Getting and physical properties of furacilin. Heterocyclic compounds Furacilin solution qualitative analysis

Date: 08.03.2020

Pyatigorsk Medical and Pharmaceutical InstituteDepartment of Pharmaceutical ChemistryCourse work On pharmaceutical chemistry on the topic: "Validation evaluation of methods for the qualitative and quantitative analysis of furacilin 0.002 with a solution of boric acid 2% 10ml." Executor: student of group 527 Mekhonoshin I.I.Supervisor:Makarova A.N.

Pyatigorsk, 2013

Content INTRODUCTION CHAPTER 1. General characteristics of furacilin ……… 1.1. General characteristics of furacilin. …… 1.2. Obtaining and physical properties of furacilin… .. 1.3. Furacilin identification methods… .. 1.4. Methods for the quantitative determination of furacilin…. 1.5. Pharmacological action, use in medicine and storage of furacilin medicinal products ....... CHAPTER 2. Development of methods for analysis of furacilin medicinal product with sodium chloride ... .. 2.1. Validation assessment of the methods of qualitative and quantitative analysis of the ingredients of the medicinal product according to the “Specificity” indicator ……… .. 2.2. Validation assessment of the method for quantitative determination of furatsilin by the indicator "Linearity" ……………. 2.3. Validation assessment of the method for quantitative determination of furacilin according to the indicator "Correctness" ……… .. 2.4. Validation evaluation of the method for quantitative determination of furacilin according to the "Precision" indicator …… ..

OUTPUT…………………………….

BIBLIOGRAPHY……………………

Introduction The first information about the synthetic production of furan substances appeared at the beginning of the 19th century, that is, at the dawn of organic chemistry as an independent science. However, only from the second half of the 19th century, from the time of the appearance and consolidation of the structural theory A.M.Butlerova and the establishment on its basis of the chemical structure of five-membered heterocycles, the necessary prerequisites were created for the isolation of the chemistry of furan compounds as derivatives of one of these parental cycles - furan. Historically, the first in the series of furan compounds was the synthesis in 1818 of pyroslucic acid during pyrogenetic decomposition of mucous acid. The resulting liquid by-product was not investigated, which delayed the discovery of furan by more than 50 years. This is followed by the accidental discovery of furfural Dobereiner in 1832, while trying to synthesize formic acid from starch and sugar by the action of sulfuric acid and manganese dioxide. Furfural was obtained again in 1840 by treating oat flour with sulfuric acid, and, in quantities sufficient for research, and Stanhouse managed to determine its most important properties and derive an empirical formula. By the same time (1845), the production of furfural from bran and the appearance of the name of this substance, which has survived to this day, appeared - furfural, which was supposed to express the source of its production and external signs (furfur - bran, oleum - oil). From this name, the now generally accepted name of the main heterocycle (furfuran, furan) and all its derivatives was subsequently derived. For 60 years, 5-nitrofuran derivatives have been used in medical practice and veterinary medicine to treat bacterial and some protozoal infections. The antimicrobial activity of this class of chemical compounds was first established in 1944. M. Dood, W. Stillman and immediately attracted the attention of doctors. Studies have shown that among the numerous derivatives of furan studied since the end of the 18th century, only compounds containing (NO 2 -group) strictly in the position of the 5th furan ring are characterized by antimicrobial properties. A number of different derivatives of 5-nitrofuran were proposed for use in medical practice in the 50-60s. Then, in connection with the introduction into clinical practice of a large number of highly effective chemotherapeutic drugs in other classes of chemical substances, which exceeded in the degree of activity of nitrofurans and had a number of advantages in pharmacokinetic and toxicological characteristics, interest in the drugs of this group decreased. Nevertheless, nitrofurans are still used in medical practice.

Chapter 1. General characteristics of furacilin.1.1. General characteristics of furacilin.

The basis of the chemical structure of drugs, derivatives of furan, is a five-membered oxygen-containing heterocycle. In medical practice, drugs are used derivatives of 5-nitrofurfural (furfural, 2-fu-rancarbaldehyde):

The drugs of this group include furacilin, furadonin, furazolidone, furagin. The drugs of this group were first obtained in England in the 1940s. when disposing of furfural. Furacilin, furadonin, furazolidone have been synthesized in our country. Medicines - derivatives of 5-nitrofurfural - antibacterial agents with a wide spectrum of action against gram-positive and gram-negative bacteria, some large viruses, Trichomonas, lamblia. Depending on the nature of the substituent, there are some differences in the spectrum of their antibacterial action. For example, furacilin affects gram-negative and gram-positive bacteria. Furazolidone is most effective against gram-negative bacteria, as well as Trichomonas and lamblia. Furadonin and furagin are most effective for urinary tract infections. The peculiarities of the action of drugs determine the indications for use and the methods of using individual drugs. The mechanism of antibacterial activity of drugs of furan derivatives is based on the violation of DNA and protein synthesis of microbial cells. When this - N0 2 -rpynna is reduced to the amino group -NH 2.

1.2. Getting and physical properties of furacilin. Furacilin (furacin, nitrofuran, nitrofurazone, 5-nitrofurfurylidene semicarbazone) C 6 H 6 O 4 N 4.

