, medical supervision and regular monitoring of hemoglobin levels are required.

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 developing 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 long-term therapy, it is necessary to conduct a complete blood count and stool examination 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. Symptoms of Reye's syndrome are prolonged vomiting, acute encephalopathy, and liver enlargement.

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 treatment period, the patient must abstain from drinking alcohol.

Form release, compound And package

Tablets 1 tab.

acetylsalicylic acid 325 mg

30 - containers (1) - packs.

50 - containers (1) - packs.

12 - blisters (1) - packs.

Pharmacopoeial article. experimental part

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

Solubility. Slightly soluble in water, easily soluble in alcohol, soluble in chloroform, ether, and solutions of caustic and carbonic alkalis.

Authenticity. 0 .5 g of the drug is boiled for 3 minutes with 5 ml of sodium hydroxide solution, then cooled and acidified with diluted sulfuric acid; a white crystalline precipitate is released. 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 has the smell of ethyl acetate. Add 1-2 drops of ferric oxide chloride solution to the precipitate; a violet color appears.

0.2 g of the drug is placed in a porcelain cup, 0.5 ml of concentrated sulfuric acid is added, stirred and 1-2 drops of water are added; 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. Shake 1.5 g of the drug with 30 ml of water and filter. 10 ml of filtrate must pass the chloride test (not more than 0.004% in the preparation).

Sulfates. 10 ml of the same filtrate must pass the test for sulfates (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 standard No. 5a.

Free salicylic acid. 0.3 g of the drug is dissolved in 5 ml of alcohol and 25 ml of water (test solution) is added. Place 15 ml of this solution in one cylinder and 5 ml of the same solution in the other. 0.5 ml of a 0.01% aqueous solution of salicylic acid, 2 ml of alcohol and dilute with water to 15 ml (reference solution). Then 1 ml of an acidic 0.2% solution of ferroammonium alum is added to both cylinders.

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

Sulfate ash And heavy metals. Sulfated ash from 0.5 g of the drug should not exceed 0.1% and must pass the test for heavy metals (not more than 0.001% in the drug).

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

1 ml 0.1 n. caustic soda solution corresponds to 0.01802 g of C9H8O4, which must be at least 99.5% in the preparation.

Storage. In a well-closed container.

Antirheumatic, anti-inflammatory, analgesic, antipyretic.

Pharmaceutical chemistry is a science that, based on the general laws of chemical sciences, studies methods of production, structure, physical and chemical properties of medicinal substances, the relationship between their chemical structure and effect on the body; methods of quality control of drugs and changes that occur during their storage.

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

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

To learn pharmaceutical chemistry, the future pharmacist must have deep knowledge in the field of general theoretical chemical and biomedical disciplines, physics, and mathematics. A solid knowledge of philosophy is also required, because pharmaceutical chemistry, like other chemical sciences, deals with the study of the chemical form of the movement 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 biomedical and chemical sciences. The object of drug use is the body of a sick person. The study of the processes occurring in the body of a sick person and his treatment are carried out by specialists working in the field of clinical medical sciences (therapy, surgery, obstetrics and gynecology, etc.), as well as theoretical medical disciplines: anatomy, physiology, etc. The variety of applied in medicine, drugs require the joint work of a doctor and a pharmacist when treating a patient.

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

When developing methods for quality control of drugs and dosage forms in pharmaceutical chemistry, methods of analytical chemistry are used. However, pharmaceutical analysis has its own specific features and includes three mandatory stages: establishing the authenticity of the drug, monitoring its purity (establishing acceptable limits for impurities) and 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 understand the physical methods of studying medicinal substances and the various calculation methods used in pharmaceutical analysis.

In pharmaceutical analysis, a variety of research methods are used: physical, physicochemical, chemical, biological. The use of physical and physicochemical 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 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, and chromatographic.

Chemical methods of analysis are based on performing chemical reactions.

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

The methods used in pharmaceutical analysis must be sensitive, specific, selective, rapid and suitable for rapid analysis in a pharmacy setting.

Bibliography

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. Melentyeva G.A., Antonova L.A. Pharmaceutical chemistry. M.: 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 pharmaceutical in-tov i fak. honey. Inst. M.: Higher. school, 1993.

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

8. International Pharmacopoeia, Third Edition, Vol.2. World Health Organization. Geneva. 1983, 364 pp.

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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 the control of raw materials to assessing the quality of the resulting drug substance, studying its stability, establishing expiration dates and standardizing 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 natures are subjected to analysis: inorganic, organoelement, radioactive, organic compounds from simple aliphatic to complex natural biologically active substances. The range of concentrations of the analyzed substances is extremely wide. 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 for pharmaceutical analysis require systematic improvement due to the continuous increase in requirements for the quality of drugs, and the requirements for both the degree of purity of drugs and their quantitative content are growing. Therefore, it is necessary to widely use not only chemical, but also more sensitive physicochemical methods to assess the quality of drugs.

There are high demands on pharmaceutical analysis. It must be quite specific and sensitive, accurate in relation to the standards stipulated by the State Pharmacopoeia XI, VFS, FS and other scientific and technical documentation, carried out in short periods of time using minimal quantities of test drugs and reagents.

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

An integral part of pharmaceutical analysis is pharmacopoeial analysis. It is a set of methods for studying drugs and dosage forms set out 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 about the compliance of the medicinal product with the requirements of the Global Fund or other regulatory and technical documentation. If you deviate from these requirements, the medicine is not allowed for use.

