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

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.

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

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

In some private articles of the State Fund X it is recommended to determine the solidification temperature or boiling point (according to the State Fund XI - “temperature limits of distillation”) for a number of liquid drugs. The boiling point must be within the range given in the private article. A wider interval indicates the presence of impurities.

Many private articles of the State Fund X provide acceptable values ​​of density, and less often viscosity, confirming the authenticity and good quality of the drug.

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

Physical methods of analysis

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

The degree of whiteness (shade) of solid medicinal substances can be assessed by various instrumental methods based on the spectral characteristics of the light reflected from the sample. To do this, reflectance is measured when the sample is illuminated with white light. Reflectance is the ratio of the amount of reflected light flux to the amount of incident light flux. It allows you to determine the presence or absence of a color shade in medicinal substances by the degree of whiteness and degree of brightness. For white or white substances with a grayish tint, the degree of whiteness is theoretically equal to 1. Substances for which it is 0.95-1.00, and the degree of brightness< 0,85, имеют сероватый оттенок.

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

The constant characterizing the homogeneity of solids is the melting point. It is used in pharmaceutical analysis to determine the identity and purity of most solid drug substances. It is known to be the temperature at which a solid is in equilibrium with the liquid phase under a saturated vapor phase. The melting point is a constant value for an individual substance. The presence of even a small amount of impurities changes (as a rule, reduces) the melting point of the substance, which makes it possible to judge the degree of its purity. Melting temperature refers to the temperature range at which the melting process of the test drug occurs from the appearance of the first drops of liquid to the complete transition of the substance to the liquid state. Some organic compounds decompose when heated. This process occurs at the decomposition temperature and depends on a number of factors, in particular the heating rate. The given melting temperature intervals indicate that the interval between the beginning and end of melting of the medicinal substance should not exceed 2°C. If the transition of a substance from a solid to a liquid state is unclear, then instead of the melting temperature range, a temperature is set at which only the beginning or only the end of melting occurs. It should be taken into account that the accuracy of establishing the temperature range at which the test substance melts can be influenced by the sample preparation conditions, the rate of rise and the accuracy of temperature measurement, and the experience of the analyst.

Boiling point is the interval between the initial and final boiling temperatures at normal pressure of 760 mmHg. (101.3 kPa). The temperature at which the first 5 drops of liquid were distilled into the receiver is called the initial boiling point, and the temperature at which 95% of the liquid transferred to the receiver is called the final boiling point. The specified temperature limits can be set using the macromethod and the micromethod. It should be taken into account that the boiling point depends on atmospheric pressure. The boiling point is set only for a relatively small number of liquid drugs: cyclopropane, chloroethyl, ether, fluorothane, chloroform, trichlorethylene, ethanol.

When establishing density, take the mass of a substance of a certain volume. Density is determined using a pycnometer or hydrometer, strictly observing the temperature regime, since density depends on temperature. This is usually achieved by thermostatting the pycnometer at 20°C. Certain intervals of density values ​​confirm the authenticity of ethyl alcohol, glycerin, vaseline oil, petroleum jelly, solid paraffin, halogenated hydrocarbons (chloroethyl, fluorothane, chloroform), formaldehyde solution, ether for anesthesia, amyl nitrite, etc.

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

To assess the quality of liquid preparations that have a viscous consistency, for example glycerin, petroleum jelly, oils, relative viscosity is usually determined. It is the ratio of the viscosity of the liquid under study to the viscosity of water, taken as unity.

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

The method for determining solubility is based on the fact that a sample of a previously ground (if necessary) drug is added to a measured volume of solvent and continuously stirred for 10 minutes at (20±2)°C. A drug is considered dissolved if no particles of the substance are observed in the solution in transmitted light. If the drug requires more than 10 minutes to dissolve, then it is classified as slowly soluble. Their mixture with the solvent is heated in a water bath to 30°C and the completeness of dissolution is observed after cooling to (20±2)°C and vigorous shaking for 1-2 minutes.

The phase solubility method makes it possible to quantify the purity of a drug substance by accurately measuring solubility values. The essence of establishing phase solubility is the sequential addition of an increasing mass of the drug to a constant volume of solvent. To achieve a state of equilibrium, the mixture is subjected to prolonged shaking at a constant temperature, and then the content of dissolved drug substance is determined using diagrams, i.e. determine whether the test product is an individual substance or a mixture. The phase solubility method is objective and does not require expensive equipment or knowledge of the nature and structure of impurities. This allows it to be used for qualitative and quantitative analyses, as well as for studying stability and obtaining purified drug samples (up to a purity of 99.5%). An important advantage of the method is the ability to distinguish optical isomers and polymorphic forms of medicinal substances. The method is applicable to all types of compounds that form true solutions.