It is a yellow or greenish-yellow crystalline powder, odorless, bitter in taste. Melts at a temperature of 227-232 ° C with decomposition. Furacilin is very slightly soluble in water (1: 4200), slightly soluble in 95% alcohol, practically insoluble in ether, and soluble in alkalis. The solution is yellow or colorless. Aqueous solutions lose antimicrobial activity during long-term storage. The initial product for the synthesis of all preparations of the nitrofuran series is a very accessible substance, furfural, obtained from the waste of various agricultural products (corn cobs, sunflower husks). The production of furacilin is based on the nitration of furfural in a mixture of acetic anhydride and acetic acid. The resulting 5-nitrofurfurfural diacetate is hydrolyzed and the resulting 5-nitrofurfural is condensed with hydrochloric semicarbazide:

1.3. Furacilin identification methods. For authenticity testing, the IR spectra of nitrofuran derivatives are used. They are compressed in the form of tablets with potassium bromide and the spectra are recorded in the range of 1900-1700 cm -1. The IR spectra should completely coincide with the IR spectra of the GSO. The IR spectrum of furacilin has absorption bands at 971, 1020, 1205, 1250, 1587, 1784 cm -1. Chemical reactions used to identify furacilin. The authenticity of furacilin is established by a color reaction with an aqueous solution of sodium hydroxide. When using dilute alkali solutions, nitrofural forms an orange-red acisol: When furacilin is heated in solutions of alkali metal hydroxides, the furan cycle breaks down and forms sodium carbonate, hydrazine and ammonia. The latter is detected by a change in the color of the wet red litmus paper:

Typical color reactions, which make it possible to distinguish 5-nitrofuran derivatives from each other, give an alcoholic solution of potassium hydroxide in combination with acetone: nitrofural acquires a dark red color. Furacilin is also identified by the general formation reaction of 2,4-dinitrophenylhydrazone (melting point 273 ° C). It precipitates when a solution of the drug in dimethylformamide is boiled with a saturated solution of 2,4-dinitrophenylhydrazine and a 2 M solution of hydrochloric acid. A solution of nitrofural in dimethylformamide after adding a freshly prepared 1% sodium nitroprusside solution and 1 M sodium hydroxide solution gives a red color. Nitrofuran derivatives form colored insoluble complex compounds with salts of silver, copper, cobalt and other heavy metals in a slightly alkaline medium. When a 1% solution of copper (II) sulfate, a few drops of pyridine, and 3 ml of chloroform are added to the nitrofurantoin solution (in a mixture of dimethylformamide and water), the chloroform layer becomes green. Complex compounds of nitrofural and furazolidone under these conditions are not recovered by chloroform. Redox reactions (formation of a "silver mirror", with Fehling's reagent) can be performed after alkaline hydrolysis, accompanied by the formation of aldehydes. 1.4. Methods for the quantitative determination of furacilin. The quantitative determination of nitrofural exhibiting reducing properties is performed iodometric method based on oxidation with iodine in an alkaline medium (to improve solubility, sodium chloride is added to the sample and the mixture is heated). A titrated solution of iodine in an alkaline medium forms hypoiodite: Hypoiodite oxidizes nitrofural to 5-nitrofurfural:
After the end of the furacilin oxidation process, the solution is acidified and the released excess iodine is titrated with sodium thiosulfate:
A known method for the determination of nitrofural bromatometric method based on the oxidation of the hydrazine group in the presence of concentrated acids at a temperature of 80-90 ° C:
Furazidine-potassium is quantitatively determined acidimetrically by titrating with 0.01 M hydrochloric acid solution (bromothymol blue indicator). To authenticate and quantify nitrofural, use UV spectra its 0.0006% - solutions in a mixture of dimethylformamide with water (1:50). The absorption maxima of such a solution in the region of 245-450 nm are at 260 and 375 nm, and the minimum is at 306 nm. The maxima of the second absorption band (365-375 nm) are more specific to the 5-nitrofuran derivatives, since they are due to the presence of various electron-donor groups in position 2 of the furan ring. Quantitative spectrophotometric determination is performed at 375 nm and the content is calculated using a standard nitrofural sample. The solvent for UV spectrophotometric determination can be a 50% sulfuric acid solution, in which nitrofural has an absorption maximum at 227 nm. Also quantitative determination of nitrofural, you can carry out photocolorimetric method based on the use of color reactions with caustic alkali in various solvents. 1.5. Pharmacological action, use in medicine and storage of furacilin drugs. pharmachologic effect... It is an antibacterial substance that acts on various gram-positive and gram-negative bacteria (staphylococci, streptococci, dysentery bacillus, Escherichia coli, paratyphoid salmonella, the causative agent of gas gangrene, etc.) III degree, to prepare the granulating surface for skin transplants and for the secondary suture, irrigate the wound with an aqueous solution of furacilin and apply wet dressings; in case of osteomyelitis, after the operation, the cavity is washed with an aqueous solution of furacilin and a wet bandage is applied; with pleural empyema, pus is aspirated and the pleural cavity is washed, followed by the introduction of 20-100 ml of an aqueous solution of furacilin into the cavity. In case of anaerobic infection, in addition to the usual surgical intervention, the wound is treated with furacilin, in chronic purulent otitis media, an alcohol solution of furacilin is used in the form of drops. In addition, the drug is prescribed for boils of the external auditory canal and empyema of the paranasal sinuses; for washing the maxillary (maxillary) and other paranasal sinuses, an aqueous solution of furacilin is used; with conjunctivitis and scrofulous eye diseases, an aqueous solution of furacilin is instilled into the conjunctival sac; with blepharitis, the edges of the eyelids are lubricated with furacilin ointment, and inside for the treatment of bacterial dysentery. Forms of drug release:

Spray can.

Solution for external use 0.02% (water).

Solution for external use 0.066% (alcohol).

Tablets of 0.02 g for preparation of a solution for external use.
Tablets of 0.1 g for oral administration. Storage conditions... 5-nitrofuran derivatives are stored according to list B in a cool place in a well-sealed container. Protecting from light and moisture.

CHAPTER 2. Development of methods for the analysis of the drug furacilin with boric acid 2.1. Validation evaluation of the methods of qualitative and quantitative analysis of the ingredients of the medicinal product according to the "Specificity" indicator. The specificity of a technique should be understood as the ability to reliably determine an analyte in the presence of other sample components. To determine the specificity, we prepare 3 model mixtures: 1) both ingredients according to the recipe; 2) only the first ingredient according to the recipe; 3) only the second ingredient according to the recipe. Further, a validation assessment of the qualitative analysis of each of the ingredients of the drug was carried out in terms of the "specificity" indicator. To establish the specificity, one should make sure that there is no positive effect of the reaction on concomitant substances.