A conclusion about the quality of a medicinal product can only be made based on the analysis of a sample (sample). The procedure for its selection is indicated either in a private article or in the general article of the Global Fund XI (issue 2). Sampling is carried out only from undamaged packaging units, sealed and packaged in accordance with the requirements of the normative and technical documentation. In this case, the requirements for precautionary measures for working with poisonous and narcotic drugs, as well as for the toxicity, flammability, explosion hazard, hygroscopicity and other properties of drugs must be strictly observed. To test for compliance with the requirements of the normative and technical documentation, multi-stage sampling is carried out. The number of stages 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 regulatory organizations, then for six such analyses).

From the Angro packaging, spot 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. Bulk and viscous drugs are taken with a sampler made of inert material. Liquid drugs 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 makes it possible to establish the authenticity of the drug, its purity, and determine the quantitative content of the pharmacologically active substance or ingredients included in the dosage form. Although each of these stages has its own specific purpose, they cannot be viewed in isolation. They are interconnected and mutually complement each other. For example, melting point, solubility, pH of an aqueous solution, etc. are criteria for both the authenticity and purity of the 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 performing the analysis, and the amount of the analyzed drug (dosage form) are used.

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 analytical techniques 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 a drug, methods are used that are highly sensitive, allowing one to establish the minimum content of impurities.

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

When quantitatively determining a drug 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 the analysis with a large sample of the drug.

A measure of the sensitivity of a reaction is the detection limit. It means the lowest content at which, using this method, the presence of the analyte component can be detected with a given confidence probability. 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 factors such as 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 absorption indicator (specific or molar) established by the spectrophotometric method is increasingly being used. In chemical analysis, sensitivity is determined by the value of the detection limit of a given reaction. Physicochemical methods are distinguished by high sensitivity analysis.The most highly sensitive are radiochemical and mass spectral methods, allowing the determination of 10 -8 -10 -9% of the analyte, polarographic and fluorimetric 10 -6 -10 -9%; the sensitivity of spectrophotometric methods is 10 -3 -10 -6%, potentiometric 10 -2%.

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

Thus, 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 general error of measuring and leakage of ±0.04 ml, 20 ml of titrant is consumed for titration, then the relative error will be 0.2%. As the sample size and the number of milliliters of titrant decrease, 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 microburettes, the use of which significantly reduces errors from inaccurate measuring, leakage and the influence of temperature. An error is also allowed when taking a sample.

When performing analysis of a medicinal substance, weighing of the sample 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 the weighing accuracy is ±0.2 mg, the relative error will be equal to 0.4%. When analyzing dosage forms or performing express analysis, such accuracy when weighing is not required, so the sample is taken with an accuracy of ±(0.001-0.01) g, i.e. with a maximum 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 Errors possible during pharmaceutical analysis

When performing a quantitative determination by any chemical or physicochemical method, three groups of errors can be made: gross (misses), systematic (definite) and random (undetermined).

Gross errors are the result of a miscalculation by 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 a certain constant value. The cause of systematic errors in the analysis may be, for example, the hygroscopicity of the drug when weighing out its sample; imperfection of measuring and physical-chemical instruments; experience of the analyst, etc. Systematic errors can be partially eliminated by making corrections, calibrating the device, 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 caused by uncontrollable 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 determination results is expressed by absolute error and relative error.

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

The relative error of 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 (multiplying the resulting value by 100). Relative errors in determinations by physical and chemical methods include both the accuracy of preparatory operations (weighing, measuring, dissolving) and the accuracy of measurements on the device (instrumental error).

The values of relative errors depend on the method by which the analysis is performed and what the analyzed object is - an individual substance or a multicomponent mixture. Individual substances can be determined by analysis using a 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 approximately doubles. The combination of chromatography with other methods, in particular the use of chromato-optical and chromato-electrochemical 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 increase accuracy, the State Fund XI introduced 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, in pharmaceutical analysis, 3-6 parallel measurements are performed. 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 authenticity of medicinal substances

An 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). Tests are performed using 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 influence the pharmacological effect are confirmed. Chemical reactions used in pharmaceutical analysis are accompanied by the formation of colored compounds and 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 production of medicines. The material from which the equipment is made (metal, glass) can serve as a source of impurities of heavy metals and arsenic. If cleaning is poor, the preparations may contain impurities of solvents, fibers of fabrics or filter paper, sand, asbestos, etc., as well as residues of acids or alkalis.

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 substances, temperature, pressure, pH of the environment, 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 stages. In this case, the formation of side reaction products or decomposition products may occur, as well as processes of interaction of initial and intermediate synthesis products with the formation of substances from which it is then difficult to separate the final product. During the synthesis process, 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 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 crystal modifications, or polymorphism. About 65% of medicinal substances classified as 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 physicochemical properties (melting point, density, solubility) and pharmacological action, but have different values of free surface energy, and therefore, unequal resistance to the action of oxygen, light, and 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 temperature. The transformation of one polymorphic form into another occurs during storage, drying, and 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 production premises of chemical and pharmaceutical enterprises can have a great influence on the contamination of some drugs by impurities by others. In the work area of these premises, provided that one or more drugs (dosage forms) are received, all of them can be contained in the form of aerosols in the air. In this case, so-called “cross-contamination” occurs.

In 1976, the World Health Organization (WHO) developed special rules for organizing the production and quality control of medicines, which provide conditions for preventing “cross-contamination.”