Physico-chemical methods

They are becoming increasingly important for the purposes of objective identification and quantification of medicinal substances. Non-destructive analysis (without destroying the analyzed object), which has become widespread in various industries, also plays an important role in pharmaceutical analysis. Many physicochemical methods are suitable for its implementation, in particular optical, NMR, PMR, UV and IR spectroscopy, etc.

In pharmaceutical analysis, physicochemical methods are most widely used, which can be classified into the following groups: optical methods; methods based on radiation absorption; methods based on radiation emission; methods based on the use of a magnetic field; electrochemical methods; separation methods; thermal methods.

Most of the listed methods (with the exception of optical, electrochemical and thermal) are widely used to determine the chemical structure of organic compounds.

Physicochemical methods of analysis have a number of advantages over classical chemical methods. They are based on the use of both physical and chemical properties of substances and in most cases are characterized by rapidity, selectivity, high sensitivity, and the possibility of unification and automation.

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 λ, 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 λ.

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:

or

The value log I /I 0 is called the optical density of the absorbing substance and is denoted 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 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 ε, 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;

Colorimetric titration or duplication method;

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).

The 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.

The equalization 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. The optical density of this solution is determined at a certain wavelength D fl. Then the optical density of the test solution D x is determined 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.

The optical density of standard solutions is measured and a graph of D(C) is plotted. Having determined D x of the solution under study, C x is found from the calibration graph (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)

The additive method 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-beam 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 λ, but their intensities are different. For example, in the spectrum of phenol there is an absorption band at λ = 255 nm, for which the molar absorption coefficient at the absorption maximum is ε max = 1450. At the same wavelength, acetone has a band for which ε 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.

Based on the absorption of X-ray radiation by atoms. Ultraviolet spectrophotometry is the simplest and most widely used absorption analysis method in pharmacy. It is used at all stages of pharmaceutical analysis of medicinal products (testing of authenticity, purity, quantitative determination). A large number of methods for qualitative and quantitative analysis have been developed...

Enveloping agents and analgesics are given, O2 is supplied to ensure adequate ventilation of the lungs, and the water-electrolyte balance is corrected. 7. Physico-chemical methods for the determination of phenol 7.1 Photocolorimetric determination of the mass fraction of phenols in purified industrial wastewater after the de-tarring plant phenol chemical toxic production 1. Purpose of the work. ...

In-pharmacy control, rules and terms of storage and dispensing of drugs. In-pharmacy control is carried out in accordance with Order of the Ministry of Health of the Russian Federation dated July 16, 1997 No. 214 “On quality control of medicines manufactured in pharmacies.” The order approved three documents (appendices to order 1, 2, 3): 1. “Instructions for quality control of medicines manufactured in pharmacies”...

Titles. Trade names under which JIC is registered or produced in the Russian Federation will also be given as the main synonym. 4 Methodological basis for the classification of medicines The number of drugs in the world is constantly increasing. More than 18,000 drug names are currently circulating on the pharmaceutical market in Russia, which is 2.5 times more than in 1992...

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

To establish the purity of medicinal substances, various physical, physicochemical, chemical methods of analysis or a combination thereof are used.

The Global Fund offers the following methods for drug quality control.

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

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

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

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

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

A wider interval indicates the presence of impurities.

Many private articles of the State Fund X provide acceptable values ​​of density, and less often viscosity, confirming the authenticity and good quality of the drug.

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

Purity criteria also include the color of the drug and/or the transparency of liquid dosage forms.

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

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

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

Biological methods. Biological methods for drug quality control are very diverse. These include tests for toxicity, sterility, and microbiological purity.