Furacilin qualitative analysis technique: To 0.5 ml of the test solution add 2 drops of sodium hydroxide solution - an orange-red color appears

Technique for the qualitative analysis of boric acid: Evaporate to dryness 5 drops of the drug, add 1 ml of alcohol 95% and ignite. The flame turns green.

In the model mixture No. 1, which contains both ingredients according to the recipe (furacilin and boric acid), using qualitative reactions, they prove the authenticity of each component of the drug. In the model mixture No. 2, containing only furacilin, using qualitative reactions to the second component (boric acid), the absence of an analytical effect in the first component was confirmed. In model mixture No. 3, containing only boric acid, qualitative reactions to the first component (furacilin) confirm the absence of an analytical effect in the second component. Thus, according to the studies carried out, the specificity of the methods for identifying furacilin and boric acid in the drug has been proven.

Method for the quantitative determination of furacilin:

Furacilin solution 0.02%, 1 ml of the test solution is introduced into a volumetric flask with a capacity of 50 ml, 20 ml of water, 5 ml of 1 M sodium hydroxide solution are poured, the volume of the solution is brought to the mark with water, stirred and through

The optical density of the solution (Ax) is measured for 20 minutes on a spectrophotometer at a wavelength of about 440 nm. The thickness of the solution layer in the cuvette is 10 mm, the reference solution is water.

In parallel, a similar determination of optical density is carried out using 1 ml of 0.02% (0.0002 g / ml) solution of PCO furacilin (Ast). The furacilin content (X) in percent is calculated by the formula

X =

Boric acid... To 0.5 ml of the drug add 3 ml of glycerin neutralized by phenolphthalein and titrate with shaking with 0.1 M sodium hydroxide solution until pink coloration

1 ml of 0.1 M sodium hydroxide solution corresponds to 0.006183 g of boric acid.

In the model mixture No. 1, which contains both ingredients according to the recipe (furacilin and boric acid), using quantitative reactions, we determine two components. In the model mixture No. 2, containing only furacilin, using quantitative reactions on the second component (boric acid), we prove the absence of the influence of the first component on the analysis In the model mixture No. 3, containing only boric acid, by means of a quantitative reaction to the first component (furacilin), the absence of the influence of the second component on the analysis was confirmed. Conclusion: We determined the validation score for the specificity indicator

2.2. Validation evaluation of the method for the quantitative determination of furacilin by the "Linearity" indicator. The linearity of the method is the presence of a direct proportional dependence of the analytical signal on the concentration or amount of the analyte in the analyzed sample. Linearity is expressed by the equation y = ax + b ... This equation is called linear regression. Parameter b of the calibration function characterizes the segment cut off on the ordinate axis and corresponding to the value of the blank experiment, and the coefficient a characterizes the slope of the calibration curve and is a reflection of the sensitivity of the technique. If during the control experiment, the titrant is not consumed, then the calibration graph takes the form of a straight line coming out of the origin and having a slope equal to 1. The main characteristic of linearity is the correlation coefficient, a measure of the relationship of the measured phenomena. The correlation coefficient (denoted by "r") is calculated using a special formula:

For analytical purposes, you can only use the technique for which the dependence of the function on the argument is correlated with the coefficient r, which should be ≥ 0.99.

To check the linearity, 5 experimental points were taken. Accurate weighed portions of furacilin (0.02 g) were used, placed in a volumetric flask with a capacity of 100 ml, dissolved in 10 ml of dimethylformamide, cooled, the volume of the solution was adjusted to the mark with water, and solutions were prepared from them so that the concentration of furacilin in solutions was 0.0004 %, 0.0003%, 0.0004%, 0.0005%, 0.0006%. The optical density of each solution was measured on a spectrophotometer at a wavelength of 375 nm in a cuvette with a layer thickness of 10 mm. Purified water was used as a reference solution. Table 1 - The results of measuring the optical density.

Vml
C %

Furacilin concentration in solution%

The data obtained were used to construct a calibration graph of the dependence of optical density on concentration.

Figure 1- Calibration graph of the dependence of optical density on the concentration of furacilin. The obtained data were used to calculate the linearity equation coefficient and the correlation coefficient. y = 606 x + 0,0046 r = 0,9863 Conclusion: For this sample, the value of the correlation coefficient was 0.9963. This allows us to assert that there is a linear dependence of optical density on concentration.

2.3. Validation evaluation of the method for the quantitative determination of furacilin and boric acid according to the "Correctness" indicator. Right analytical technique is the degree of closeness of the experimental results to the true value in the entire measurement area. The main factor determining correctness is the bias value. To determine the correctness, we prepare 3 samples: - the first (low concentration) - the second (medium concentration) - the third (high concentration) Solution A1. Accurate weighed portions of furacilin (0.01 g) and boric acid (1.0 g) were placed in a volumetric flask with a capacity of 100 ml, dissolved in 30 ml of water when heated, and after cooling, brought to the mark with water. Solution A2. Accurate weighed portions of furacilin (0.02 g) and boric acid (2.0 g) were placed in a volumetric flask with a capacity of 100 ml, dissolved in 30 ml of water when heated, and after cooling, brought to the mark with water. Solution A 3. Accurate weighed portions of furacilin (0.03 g) and boric acid (3.0) were placed in a volumetric flask with a capacity of 100 ml, dissolved in 30 ml of water when heated, and after cooling, brought to the mark with water. Then, three parallel determinations of each model sample were carried out. To evaluate the results obtained, the simplest and most obvious criterion is openability (R), which is calculated by the formula:

R = × 100%; Statistical processing of the analysis results is presented in table 2. .

Table 2- The results of establishing the method of quantitative determination by the indicator "correctness"

		Found, g



2 (medium)
2 (medium)
2 (medium)
3 (top)
3 (top)
3 (top)

SD = = = 0.92;

T = = 2,14.

GFXI tabular coefficient = 2.306. Since the Student's experimental criterion = 2.14 ˂ of the table, the method is correct and does not contain systematic errors.