Not only the technological process, but also storage conditions are important for the quality of drugs. The quality of drugs 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 nature of pharmacological action are formed. When storing crystalline hydrate preparations (sodium arsenate, copper sulfate, etc.), it is necessary, on the contrary, to observe conditions that prevent the loss of water of crystallization.

When storing and transporting drugs, it is necessary to take into account the effects of light and atmospheric oxygen. 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 to store medicines, as well as the material from which it is made, is of great importance. 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 raw materials or formed during the production process, and impurities acquired during storage or transportation, under the influence of various factors (heat, light, 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 drugs in such quantities that interfere with their use for specific purposes. In other words, the drug 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 have also been tested for the presence of heavy metal impurities. The importance of conducting such tests is due to the fact that when conducting studies 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. Their content in most cases significantly exceeds the established maximum permissible 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. According to the WHO Expert Committee, such trials should be carried out for medicinal products having single doses of at least 0.5 g.

1.5 General requirements for purity tests

Assessing the degree of purity of a drug is one of the important stages of pharmaceutical analysis. All drugs, regardless of the method of preparation, are tested for purity. At the same time, the content of impurities is determined. Their

8-09-2015, 20:00

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MINISTRY OF EDUCATION

STATE BUDGETARY EDUCATIONAL INSTITUTION OF HIGHER PROFESSIONAL EDUCATION "SIBERIAN

STATE MEDICAL UNIVERSITY" MINISTRY OF HEALTH AND SOCIAL DEVELOPMENT OF THE RF

Analysis of complex dosage forms

Part 1. Pharmaceutical dosage forms

Tutorial

For self-preparation and guidance for laboratory classes in pharmaceutical chemistry for full-time and part-time students of pharmaceutical faculties of universities

UDC 615.07 (071) BBK R 282 E 732

E.V. Ermilova, V.V. Dudko, T.V. Kadyrov Analysis of complex dosage forms Part 1. Dosage forms of pharmaceutical production: Uch. allowance. – Tomsk: Publishing house. 20012. – 169 p.

The manual contains methods for analyzing pharmaceutical dosage forms. It discusses terminologies, classifications of dosage forms, provides regulatory documents that control the quality of medicines produced by pharmaceutical manufacturers, and indicates the features of intrapharmacy express analysis; The main stages of analysis of dosage forms are described in detail, with special attention paid to chemical control.

The main part of the manual is devoted to the presentation of material on the analysis of dosage forms: liquid (potions, sterile) and solid (powders), numerous examples are given.

The appendix contains extracts from orders, refractometric tables, information on indicators, and forms of reporting journals.

For students of pharmaceutical faculties of higher educational institutions.

Table 21. Ill. 27. Bibliography: 18 titles.

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

I. INTRODUCTION TO DOSAGE FORM ANALYSIS

1.1. Terms used in pharmacy. . . . . . . . . . . . . . . . ………. 5 1.1.1. Terms characterizing medicines.. ….5 1.1.2. Terms characterizing dosage forms. . . ….5 1.2. Classification of dosage forms. . . . . . . . . . . . . . . . . . . . . . 7

1.3. Regulatory documents and requirements for the quality of pharmaceutical products. . . . . . . . . . . . . …...7 1.4. Features of express analysis of pharmaceutical drugs. . . . . . . . . . . . . . . . . . . . . . . . . . ……………8

1.4.1. Features of determining authenticity using the express method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ………..9

1.4.2. Features of quantitative express analysis. . . . . . . . …9

2.1. Organoleptic and physical control. . . . . . . . . . . . . . . . . . 10 2.1.1. Organoleptic control. . . . . . . . . . . . . . . . . . . . . . . . . . .10 2.1.2. Physical control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 2.2.Chemical control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 2.2.1.Authenticity tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 2.2.2.. Quantitative analysis. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 14

2.2.2.1. Methods of expressing concentrations. . . . . . . . . . . . . . . . .15 2.2.2.2. Methods of titrimetric analysis. . . . . . . . . . . . . . . 16 2.2.2.3. Calculation of the mass (volume) of the dosage form and the volume of the titrant for analysis. . . . . . . . . . . . . . . . . . . . . 17

2.2.2.4. Processing of measurement results. . . . . . . . . . . . . . . . . .19 2.2.2.5. Presentation of analysis results. . . . . . . . . . . . . . . . . . 32

III. ANALYSIS OF DOSAGE FORMS

Liquid dosage forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

3.1. Analysis of potions. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .33 3.2. Analysis of sterile dosage forms. . . . . . . . . . . . . . . . . . . . .59

Solid dosage forms

3.3. Powders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89

Self-training control issues. . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Test control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125

Test control answers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130

APPLICATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131

Bibliography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .168

Preface

The basis for writing the textbook was the program on pharmaceutical chemistry for students of pharmaceutical universities (faculties)

M.: GOU VUNMC, 2003.

One of the components of pharmaceutical analysis is the analysis of pharmaceutical and factory-produced medicines, carried out by methods of pharmacopoeial analysis, according to the requirements of various instructions,

manuals, instructions, etc.

The textbook is devoted to methods of researching dosage forms

(potions, sterile, powders) manufactured in a pharmacy, where all types of in-pharmacy control are used, but the most effective is chemical control, which makes it possible to check the compliance of the manufactured dosage form with the prescription, both in authenticity and in quantitative content. The presented methods for determining the authenticity and quantitative content are designed in such a way as to use optimal research methods, and a minimum amount of medicinal product is spent on analysis.