To carry out physico-chemical analysis of intermediate products, drug substances and finished dosage forms when checking their quality for compliance with the requirements of the Federal Law, the control and analytical laboratory must be equipped with the following minimum set of equipment and instruments:

IR spectrophotometer (to determine authenticity);

spectrophotometer for spectrometry in the visible and UV region (identification, quantitation, dosage uniformity, solubility);

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

chromatograph for high-performance liquid chromatography (HPLC) (identification, quantitation, determination of related impurities, dosage uniformity, solubility);

gas-liquid chromatograph (GLC) (impurity content, determination of dosage uniformity);

polarimeter (identification, quantification);

potentiometer (pH measurement, quantitative determination);

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

K. Fischer titrator (determination of water content);

derivatograph (determination of weight loss upon drying).

As is known, pharmacopoeial analysis aims to establish the authenticity, determine the purity and quantify the active substance or ingredients of a complex dosage form. Despite the fact that each of these stages of pharmacopoeial analysis solves its own specific problem, they cannot be considered in isolation. Thus, performing an authenticity reaction sometimes gives an answer to the presence or absence of a particular impurity. In the PAS-Na preparation, a qualitative reaction is carried out with a solution of iron (III) chloride (as a derivative of salicylic acid forms a violet-red color). But the appearance of a precipitate in this solution after three hours indicates the presence of an admixture of 5-aminosalicylic acid, which is not pharmacologically active. However, such examples are quite rare.

Determining some constants - melting point, density, specific absorption rate - allows one to simultaneously draw a conclusion about the authenticity and purity of a given substance. Since the methods for determining certain constants for various drugs are identical, we study them in general methods of analysis. You will need knowledge of the theoretical foundations and the ability to make determinations in the subsequent analysis of various groups of drugs.

Pharmacopoeial analysis is an integral part of pharmaceutical analysis and is a set of methods for studying medicines and dosage forms, set out in the State Pharmacopoeia and other ND (FS, FSP, GOST) and used to determine the authenticity, purity and quantitative analysis.

In quality control of medicines, physical, physico-chemical, chemical and biological methods of analysis are used. ND tests include several main stages:

description;

solubility;

authenticity;

physical constants (melting, boiling or distillation points, refractive index, specific rotation, density, spectral characteristics);

transparency and color of solutions;

acidity or alkalinity, solution pH;

determination of impurities;

weight loss upon drying;

sulfated ash;

quantitation.

Depending on the nature of the drug, some of these tests may be either absent or others included, such as acid value, iodine value, saponification value, etc.

A private pharmacopoeial monograph for any drug begins with a section "Description", which mainly characterizes the physical properties of a substance:

state of aggregation (solid, liquid, gas), if the substance is a solid, then the degree of its dispersion (fine-crystalline, coarse-crystalline), and the shape of the crystals (needle-shaped, cylindrical) are determined.

color of substance – an important indicator of authenticity and purity. Most drugs are colorless, that is, they are white. Coloring visually when determining the state of aggregation. A small amount of the substance is placed in a thin layer on a Petri dish or watch glass and viewed against a white background. In the State Fund X1 there is an article “Determination of the degree of whiteness of powdered drugs.” The determination is carried out using the instrumental method using special “Specol-10” photometers. It is based on the spectral characteristics of light reflected from a drug sample. They measure the so-called reflection coefficient– the ratio of the magnitude of the reflected light flux to the magnitude of the incident one. The measured reflectances make it possible to determine the presence or absence of a color or grayish tint in substances by calculating the degree of whiteness (α) and the degree of brightness (β). Since the appearance of shades or a change in color is, as a rule, a consequence of chemical processes - oxidation, reduction, even this initial stage of studying substances allows us to draw conclusions. This the method is excluded from the GF X11 edition.

Smell rarely determined immediately after opening the package at a distance of 4-6 cm. No smell after opening the package immediately according to the method: 1-2 g of the substance are evenly distributed on a watch glass with a diameter of 6-8 cm and after 2 minutes the smell is determined at a distance of 4-6 cm.

There may be instructions in the "Description" section on the possibility of changes in substances during storage. For example, in the calcium chloride preparation it is indicated that it is very hygroscopic and dissolves in air, and sodium iodide - in air it becomes damp and decomposes with the release of iodine; crystalline hydrates, in case of weathering or non-compliance with the conditions of crystallization in production, will no longer have the desired appearance or shape crystals, nor color.

Thus, the study of the appearance of a substance is the first, but very important stage in the analysis of substances, and it is necessary to be able to associate changes in appearance with possible chemical changes and draw the correct conclusion.