2.4. Validation evaluation of the method for the quantitative determination of furacilin by the indicator "Precision" Precision(reproducibility) is a characteristic of random scattering. It is essentially a measure of the sum of random errors. When establishing precision, it should be borne in mind that this characteristic is of 3 levels: - repeatability (convergence); - intermediate precision (within laboratory reproducibility); - interlaboratory reproducibility. For pharmaceutical analysis purposes, only the first level is sufficient. When establishing repeatability, at least 6 parallel determinations are carried out, then the standard deviation (SD) and relative deviation (RSD) are calculated. It should be noted that not a single regulatory document establishes the lower limit of precision and it is determined by the used analysis method: SD = ; RSD = × 100%. Quantitative determination method. To determine the precision, we prepare a model solution of furacilin with boric acid No. 2. To do this, they took exact weights of furacilin (0.02 g) and boric acid (0.9 g), placed in a volumetric flask with a capacity of 100 ml, dissolved in 30 ml of water when heated, and after cooling, brought it to the mark with water. Three parallel titrations were carried out at three concentration levels (9 determinations). Definition # 1. Three parallel titrations were carried out, measuring 1 ml of LP each time. Definition number 2. Three parallel titrations were carried out, measuring 2 ml of LP each time. Definition number 3. Three parallel titrations were carried out, measuring 3 ml of LP each time. The calculation of the boric acid content (g) is carried out according to the following formula:; We enter all the data obtained in table No. 3. Table 3- The results of establishing the method of quantitative determination by the indicator "precision".

State University of Medicine and Pharmacy

them. N. Testemitanu

PHARMACEUTICAL FACULTY

CHAIR

PHARMACEUTICAL AND TOXICOLOGICAL CHEMISTRY

Furan derivatives

^ Methodical instruction for IV year students

CHISINAU 2011

Introduction
Currently, heterocyclic compounds account for more than half of the medicinal substances used in medicine.

These substances include medicinal substances derived from furan:

Some nitrofuran derivatives have antimicrobial activity and are used to treat infectious diseases.
Target: To be able to analyze the quality of medicinal substances, derivatives of furan in relation to the chemical structure that determines their production, methods of analysis, storage and use.
Target tasks

On the basis of literature data and analytical normative documentation (IDA), learn how to analyze medicinal substances of the studied groups by comparative assessment of physical, physicochemical and chemical properties.
To be able to determine the quality of medicinal substances of the topic under study in accordance with the requirements of the AED, with the preparation of the necessary documentation.

Topic study plan

One lesson is devoted to the study of the topic.
Form of classes

Independent preparation for the implementation of target tasks;
Practical laboratory work;
Final control.

Information material

Derivatives of 5-nitrofuran

In medical practice, 5-nitrofuran derivatives are used (table 1) with the general formula:

Table 1

5-Nitrofuran Derivatives

Description, solubility

Nitrofuralum

Nitrofuralul (Furacilină)

5-nitrofurfural semicarbazone

Flavourless yellow or greenish-yellow fine crystalline powder.

We will dissolve very little in water, we will slightly dissolve in 95% alcohol, we will dissolve in alkalis.

M r =198,14.

Nitrofurantoinum

Nitrofurantoină (Furadonină)

N- (5-nitro-2-furfuralidene) -1-aminohydantoin

Flavourless yellow or orange-yellow fine crystalline powder.

We will dissolve very little in water, we will slightly dissolve in 95% alcohol, we will slightly dissolve in acetone.

M r =256,18.

Furazolidonum

Furazolidonă

N- (5-nitro-2-furfuralidene) -3-aminooxazolidone-2

Flavourless yellow or greenish-yellow fine crystalline powder.

Practically insoluble in water and ether, very little soluble in 95% alcohol.

M r =225,16.

Physicochemical properties

Nitrofuran derivatives are yellow crystalline substances with greenish or orange hues, odorless. They are very slightly soluble or practically insoluble in water and ethanol, and slightly soluble in dimethylformamide.

Nitrofural (furacilin) exhibits acidic properties (imide group) in solutions and dissolves in alkalis better than other drugs.

For authentication and quantitative determination, UV spectra are used in various solvents (ethanol, dimethylformamide, etc.).

Chemical properties and methods of analysis

Derivatives of 5-nitrofuran are acidic substances: nitrofural (furacilin) and nitrofurantoin (furadonin) - NH-acids, furazolidone - CH-acid. The nitro group as a strong electron acceptor enhances their acidic properties. In nitrofural, they are due to the mobile hydrogen atom of the imide group. And in nitrofurantoin - ketoenol and lactim-lactam tautomerism in the hydantoin core.

The authenticity of preparations derived from 5-nitrofuran is established by a color reaction with an aqueous solution of sodium hydroxide. When interacting with dilute alkali solutions without heating, salts are formed without destruction of the furan cycle:

nitrofural (furacilin) orange-red staining
Nitrofurantoin (furadonin) in dilute alkali solutions at room temperature forms a dark red salt as a result of tautomeric transformations of the hydantoin residue:

nitrofurantoin (furadonin) dark red coloration
A solution of furazolidone under the same conditions, but when heated, acquires a red-brown color due to the rupture of the lactone cycle and the formation of salt:

furazolidone red-brown staining
Furazolidone and nitrofurantoin (furadonin) can be distinguished from each other by the different colors of the products of the interaction of drug solutions with alcoholic solutions of alkalis in a medium of non-aqueous solvents of the basic nature (dimethylformamide - DPA) (tables 2, 3).
table 2

^ Results of the reaction with a water-alcohol solution of potassium hydroxide

in a non-aquatic environment

^ Medicinal substance	Results of interaction with
^ Medicinal substance	solvent - DPA	DPA and water-alcohol KOH solution
Nitrofurantoin (furadonin)	yellow coloration	brownish yellow coloration
Furazolidone	yellow coloration	purple coloration, and on tube walls blue
Nitrofural (furacilin)	purple coloration	purple-red staining on the walls of the test tube

Table 3

^ Results of the interaction of 5-nitrofuran derivatives with an alcoholic solution of potassium hydroxide in combination with acetone

The quantitative determination of 5-nitrofuran derivatives can be carried out by a photocolorimetric method based on the use of color reactions of drugs with alkali solutions.