The main part provides numerous examples of the use of refractometry in the quantitative analysis of drugs, since this method is widely used in pharmacy practice.

The proposed textbook contributes to the development of chemical analytical thinking among students.

I. INTRODUCTION TO DOSAGE FORM ANALYSIS

1.1. Terms used in pharmacy

1.1.1. Terms characterizing medicines

Medicines – substances used for prophylaxis,

diagnosis, treatment of disease, prevention of pregnancy, obtained from

biological technologies.

Medicinal substance- a medicine that is an individual chemical compound or biological substance.

Medicine- medicine in the form of a certain

dosage form.

Dosage form- a condition given to a medicinal product or medicinal plant material that is convenient for use, in which the necessary therapeutic effect is achieved.

1.1.2. Terms characterizing dosage forms

Powders are a solid dosage form for internal and external use, consisting of one or more crushed substances and having the property of flowability.

Tablets are a dosage form obtained by pressing medicinal or a mixture of medicinal and auxiliary substances, intended for internal, external, sublingual,

implantation or parenteral use.

Capsules are a dosage form consisting of a drug enclosed in a shell.

Ointments are a soft dosage form intended for application to the skin, wounds or mucous membranes and consisting of a medicinal substance and a base.

Pastes - ointments with a powder content of over 20-25%.

Suppositories are dosed dosage forms that are solid at room temperature and melt at body temperature.

Solutions are a liquid dosage form obtained by dissolving one or more medicinal substances intended for injection, internal or external use.

Drops are a liquid dosage form intended for internal or external use, dosed in drops.

Suspensions are a liquid dosage form containing as a dispersed phase one or more crushed powdered medicinal substances distributed in a liquid dispersion medium.

Emulsions are a dosage form that is homogeneous in appearance,

consisting of mutually insoluble finely dispersed liquids,

intended for internal, external or parenteral use.

Extracts are concentrated extracts from medicinal plant materials. There are liquid extracts (Extracta fluida); thick extracts (Extracta spissa) – viscous masses with a moisture content of no more than 25%;

dry extracts (Extracta sicca) – loose masses with a moisture content of no more than

Infusions are a dosage form that is an aqueous extract from medicinal plant materials or an aqueous solution of dry or liquid extracts (concentrates).

Decoctions are infusions, differing in the extraction mode.

Aerosols are a dosage form in which medicinal and auxiliary substances are under the pressure of a propellant gas

(propellant) in an aerosol can, hermetically sealed with a valve.

1.2. Classification of dosage forms

The classification of dosage forms is carried out depending on:

1.2.1. Physical state Solid : powders, tablets, dragees, granules, etc.

Liquid: true and colloidal solutions, drops, suspensions, emulsions,

liniments, etc.

Soft: ointments, suppositories, pills, capsules, etc.

Gaseous: aerosols, gases.

1.2.2. Quantities of medicinal substances

One-component

Multicomponent

1.2.3. Places of manufacture

Zavodsky

Pharmacy

1.2.4. Manufacturing method

Injection solutions Medicines Eye drops Decoctions Infusions Aerosols Infusions

Homeopathic remedies, etc.

1.3. Regulatory documents and quality requirements

Pharmaceutical medicines

All production activities of a pharmacy should be aimed at ensuring high-quality production of medicines.

One of the most important factors determining the quality of medicines manufactured in a pharmacy is the organization of in-pharmacy control.

Intrapharmacy control is a set of measures aimed at timely detection and prevention of errors that occur during the manufacturing, registration and dispensing of drugs.

Pharmacy-produced medicines are subject to several types of control depending on the nature of the dosage form.

The system of in-pharmacy quality control of medicines provides for preventive measures, acceptance, organoleptic, written, survey, physical, chemical and dispensing control.

According to the instructions of the Ministry of Health of the Russian Federation “On quality control of medicines manufactured in pharmacies” (Order No. 214 of July 16, 1997), all medicines are subject to intrapharmacy control: organoleptic, written and control during dispensing - mandatory, survey and physical - selectively, and chemical - in accordance with paragraph 8 of this order (see appendix).

1.4. Features of express analysis of drugs

pharmaceutical production

The need for in-pharmacy control is due to the corresponding high quality requirements for medicines manufactured in pharmacies.

Since the production and dispensing of drugs in pharmacies is limited to short deadlines, their quality is assessed using express methods.

The main requirements for express analysis are the consumption of minimal quantities of drugs with sufficient accuracy and sensitivity, simplicity and speed of implementation, if possible without separating the ingredients, the ability to carry out analysis without removing the prepared drug.

If it is not possible to perform the analysis without separating the components, then use the same separation principles as for macro-analysis.

1.4.1. Features of determining authenticity using the express method

The main difference between determining the authenticity of the express method and macro-analysis is the use of small quantities of test mixtures without their separation.

The analysis is performed by the drop method in micro-test tubes, porcelain cups, on watch glasses, and from 0.001 to 0.01 g of powder or 1 5 drops of the test liquid is consumed.

To simplify the analysis, it is enough to carry out one reaction for a substance, the simplest one, for example, for atropine sulfate it is enough to confirm the presence of sulfate ion, for papaverine hydrochloride - chloride ion by classical methods.

1.4.2. Features of quantitative express analysis

Quantitative analysis can be performed by titrimetric or physicochemical methods.