Solubility(GF XI, issue 1, p. 175, GF XII, issue 1, p. 92)

Solubility is an important indicator of the quality of a drug substance. As a rule, the RD contains a certain list of solvents that most fully characterizes this physical property so that in the future it can be used to assess the quality at one or another stage of the study of this medicinal substance. Thus, solubility in acids and alkalis is characteristic of amphoteric compounds (zinc oxide, sulfonamides), organic acids and bases (glutamic acid, acetylsalicylic acid, codeine). A change in solubility indicates the presence or appearance during storage of less soluble impurities, which characterizes a change in its quality.

In SP XI, solubility means not a physical constant, but a property expressed by approximate data and serving for the approximate characteristics of drugs.

Along with the melting point, the solubility of a substance at constant temperature and pressure is one of the parameters, according to which they establish authenticity and purity (good quality) of almost all medicines.

It is recommended to use solvents of different polarities (usually three); The use of low-boiling and flammable (diethyl ether) or very toxic (benzene, methylene chloride) solvents is not recommended.

Pharmacopoeia XI ed. accepted two ways to express solubility :

In parts (ratio of substance and solvent). For example, for sodium chloride according to the FS, the solubility in water is expressed in the ratio 1:3, which means that no more than 3 ml of water is needed to dissolve 1 g of the drug substance.

In conventional terms(GF XI, p. 176). For example, for sodium salicylate in the PS the solubility is given in conditional terms - “very easily soluble in water.” This means that to dissolve 1 g of a substance, up to 1 ml of water is needed.

Pharmacopoeia XII edition only in conditional (in terms of 1 g)

Conventional terms and their meanings are given in table. 1. (GF XI, issue 1, p. 176, GF XII, issue 1, p. 92).

Conventional solubility terms

Conditional terms	Abbreviations	Amount of solvent (ml), required for dissolution 1g substances
Very easily soluble
Easily soluble		More than 1 to 10
Let's dissolve
Moderately soluble
Slightly soluble		» 100 to 1000
Very slightly soluble		» 1000 to 10000
Practically insoluble

The conditional term corresponds to a certain range of solvent volumes (ml), within which complete dissolution of one gram of the drug substance should occur.

The dissolution process is carried out in solvents at temperature 20°С. In order to save the medicinal substance and solvent, the mass of the drug is weighed in such a way (with an accuracy of 0.01 g) that no more than 100 ml is spent to establish the solubility of water, and no more than 10-20 ml of organic solvents.

Medicinal substance (substance) considered soluble , if no particles of the substance are detected in the solution when observed in transmitted light.

Methodology . (1 way). A weighed mass of the drug, previously ground into a fine powder, is added to a measured volume of solvent corresponding to its minimum volume and shaken. Then, in accordance with table. 1, gradually add the solvent to its maximum volume and shake continuously for 10 minutes. After this time, no particles of the substance should be detectable in the solution with the naked eye. For example, weigh out 1 g of sodium benzoate, place it in a test tube with 1 ml of water, shake and gradually add 9 ml of water, because sodium benzoate is easily soluble in water (from 1 to 10 ml).

For slowly soluble medicines that require more than 10 minutes for complete dissolution, Heating in a water bath up to 30°C is allowed. Observation is carried out after cooling the solution to 20°C and vigorous shaking for 1-2 minutes. For example, caffeine is slowly soluble in water (1:60), codeine is slowly and slightly soluble in water (100-1000), calcium gluconate is slowly soluble in 50 parts of water, calcium lactate is slowly soluble in water, boric acid is slowly soluble in 7 parts .glycerin.

Method 2. Solubility, expressed in parts, shows the volume of solvent in ml required to dissolve 1 g of a substance.

Methodology. (2nd method) The mass of the drug weighed on a hand scale is dissolved in the specified ND volume of solvent. There should be no particles of undissolved substance in the solution.

Solubility in parts is indicated in pharmacopoeial monographs for the following drugs: boric acid(dissolve in 25 parts of water, 25 parts of alcohol, 4 parts of boiling water); potassium iodide(soluble in 0.75 parts of water, 12 parts of alcohol and 2.5 parts of glycerin); sodium bromide(soluble in 1.5 parts of water, 10 parts of alcohol); potassium bromide(soluble in 1.7 parts of water and mixed alcohol); potassium chloride and sodium chloride(r. in 3 hours of water).

In the case of testing, for example, sodium bromide, proceed as follows: weigh 1 g of sodium bromide on a hand scale, add 1.5 ml of water and shake until completely dissolved.