Nitrofuran derivatives form colored insoluble compounds with heavy metal salts (AgNO 3, CuSO 4, CoCl 2, etc.). In particular, nitrofural (furacilin) with silver ions forms an abundant reddish precipitate:

red sediment
Hydrolytic degradation. Under severe exposure to alkali solutions, all derivatives of 5-nitrofuran break the furan cycle. Other transformations are individual for each drug, depending on the nature of the substituent. For example, when nitrofural (furacilin) is heated in an alkali solution, hydrazine, sodium carbonate and ammonia are formed, which is detected by the blue discoloration of wet red litmus paper:

Formation of hydrazones. All 5-nitrofuran derivatives react with phenylhydrazine or 2,4-nitrophenylhydrazine to give the corresponding hydrazones, which can be identified by their melting point. So, when boiling solutions of drugs in dimethylformamide with a saturated solution of 2,4-dinitrophenylhydrazine and a 2 mol / L solution of hydrochloric acid, a precipitate is formed with a melting point of 273 0 С:

nitrofurantoin

5-nitro-2-furfurylidine-phenylhydrazone 1-aminohydantoin
Redox properties. As a result of alkaline hydrolysis of derivatives of the 5-nitrofuran group, an aldehyde (5-nitrofurfural) is formed on which characteristic redox reactions can be carried out ("silver mirror", with Fehling's reagent).

The hydrolysis product of nitrofural (furacilin) is also hydrazine, an energetic reducing agent:

quantitation

The reducing properties of nitrofural are used for its quantitative determination by the iodometric method in an alkaline medium (to improve solubility, sodium chloride is added to the sample and the mixture is heated). A titrated iodine solution in an alkaline medium forms hypoioditis:

Hypoioditis oxidizes nitrofural to 5-nitrofurfural:

After the end of the nitrofural oxidation process, the solution is acidified and the liberated excess of iodine is titrated with sodium thiosulfate:

Nitrofurantoin and furazolidone, which exhibit weak basic properties, are quantitatively determined by non-aqueous titration in dimethylformamide. Titrate with 0.1 M sodium methoxide solution (indicator thymol blue).

The quantitative determination of nitrofural, nitrofurantoin and furazolidone can be carried out by a photocolorimetric method based on the use of color reactions with caustic alkali in various solvents.
^ Mechanism of action and use of 5-nitrofuran derivatives
The mechanism of action of 5-nitrofuran derivatives is the simultaneous blockade of several enzyme systems of the microbial cell. Nitrofurans are quite well absorbed from the gastrointestinal tract; their bioavailability ranges from 50 to 90-95%.
Nitrofural (furacillin) – locally, externally. Outwardly, in the form of aqueous 0.02% (1: 5000) or alcoholic 0.066% (1: 1500) solutions - irrigate wounds and apply wet bandages.
Nitrofurantoin (furadonin)- with bacterial infections of the urinary tract (pyelitis, pyelonephritis , cystitis, urethritis), prevention of infections during urological operations or examination (cystoscopy, catheterization, etc.).
Furazolidone - dysentery, paratyphoid fever, giardiasis, foodborne toxicoinfections; Trichomonas colpitis, urethritis; infected wounds and burns.

Furazolidone is not used in the treatment of children under 1 month of age.
Benzofuran derivatives

B
benzofuran underlies the chemical structure of amiodarone and griseofulvin (Table 4).

furan benzofuran
In addition to the benzofuran nucleus, the amiodarone molecule contains a phenyl radical with two iodine atoms and two aliphatic chains. The basis of the chemical structure of griseofulvin is the grisan heterocyclic system:

grisan

Tabela 4

Medicinal substances, benzofuran derivatives

Latin, Romanian and chemical names. Structural formula

Description, solubility

Amiodaronum

A
miodaron (Cordaronum)
--ketone hydrochloride

White or almost white crystalline powder.

T. pl. 159-163 0 C

^ Griseofulvinum Griseofulvină

7-chloro-2 ", 4,6-trimethoxy-6" -methylgrisen-2 "-dione-3,4"

White or white with a creamy shade, the smallest crystalline powder with a weak specific odor.

Practically insoluble in water, slightly soluble in alcohol, acetone, readily soluble in dimethylformamide and methylene chloride.

T. pl. 218-224 0 C.

from +355 0 to +366 0 in terms of dry matter (1% solution in dimethylformamide)

M r =352,76

To determine the authenticity of amiodarone and griseofulvin, IR spectroscopy and UV spectrophotometry are used, as well as TLC and HPLC methods.

The identification of drugs is carried out using chemical methods, so a solution of griseofulvin in concentrated sulfuric acid under the action of potassium dichromate acquires a red color.

The presence of chloride ion is determined in amiodarone.

The quantitative determination of amiodarone is performed by the neutralization method. The weighed portion is dissolved in a mixture of ethanol and a 0.01 M solution of hydrochloric acid. Titration is carried out by potentiometric method using 0.1 M sodium hydroxide solution. The volume of titrant used for titration is set on a potentiometric curve between two inflection points.

The quantitative determination of amiodarone and griseofulvin can be performed by HPLC. Spectrophotometric method in anhydrous ethanol can determine the quantitative content of griseofulvin. Other methods have also been developed.
^ Mechanism of action and use of benzofuran derivatives

Amiodarone, unlike many antiarrhythmic drugs, has a dual mechanism of action at the same time: antiarrhythmic and antianginal effects.

Amiodarone is used internally for chronic heart ischemia with angina pectoris syndrome and heart rhythm disturbances in the form of 0.2 g tablets or a 5% solution is injected intravenously.

The mechanism of action of griseofulvin is not fully disclosed. The characteristic morphological changes caused by griseofulvin (twisting, increased branching and curvature of the hyphae), apparently, are due to a violation of the synthesis of the cell wall. In accordance with modern concepts, the antifungal effect of the drug is associated with the suppression of DNA replications and the subsequent suppression of cell division in dermatophytes.