Titrimetric express analysis differs from macro methods in the consumption of smaller quantities of the analyzed drugs: 0.05-0.1 g of powder or 0.5-2 ml of solution, and the exact mass of the powder can be weighed on a hand scale; to increase accuracy, you can use diluted titrant solutions: 0.01 0.02 mol/l.

A sample of the powder or a volume of the liquid dosage form is taken so that 1–3 ml of titrant solution is consumed for the determination.

Of the physicochemical methods in pharmacy practice, the economical method of refractometry is widely used in the analysis of concentrates,

semi-finished products and other dosage forms.

II. MAIN STAGES OF PHARMACEUTICAL ANALYSIS

2.1. Organoleptic and physical control

2.1.1. Organoleptic control

Organoleptic control consists of checking the dosage form for the following indicators: appearance (“Description”), smell,

homogeneity, absence of mechanical impurities. The taste is randomly tested, and all dosage forms prepared for children are tested.

Uniformity of powders, homeopathic triturations, ointments, pills,

suppositories are checked before dividing the mass into doses in accordance with the requirements of the current State Pharmacopoeia. The check is carried out randomly at each pharmacist during the working day, taking into account the types of dosage forms. The results of organoleptic control are recorded in a journal.

2.1.2. Physical control

Physical control consists of checking the total weight or volume of the dosage form, the number and weight of individual doses (at least three doses),

included in this dosage form.

This checks:

Each series of packaging or in-pharmacy preparation in an amount of at least three packages;

Dosage forms manufactured according to individual recipes (requirements), selectively during the working day, taking into account all types of dosage forms, but not less than 3% of the number of dosage forms manufactured per day;

Introduction

1.2 Errors possible during pharmaceutical analysis

1.3 General principles for testing the authenticity 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 Testing physical properties or measuring physical constants of medicinal substances

2.2 Setting the pH of the medium

2.3 Determination of transparency 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. Physico-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 radiation emission

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. Biological methods of analysis1

5.1 Biological quality control of medicinal products

5.2 Microbiological control of medicinal products

List of used literature

Introduction

Chapter 1. Basic principles of pharmaceutical analysis

1.1 Pharmaceutical analysis criteria

Physico-chemical or instrumental methods of analysis

Physico-chemical or instrumental methods of analysis are based on measuring, using instruments (instruments), the physical parameters of the analyzed system, which arise or change during the execution of the analytical reaction.

The rapid development of physicochemical methods of analysis was caused by the fact that classical methods of chemical analysis (gravimetry, titrimetry) could no longer satisfy the numerous demands of the chemical, pharmaceutical, metallurgical, semiconductor, nuclear and other industries, which required increasing the sensitivity of the methods to 10-8 - 10-9%, their selectivity and speed, which would make it possible to control technological processes based on chemical analysis data, as well as perform them automatically and remotely.

A number of modern physicochemical methods of analysis make it possible to simultaneously perform both qualitative and quantitative analysis of components in the same sample. The accuracy of analysis of modern physicochemical methods is comparable to the accuracy of classical methods, and in some, for example, in coulometry, it is significantly higher.

The disadvantages of some physicochemical methods include the high cost of the instruments used and the need to use standards. Therefore, classical methods of analysis have still not lost their importance and are used where there are no restrictions on the speed of analysis and high accuracy is required with a high content of the analyzed component.

Classification of physicochemical methods of analysis

The classification of physicochemical methods of analysis is based on the nature of the measured physical parameter of the analyzed system, the value of which is a function of the amount of substance. In accordance with this, all physicochemical methods are divided into three large groups:

Electrochemical;

Optical and spectral;

Chromatographic.

Electrochemical methods of analysis are based on measuring electrical parameters: current, voltage, equilibrium electrode potentials, electrical conductivity, amount of electricity, the values of which are proportional to the content of the substance in the analyzed object.

Optical and spectral methods of analysis are based on measuring parameters that characterize the effects of interaction of electromagnetic radiation with substances: the intensity of radiation of excited atoms, absorption of monochromatic radiation, the refractive index of light, the angle of rotation of the plane of a polarized beam of light, etc.

All these parameters are a function of the concentration of the substance in the analyzed object.

Chromatographic methods are methods for separating homogeneous multicomponent mixtures into individual components by sorption methods under dynamic conditions. Under these conditions, the components are distributed between two immiscible phases: mobile and stationary. The distribution of components is based on the difference in their distribution coefficients between the mobile and stationary phases, which leads to different rates of transfer of these components from the stationary to the mobile phase. After separation, the quantitative content of each component can be determined by various methods of analysis: classical or instrumental.

Molecular absorption spectral analysis

Molecular absorption spectral analysis includes spectrophotometric and photocolorimetric types of analysis.

Spectrophotometric analysis is based on determining the absorption spectrum or measuring light absorption at a strictly defined wavelength, which corresponds to the maximum of the absorption curve of the substance under study.

Photocolorimetric analysis is based on comparison of the color intensity of the studied colored solution and a standard colored solution of a certain concentration.

Molecules of a substance have a certain internal energy E, the components of which are:

The energy of motion of electrons Eel located in the electrostatic field of atomic nuclei;

The energy of vibration of atomic nuclei relative to each other E count;

Rotation energy of a molecule E vr

and is expressed mathematically as the sum of all the above energies:

Moreover, if a molecule of a substance absorbs radiation, then its initial energy E 0 increases by the amount of the energy of the absorbed photon, that is:

From the above equality it follows that the shorter the wavelength l, the greater the vibration frequency and, therefore, the greater E, that is, the energy imparted to the molecule of a substance when interacting with electromagnetic radiation. Therefore, the nature of the interaction of radiation energy with matter will be different depending on the wavelength of light l.