General pharmacopoeial monograph " Solubility » SP XII edition is supplemented with a description of methods for determining the solubility of substances with unknown and known solubility.

Melting point (T ° pl)

The melting point is a constant characterizing cleanliness substances and at the same time its authenticity. It is known from physics that the melting point is the temperature at which the solid phase of a substance is in equilibrium with the melt. The pure substance has a clear melting point. Since drugs may have a small amount of impurities, we will no longer see such a clear picture. In this case, the interval at which the substance melts is determined. Usually this interval lies within 2 ◦ C. A more extended interval indicates the presence of impurities within unacceptable limits.

According to the formulation of the State Fund X1 under melting point substances understand the temperature interval between the beginning of melting (the appearance of the first drop of liquid) and the end of melting (the complete transition of the substance to the liquid state).

If the substance has an unclear beginning or end of melting, determine temperature of just the beginning or end of melting. Sometimes a substance melts with decomposition, in this case it is determined decomposition temperature, that is, the temperature at which it occurs sudden change in substance(eg foaming).

Methods melting point determination

The choice of method is dictated two points:

stability of the substance when heated and

ability to be ground into powder.

According to the GF X1 edition, there are 4 ways to determine T ° pl:

Method 1 – for substances that can be ground into powder and are stable when heated

Method 1a – for substances that can be ground into powder, Not heat resistant

Methods 2 and 3 - for substances that do not triturate into powder

Methods 1, 1a and 2 involve the use of 2 devices:

PTP ( device for determining Tmel): familiar to you from the organic chemistry course, it allows you to determine the melting point of substances within from 20 ◦ From up to 360 ◦ WITH

A device consisting of a round-bottomed flask with a test tube sealed into it, into which is inserted a thermometer with an attached capillary containing the starting substance. The outer flask is filled to ¾ of the volume with coolant liquid:

water (allows you to determine Tmelt up to 80 ◦ C),

Vaseline oil or liquid silicones, concentrated sulfuric acid (allows you to determine Tmelt up to 260 ◦ C),

a mixture of sulfuric acid and potassium sulfate in a ratio of 7:3 (allows you to determine Tmel above 260 ◦ C)

The technique is general, regardless of the device.

Finely ground dry substance is placed in a medium-sized capillary (6-8 cm) and introduced into the device at a temperature 10 degrees lower than expected. Having adjusted the rate of temperature rise, the temperature range of changes in the substance in the capillary is recorded. At the same time, at least 2 determinations are carried out and the arithmetic average is taken.

Melting point is determined not only for pure substances, but also for their derivatives– oximes, hydrazones, bases and acids isolated from their salts.

Unlike GF XI in GF XII ed. melting temperature in the capillary method means not the interval between the beginning and end of melting, but end melting temperature , which is consistent with the European Pharmacopoeia.

Distillation temperature limits (T° kip.)

The GF value is defined as interval between the initial and final boiling points at normal pressure. (101.3 kPa – 760 mmHg). The interval is usually 2°.

Under initial Boiling point understand the temperature at which the first five drops of liquid distilled into the receiver.

Under the final– the temperature at which 95% of the liquid passes into the receiver.

A more extended interval than indicated in the corresponding FS indicates the presence of impurities.

The device for determining TPP consists of

a heat-resistant flask with a thermometer into which the liquid is placed,

refrigerator and

receiving flask (graduated cylinder).

Chamber of Commerce and Industry, observed experimentally lead to normal pressure according to the formula:

Tispr = Tnabl + K (r – r 1)

Where: p – normal barometric pressure (760 mm Hg)

р 1 – barometric pressure during the experiment

K – increase in boiling point per 1 mm of pressure

Thus, determining the temperature limits of distillation determine authenticity and purity ether, ethanol, chloroethyl, fluorothane.

GFS GF XII " Determination of temperature limits for distillation » supplemented with definition boiling points and in private FS recommends determining solidification or boiling point for liquid drugs.

Density(GF XI, issue 1, p. 24)

Density is the mass per unit volume of a substance. Expressed in g/cm3.

ρ = m/ V

If mass is measured in grams and volume in cm3, then density is the mass of 1 cm3 of a substance.

Density is determined using a pycnometer (up to 0.001). or hydrometer (measurement accuracy up to 0.01)

For the design of the devices, see the GF X1 edition.