Griseofulvin, which is a fungicidal agent, is prescribed orally in tablets of 0.125 g or externally in the form of 2.5% liniment (suspension) for the treatment of patients with dermatomycosis caused by pathogenic fungi.

^ Self-study questions for students

General characteristics of heterocyclic compounds. Principles of classification.
Historical and biochemical preconditions for the creation of drugs, derivatives of heterocyclic compounds.
Methods of obtaining medicinal substances, derivatives of 5-nitrofuran.
Physical and chemical (acid-base, redox, etc.) properties of 5-nitrofuran derivatives.
Methods for the analysis of medicinal substances: nitrofural (furacilin), nitrofurantoin (furadonin) and furazolidone.
Methods for the analysis of medicinal substances: amiodarone and griseofulvin.
Mechanisms of action of derivatives of 5-nitrofuran and benzofuran.
Storage conditions and use of medicinal substances derived from 5-nitrofuran.

^ Practical laboratory work
Exercise 1 . Conduct a comparative assessment of the quality of medicinal substances according to the indicators: "Description" and "Solubility".

Arrange the data in the form of a table and give an opinion on the conformity of the quality according to these indicators.

Note: Solvents are used in accordance with the requirements of the AED.

Task 2. Carry out the reaction of interaction of 5-nitrofuran derivatives with heavy metal salts.

Methodology... 0.05 g of the drug is dissolved in 8 ml of 0.1 mol / L sodium hydroxide solution (the reaction of the medium should be neutral), poured into 3 test tubes and add 2-3 drops of solutions of copper sulfate (1st tube), cobalt chloride ( 2nd tube) and silver nitrate (3rd tube).

The results obtained are presented in the form of a table:

Task 3. Determine the authenticity of drugs of the 5-nitrofuran group.

Nitrofural (Furacilin)

3.1.A . The UV spectrum of a solution of the preparation prepared for quantitative determination in the region from 245 nm to 450 nm has absorption maxima at 260 nm ± 2 nm and an absorption minimum at 360 nm ± 2 nm.

3.1.B. 0.01 g of the drug is dissolved in a mixture of 5 ml of water and 5 ml of sodium hydroxide solution; an orange-red color appears. When the resulting solution is heated, ammonia is released, which is detected by the smell or by the blue discoloration of wet red litmus paper introduced into the vapor of a boiling liquid.

^ 3.2. Nitrofurantoin (Furadonin)

3.2.A. The UV spectrum of the solution of the preparation prepared for quantitative determination in the region of 220 nm and 400 nm has two absorption maxima, at 266 nm and 367 nm.

should be between 1.36 and 1.42.

3.2.V. 0.01 g of the drug is dissolved in a mixture of 5 ml of water and 5 ml of 30% sodium hydroxide solution; a dark red color appears.

3.2 C. 0.01 g of the drug is dissolved in 3 ml of pre-distilled dimethylformamide; a yellow color appears, which, after the addition of two drops of 1 mol / L sodium hydroxide solution in 50% alcohol, turns brownish yellow.
3.3. Furazolidone

3.3 A. 0.05 g of the drug is mixed with 20 ml of water and 5 ml of 30% sodium hydroxide solution and heated; a brown color appears.

3.3.V. 0.01 g of the drug is dissolved in 3 ml of pre-distilled dimethylformamide; a yellow color appears. Add two drops of 1 mol / L sodium hydroxide solution in 50% alcohol. A violet color appears, but on the walls of the test tube moistened with this solution, the color of the solution is blue. 1 ml of the solution is diluted with water to 10 ml; a yellow color appears. After adding a few drops of 1 mol / L potassium hydroxide solution in 50% alcohol, the color of the solution does not change.
3.4. Griseofulvin

3.4.A. 1 A drop of a 1% solution of the drug in acetone is applied to filter paper and dried. When it is irradiated with a mercury-quartz lamp, a bluish-lilac glow is observed.

3.4.V. 5 mg of the drug is dissolved in 1 ml of concentrated sulfuric acid and 5 mg of potassium dichromate is added; the solution turns dark red.

Task 4. Conduct a quantitative determination of drugs.
^ 4.1. Nitrofural (furacilin)

4.1.A. Iodometric determination. About 0.1 g of the preparation (accurately weighed) is placed in a volumetric flask with a capacity of 500 ml, 4 g of sodium chloride, 300 ml of water are added and dissolved by heating to 70-80 ° C in a water bath. The cooled solution is brought to the mark with water and stirred (solution A). To 5 ml of 0.01 mol / l iodine solution placed in a 50 ml flask, add 0.1 ml of sodium hydroxide solution and 5 ml of solution A. After 1-2 minutes, add 2 ml of diluted sulfuric acid to the solution and titrate the released iodine from a microburette 0.01 mol / l sodium thiosulfate solution (indicator - starch).

A control experiment is carried out in parallel.

1 ml of 0.01 mol / l iodine solution corresponds to 0.0004954 g of C 6 H 6 N 4 O 4, which should be at least 97.5% in the preparation.

4.1.V. Photocolorimetric determination. About 0.02 g of the preparation (accurately weighed) is dissolved in 70-80 ml in a 100 ml volumetric flask when heated in a water bath at 70-80 0 C. After cooling, the volume is brought up to the mark with water.

To 0.5 ml of the resulting solution are added 7.5 ml of water, 2 ml of 0.1 mol / l sodium hydroxide solution and stirred. After 20 minutes, measure the optical density of the resulting solution (A x) on a photocolorimeter at a wavelength of about 450 nm (blue filter) in a cuvette with a layer thickness of 3 mm. In parallel, a reaction is carried out with 0.5 ml of a 0.02% standard solution of furacilin and the optical density (A c t) is measured.