The set of all frequencies (wavelengths) of electromagnetic radiation is called the electromagnetic spectrum. The wavelength interval is divided into regions: ultraviolet (UV) approximately 10-380 nm, visible 380-750 nm, infrared (IR) 750-100000 nm.

The energy imparted to the molecule of a substance by radiation from the UV and visible parts of the spectrum is sufficient to cause a change in the electronic state of the molecule.

The energy of IR rays is less, so it is only sufficient to cause a change in the energy of vibrational and rotational transitions in the molecule of a substance. Thus, in different parts of the spectrum one can obtain different information about the state, properties and structure of substances.

Laws of radiation absorption

Spectrophotometric methods of analysis are based on two basic laws. The first of them is the Bouguer-Lambert law, the second law is Beer's law. The combined Bouguer-Lambert-Beer law has the following formulation:

The absorption of monochromatic light by a colored solution is directly proportional to the concentration of the light-absorbing substance and the thickness of the layer of solution through which it passes.

The Bouguer-Lambert-Beer law is the basic law of light absorption and underlies most photometric methods of analysis. Mathematically it is expressed by the equation:

Size lgI/I 0 is called the optical density of the absorbing substance and is designated by the letters D or A. Then the law can be written as follows:

The ratio of the intensity of the flux of monochromatic radiation passing through the test object to the intensity of the initial flux of radiation is called the transparency, or transmittance, of the solution and is denoted by the letter T: T = I/I 0

This ratio can be expressed as a percentage. The value T, which characterizes the transmission of a layer 1 cm thick, is called the transmittance. Optical density D and transmittance T are related to each other by the relation

D and T are the main quantities that characterize the absorption of a solution of a given substance with a certain concentration at a certain wavelength and thickness of the absorbing layer.

The dependence D(C) is linear, and T(C) or T(l) is exponential. This is strictly observed only for monochromatic radiation fluxes.

The value of the extinction coefficient K depends on the method of expressing the concentration of the substance in the solution and the thickness of the absorbing layer. If the concentration is expressed in moles per liter and the layer thickness is in centimeters, then it is called the molar extinction coefficient, denoted by the symbol e and is equal to the optical density of a solution with a concentration of 1 mol/l placed in a cuvette with a layer thickness of 1 cm.

The value of the molar light absorption coefficient depends on:

From the nature of the solute;

Wavelengths of monochromatic light;

Temperatures;

Nature of the solvent.

Reasons for non-compliance with the Bouguer-Lambert-Beer law.

1. The law was derived and is valid only for monochromatic light, therefore, insufficient monochromatization can cause a deviation of the law, and to a greater extent, the less monochromatic the light is.

2. Various processes can occur in solutions that change the concentration of the absorbing substance or its nature: hydrolysis, ionization, hydration, association, polymerization, complexation, etc.

3. Light absorption of solutions depends significantly on the pH of the solution. When the pH of the solution changes, the following may change:

The degree of ionization of a weak electrolyte;

The form of existence of ions, which leads to a change in light absorption;

Composition of the resulting colored complex compounds.

Therefore, the law is valid for highly dilute solutions, and its scope is limited.

Visual colorimetry

The color intensity of solutions can be measured by various methods. Among them, there are subjective (visual) colorimetric methods and objective, that is, photocolorimetric.

Visual methods are those in which the assessment of the color intensity of the test solution is made with the naked eye. In objective methods of colorimetric determination, photocells are used instead of direct observation to measure the color intensity of the test solution. The determination in this case is carried out in special devices - photocolorimeters, which is why the method is called photocolorimetric.

Visible colors:

Visual methods include:

- standard series method;

- method of colorimetric titration, or duplication;

- equalization method.

Standard series method. When performing analysis using the standard series method, the color intensity of the analyzed colored solution is compared with the colors of a series of specially prepared standard solutions (with the same layer thickness).

Colorimetric titration (duplication) method is based on comparing the color of the analyzed solution with the color of another solution - the control. The control solution contains all the components of the test solution, with the exception of the substance being determined, and all the reagents used in preparing the sample. A standard solution of the substance being determined is added to it from a burette. When so much of this solution is added that the color intensities of the control and analyzed solutions are equal, it is considered that the analyzed solution contains the same amount of the analyte as it was introduced into the control solution.

Adjustment method differs from the visual colorimetric methods described above, in which the similarity of the colors of the standard and test solutions is achieved by changing their concentration. In the equalization method, similarity of colors is achieved by changing the thickness of the layers of colored solutions. For this purpose, when determining the concentration of substances, drain and immersion colorimeters are used.

Advantages of visual methods of colorimetric analysis:

The determination technique is simple, there is no need for complex expensive equipment;

The observer's eye can evaluate not only the intensity, but also the shades of color of solutions.

Flaws:

It is necessary to prepare a standard solution or series of standard solutions;

It is impossible to compare the color intensity of a solution in the presence of other colored substances;

When comparing the color intensity of a person's eyes for a long time, a person gets tired and the determination error increases;

The human eye is not as sensitive to small changes in optical density as photovoltaic devices, making it impossible to detect differences in concentration up to about five relative percent.

Photoelectrocolorimetric methods

Photoelectrocolorimetry is used to measure the light absorption or transmittance of colored solutions. The instruments used for this purpose are called photoelectric colorimeters (PECs).

Photoelectric methods for measuring color intensity involve the use of photocells. Unlike instruments in which color comparisons are made visually, in photoelectrocolorimeters the receiver of light energy is a device - a photocell. This device converts light energy into electrical energy. Photocells allow colorimetric determinations not only in the visible, but also in the UV and IR regions of the spectrum. Measuring light fluxes using photoelectric photometers is more accurate and does not depend on the characteristics of the observer's eye. The use of photocells makes it possible to automate the determination of the concentration of substances in the chemical control of technological processes. As a result, photoelectric colorimetry is much more widely used in factory laboratory practice than visual colorimetry.

In Fig. Figure 1 shows the usual arrangement of nodes in instruments for measuring the transmission or absorption of solutions.

Fig. 1 Main components of devices for measuring radiation absorption: 1 - radiation source; 2 - monochromator; 3 - cuvettes for solutions; 4 - converter; 5 - signal indicator.

Photocolorimeters, depending on the number of photocells used in measurements, are divided into two groups: single-beam (single-arm) - devices with one photocell and double-beam (double-arm) - with two photocells.

The measurement accuracy obtained with single-beam FECs is low. In factory and scientific laboratories, photovoltaic installations equipped with two photocells are most widely used. The design of these devices is based on the principle of equalizing the intensity of two light beams using a variable slit diaphragm, that is, the principle of optical compensation of two light fluxes by changing the opening of the pupil of the diaphragm.

The schematic diagram of the device is shown in Fig. 2. Light from incandescent lamp 1 is divided into two parallel beams using mirrors 2. These light beams pass through light filters 3, cuvettes with solutions 4 and fall on photocells 6 and 6", which are connected to the galvanometer 8 according to a differential circuit. The slot diaphragm 5 changes the intensity of the light flux incident on the photocell 6. The photometric neutral wedge 7 serves to attenuate luminous flux incident on a 6" photocell.

Fig.2. Diagram of a two-beam photoelectrocolorimeter

Determination of concentration in photoelectrocolorimetry

To determine the concentration of analytes in photoelectrocolorimetry, the following is used:

A method for comparing the optical densities of standard and test colored solutions;

Determination method based on the average value of the molar light absorption coefficient;

Calibration curve method;

Additive method.

Method for comparing the optical densities of standard and test colored solutions

For determination, prepare a standard solution of the analyte of known concentration, which approaches the concentration of the test solution. Determine the optical density of this solution at a certain wavelength D this. Then the optical density of the test solution is determined D X at the same wavelength and at the same layer thickness. By comparing the optical densities of the test and reference solutions, the unknown concentration of the analyte is found.

The comparison method is applicable for single analyzes and requires mandatory compliance with the basic law of light absorption.

Calibration graph method. To determine the concentration of a substance using this method, prepare a series of 5-8 standard solutions of varying concentrations. When choosing the concentration range of standard solutions, the following principles are used:

* it must cover the area of possible measurements of the concentration of the solution under study;

* the optical density of the test solution should correspond approximately to the middle of the calibration curve;

* it is desirable that in this concentration range the basic law of light absorption is observed, that is, the dependence graph is linear;

* the optical density value must be within the range of 0.14... 1.3.

Measure the optical density of standard solutions and plot the dependence D(C) . Having determined D X of the solution under study, according to the calibration curve they find WITH X (Fig. 3).

This method makes it possible to determine the concentration of a substance even in cases where the basic law of light absorption is not observed. In this case, a large number of standard solutions are prepared, differing in concentration by no more than 10%.

Rice. 3. Dependence of the optical density of the solution on the concentration (calibration curve)

Additive Method- this is a type of comparison method based on comparing the optical density of the test solution and the same solution with the addition of a known amount of the substance being determined.

It is used to eliminate the interfering influence of foreign impurities and to determine small amounts of the analyte in the presence of large quantities of foreign substances. The method requires mandatory compliance with the basic law of light absorption.

Spectrophotometry

This is a photometric analysis method in which the content of a substance is determined by its absorption of monochromatic light in the visible, UV and IR regions of the spectrum. In spectrophotometry, unlike photometry, monochromatization is provided not by light filters, but by monochromators, which allow the wavelength to be continuously changed. Prisms or diffraction gratings are used as monochromators, which provide significantly higher monochromaticity of light than light filters, so the accuracy of spectrophotometric determinations is higher.

Spectrophotometric methods, compared to photocolorimetric methods, allow solving a wider range of problems:

* carry out quantitative determination of substances in a wide range of wavelengths (185-1100 nm);

* carry out quantitative analysis of multicomponent systems (simultaneous determination of several substances);

* determine the composition and stability constants of light-absorbing complex compounds;

* determine the photometric characteristics of light-absorbing compounds.

Unlike photometers, the monochromator in spectrophotometers is a prism or diffraction grating, which allows the wavelength to be continuously changed. There are instruments for measurements in the visible, UV and IR regions of the spectrum. The schematic diagram of the spectrophotometer is practically independent of the spectral region.

Spectrophotometers, like photometers, come in single-beam and double-beam types. In double-beam devices, the light flux is bifurcated in some way either inside the monochromator or at the exit from it: one flux then passes through the test solution, the other through the solvent.