4.1 C. Spectrophotometric determination. About 0.75 g of the drug (accurately weighed) is placed in a volumetric flask with a capacity of 250 ml, dissolved in 30 ml of dimethylformamide. Bring the volume of the solution to the mark with water and mix. 5 ml of the resulting solution is placed in a 250 ml volumetric flask. Bring the volume of the solution to the mark with water and mix. The optical density of the resulting solution is measured on a spectrophotometer at a wavelength of 375 nm in a cuvette with a layer thickness of 10 mm.

Water is used as a control solution.

In parallel, the absorbance of a standard nitrofural sample is measured.

where A, A st- optical density of the investigated and standard solutions, respectively;

a, a st - weighed amount of the preparation and the standard, respectively, g;

4.2.A. Photocolorimetric determination. About 0.1 g of the drug (accurately weighed) is placed in a volumetric flask with a capacity of 100 ml, add about 50 ml of water and 2.5 ml of 1 mol / L sodium hydroxide solution, dissolve with stirring, bring the volume of the solution to the mark with water and mix well. 0.6 ml of the resulting solution is placed in a volumetric flask with a capacity of 100 ml, the volume of the solution is brought to the mark with water, and exactly 20 minutes after the addition of 1 mol / L sodium hydroxide solution, the optical density of the resulting solution is determined on a photoelectric colorimeter in a cuvette with a layer thickness 1 cm and a violet filter with a wavelength of about 360 nm. Water is used as a control solution.

- specific absorption (specific absorption index) of the standard sample, determined under the same conditions;

4.2.V. Non-aqueous titration . About 0.4 g of the preparation (accurately weighed) is dissolved in a mixture of 10 ml of dimethylformamide and 10 ml of dioxane. Add 0.1 ml of indicator (thymol blue solution) in dimethylformamide and titrate with 0.1 mol / L lithium (sodium) methoxide solution until it becomes green.

1 ml of 0.1 mol / l lithium (sodium) methoxide solution corresponds to 0.02382 g of C 8 H 6 N 4 O 5 (nitrofurantoin), which should be at least 99% and not more than 101.0% in the preparation.

4.2 C. Spectrophotometric determination. About 0.120 g of the drug (accurately weighed) is placed in a volumetric flask with a capacity of 1000 ml, dissolved in 50 ml of dimethylformamide. Bring the volume of the solution to the mark with water. 5 ml of the resulting solution is placed in a 100 ml volumetric flask. Make up the volume to the mark with a solution containing 1.8% sodium acetate and 0.14% anhydrous acetic acid. The optical density of the resulting solution is measured at a wavelength of 367 nm.

As a control solution, the sodium acetate solution indicated above is used.

where A Is the optical density of the test solution;

765 - specific absorption (specific absorption index) (A 1 cm 1%) of a standard sample of nitrofurantoin;

a- weight of the drug in grams.

4.3.A. Photocolorimetric determination. About 0.1 g of the drug (accurately weighed) is placed in a volumetric flask with a capacity of 50 ml, add 30 ml of dimethylformamide. After dissolution of the drug, add 2 ml of 0.05 mol / L alcoholic solution of potassium hydroxide, stir, cool to 20 ° C, bring the volume of the solution to the mark with dimethylformamide and mix. 0.6 ml of the resulting solution is placed in a volumetric flask with a capacity of 100 ml, the volume of the solution is brought to the mark with water and exactly 20 minutes later, counting from the moment of adding 0.05 mol / L of an alcoholic solution of potassium hydroxide, the optical density of the resulting solution is measured on a photoelectric colorimeter in a cuvette with a layer thickness of 0.5 cm and a violet filter with a wavelength of about 360 nm.

Water is used as a control solution.

- specific absorption index of a standard sample of furazolidone, determined under the same conditions;

a- weight of the drug in grams.

4.4. Griseofulvin

4.4.A. About 0.1 g of the drug (accurately weighed) is dissolved in absolute alcohol in a 200 ml volumetric flask, the volume of the solution is brought to the mark with absolute alcohol and mixed.

2 ml of the resulting solution is transferred into a flask with a capacity of 100 ml, the volume of the solution is brought to the mark with absolute alcohol, mixed and the optical density is determined on a spectrophotometer at a wavelength of 291 nm in a cuvette with a layer thickness of 1 cm.

For griseofulvin at a wavelength of 291 nm - 686.

The content of С 17 Н 17 СlO 6 in terms of dry matter is not less than 97.0%.
Note. The results obtained for tasks 1-4 are presented in the table:

^ Names of medicinal substances in Latin, Romanian; chemical name; structural formula; description; (for analytes)	^ Determination of the authenticity of medicinal substances: methodology (reaction conditions, analytical effect); chemistry of reactions (for analytes)	^ Quantitation: methodology, chemistry of reactions for chemical methods of analysis or the main provisions of the method for physicochemical methods of analysis; formula for calculating the quantitative content of the active substance; quality assessment of the analyte based on the results obtained

Final control

Testing theoretical knowledge on self-study and final assignments.
Checking students on the implementation of practical work.

Final tasks

Write structural formulas, Latin, Romanian and chemical names of medicinal substances, derivatives of 5-nitrofuran.
Describe the physical and chemical properties of 5-nitrofuran derivatives. The importance of these properties in assessing their quality.
Give the general scheme for the preparation of 5-nitrofuran derivatives. What is the purpose of acetylation or formation of oximes before nitration of furfural?
Indicate the amino derivatives condensable with 5-nitrofurfural in the synthesis of medicinal substances 5-nitrofuran derivatives.
Write down the structural formulas of nitrofuran, nitrofuratoin and furazolidone. Indicate common functional groups in their structure.
Indicate the structural fragments causing the color of 5-nitrofuran derivatives.
Give the chemical properties of 5-nitrofuran derivatives underlying the reactions with alkalis and heavy metal salts.
Indicate what chemical properties underlie the iodometric method for the quantitative determination of nitrofural (furacilin). Calculate the equivalence factor for nitrofural.
Calculate the volume of 0.01 mol / L sodium thiosulfate solution consumed to titrate an excess of 0.01 mol / L iodine solution according to the method described in section 4.1.A. for the quantitative determination of nitrofural. If the sample of the drug is 0.1081 g, the percentage of the drug is 99.8%.
When quantifying furadonin by AED (p. 4.2.A), it was found that A = 0.466; A 1cm 1% = 750; a = 0.1017 g. Establish whether the content (%) of furadonin meets the requirements of the AED?