Single-beam instruments are particularly useful for quantitative determinations based on absorbance measurements at a single wavelength. In this case, the simplicity of the device and ease of operation are a significant advantage. The greater speed and ease of measurement when working with dual-beam instruments are useful in qualitative analysis, when optical density must be measured over a large wavelength range to obtain a spectrum. In addition, a two-beam device can be easily adapted for automatic recording of continuously changing optical density: all modern recording spectrophotometers use a two-beam system for this purpose.

Both single and dual beam instruments are suitable for visible and UV measurements. Commercially produced IR spectrophotometers are always based on a dual-beam design, since they are usually used to scan and record a large region of the spectrum.

Quantitative analysis of single-component systems is carried out using the same methods as in photoelectrocolorimetry:

By comparing the optical densities of the standard and test solutions;

Determination method based on the average value of the molar light absorption coefficient;

Using the calibration graph method,

and has no distinctive features.

Spectrophotometry in qualitative analysis

Qualitative analysis in the ultraviolet part of the spectrum. Ultraviolet absorption spectra usually have two or three, sometimes five or more absorption bands. To unambiguously identify the substance under study, its absorption spectrum in various solvents is recorded and the data obtained are compared with the corresponding spectra of similar substances of known composition. If the absorption spectra of the substance under study in different solvents coincide with the spectrum of the known substance, then it is possible with a high degree of probability to draw a conclusion about the identity of the chemical composition of these compounds. To identify an unknown substance by its absorption spectrum, it is necessary to have a sufficient number of absorption spectra of organic and inorganic substances. There are atlases that show the absorption spectra of many, mainly organic, substances. The ultraviolet spectra of aromatic hydrocarbons have been especially well studied.

When identifying unknown compounds, attention should also be paid to the intensity of absorption. Many organic compounds have absorption bands whose maxima are located at the same wavelength l, but their intensities are different. For example, in the spectrum of phenol there is an absorption band at l = 255 nm, for which the molar absorption coefficient at the absorption maximum is e max= 1450. At the same wavelength, acetone has a band for which e max = 17.

Qualitative analysis in the visible part of the spectrum. Identification of a colored substance, such as a dye, can also be done by comparing its visible absorption spectrum with that of a similar dye. The absorption spectra of most dyes are described in special atlases and manuals. From the absorption spectrum of a dye, one can draw a conclusion about the purity of the dye, because in the spectrum of impurities there are a number of absorption bands that are absent in the spectrum of the dye. From the absorption spectrum of a mixture of dyes, one can also draw a conclusion about the composition of the mixture, especially if the spectra of the components of the mixture contain absorption bands located in different regions of the spectrum.

Qualitative analysis in the infrared region of the spectrum

Absorption of IR radiation is associated with an increase in the vibrational and rotational energies of the covalent bond if it leads to a change in the dipole moment of the molecule. This means that almost all molecules with covalent bonds are, to one degree or another, capable of absorption in the IR region.

The infrared spectra of polyatomic covalent compounds are usually very complex: they consist of many narrow absorption bands and are very different from conventional UV and visible spectra. The differences arise from the nature of the interaction between the absorbing molecules and their environment. This interaction (in condensed phases) affects the electronic transitions in the chromophore, so the absorption lines broaden and tend to merge into broad absorption bands. In the IR spectrum, on the contrary, the frequency and absorption coefficient corresponding to an individual bond usually change little with changes in the environment (including changes in the remaining parts of the molecule). The lines also expand, but not enough to merge into a stripe.

Typically, when constructing IR spectra, transmittance is plotted on the y-axis as a percentage rather than optical density. With this method of constructing, absorption bands appear as depressions in the curve, and not as maxima in the UV spectra.

The formation of infrared spectra is associated with the vibrational energy of molecules. Vibrations can be directed along the valence bond between the atoms of the molecule, in which case they are called valence. There are symmetric stretching vibrations, in which atoms vibrate in the same directions, and asymmetric stretching vibrations, in which atoms vibrate in opposite directions. If atomic vibrations occur with a change in the angle between bonds, they are called deformation. This division is very arbitrary, because during stretching vibrations, angles are deformed to one degree or another and vice versa. The energy of bending vibrations is usually less than the energy of stretching vibrations, and the absorption bands caused by bending vibrations are located in the region of longer waves.

The vibrations of all atoms of a molecule cause absorption bands that are individual to the molecules of a given substance. But among these vibrations one can distinguish vibrations of groups of atoms, which are weakly coupled with the vibrations of the atoms of the rest of the molecule. Absorption bands caused by such vibrations are called characteristic bands. They are observed, as a rule, in the spectra of all molecules that contain these groups of atoms. An example of characteristic bands are the bands at 2960 and 2870 cm -1. The first band is due to asymmetric stretching vibrations of the C-H bond in the CH 3 methyl group, and the second is due to symmetric stretching vibrations of the C-H bond of the same group. Such bands with a slight deviation (±10 cm -1) are observed in the spectra of all saturated hydrocarbons and, in general, in the spectrum of all molecules that contain CH 3 groups.

Other functional groups can influence the position of the characteristic band, and the frequency difference can be up to ±100 cm -1, but such cases are few in number and can be taken into account based on literature data.

Qualitative analysis in the infrared region of the spectrum is carried out in two ways.

1. Take a spectrum of an unknown substance in the region of 5000-500 cm -1 (2 - 20 μ) and look for a similar spectrum in special catalogs or tables. (or using computer databases)

2. In the spectrum of the substance under study, characteristic bands are looked for, from which one can judge the composition of the substance.

Research work "analysis of drugs". Methods for analyzing medicinal products Physicochemical methods for analyzing the composition of medicinal products

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