Literature

Lecture notes.
Babilev F.V. Chimie farmaceutică, Chişinău: Universitas, 1994. - 675 p.
Farmacopea română. Ediţia X-a –Bucureşti: Editura medicală, 1993.-1315 p.
Matcovschi C., Safta V. Ghid farmacoterapeutic. - Ch .: “Vector V-N” SRL, (F.E.-P. “Tipografia centrală”), 2010. - 1296 p.
Belikov V.G. Pharmaceutical Chemistry.- M .: MEDpress-inform, 2007. - 624 p.
Vartanyan R.S. Synthesis of essential drugs. - M.: MIA, 2004 .-- 844 p.
State Pharmacopoeia of the USSR: Vol. 1, XI ed., - M .: Medicine, 1987 .-- 336 p.
State Pharmacopoeia of the USSR: Vol. 2, XI ed., - M .: Medicine, 1989. - 400 p.
Mashkovsky M.D. Medicines. - 15th ed., - M .: Publishing house LLC

New Wave ", 2005. - 1200 p.

A guide to laboratory studies in pharmaceutical chemistry. Ed. Arzamastseva A.P. - M .: Medicine, 2001 .-- 384 p.
Pharmaceutical chemistry. Ed. Arzamastseva A.P. - M .: GEOTAR-Media, 2006 .-- 640 p.

Equipment and reagents on the topic "Medicinal substances, derivatives of furan"
Medicinal substances:

Nitrofuralul (Furacilină)
Nitrofurantoină (Furadonină)
Furazolidonă
Amiodaron (Cordaronum)
Griseofulvină

Reagents:

Sulfuric acid solution
Concentrated sulfuric acid
Sodium hydroxide solution
30% sodium hydroxide solution
Dimethylformamide
Potassium dichromate
1 mol / L sodium hydroxide solution in 50% alcohol
1 mol / L solution of potassium hydroxide in 50% alcohol
0.1 mol / L lithium (sodium) methoxide solution
0.05 mol / L alcoholic solution of potassium hydroxide
Copper (II) sulfate solution
Silver nitrate solution
Cobalt chloride solution
50% alcohol
0.1 mol / L sodium hydroxide solution
1 mol / L sodium hydroxide solution
0.01 mol / L sodium thiosulfate solution
Acetone
Sodium chloride
0.01 mol / l iodine solution
Starch solution
Dioxan
A mixture of 1.8% sodium acetate and 0.14% anhydrous acetic acid
Absolute alcohol

Crockery and utensils:

Spectrophotometer
Volumetric flask, 50 ml
Volumetric flask, 100 ml
Volumetric flask 200 ml
Volumetric flask, 500 ml
Red litmus paper
Microburette
Mercury quartz lamp
Water bath
Glass pencils
Test tubes
Filter paper

In the nitrofural molecule, the nitrogen of the imine group has basic properties and is involved in complexation reactions with heavy metal cations.

As a result of the shift of the electron density to carbonyl oxygen, nitrofural exhibits the properties of a weak NH-acid.

Nitrofural is characterized by prototropic tautometry:

Quality control

Determination of authenticity. Determination of the authenticity of furacilin is carried out by spectrometric methods.

Identification by IR spectroscopy consists in comparing the obtained spectrum with the spectrum of a working standard furacilin sample.

The absorption of a furacilin solution obtained by dissolving a weighed portion of the substance in DMF has two maxima: at 260 and 375 nm. The ratio of absorbance measured at 375 nm to absorbance measured at 260 nm is 1.15 to 1.30.

The determination of the authenticity by the ratio of the absorption of the solution at two wavelengths A 375 / A 260 allows the test to be carried out without a standard sample.

A standard nitrofural sample is required for authenticity determination by thin layer silica gel chromatography. 10 mg of nitrofural and 10 mg of its standard sample are dissolved in 10 ml of methanol. A mixture of methanol and nitromethane (10:90 V / V) is used as a mobile phase, and a solution of phenylhydrazine hydrochloride is used as a developer. The main spot of the analyte in size, position and color intensity should coincide with the results of TLC determination for the nitrofural standard.

The authenticity of nitrofural is also determined by a chemical method. For this, about 1 mg of the substance is dissolved in 1 ml of dimethylformamide. An alcoholic solution of KOH is added to the resulting solution, a red-violet color appears. It can be assumed that, like aliphatic nitro compounds, potassium nitronate is formed in solution:

The interaction of furan derivatives with concentrated alkalis leads to rupture of the furan cycle and side chain with the formation of various decomposition products: formaldehyde with a characteristic pungent odor and ammonia, which gives a blue discoloration of wet litmus paper.

The reaction of hydrolytic cleavage of furacilin in an alkaline medium:

Unofficial reaction: the formation of crystals of 2,4-dinitrophenylhydrazone-5-nitrofurfural (Tm 273 ° C) as a result of boiling the drug solution in a DMF solution with a saturated solution of 2,4-dinitrophenylhydrazine and a 2 mol / L solution of hydrochloric acid. 1st stage:

Complexation reactions are characteristic of nitrofural. In a solution of the substance in dimethylformamide, when pyridine and a solution of copper salt CuSO 4 are added, a colored coordination compound is formed:

Purity tests. The pH value of the furacilin solution is monitored. To do this, 1.0 g of the substance is dissolved in 100 ml of water (freed from carbon dioxide), shaken and filtered. The pH of the filtrate is 5.0-7.0.

The impurities of related substances are controlled by liquid chromatography. These include, for example:

Sulphated ash - no more than 0.1% per 1.0 g.

In a purity test, the weight loss on drying is determined. The mass of the substance should not decrease by more than 0.5% for a sample of 1 g when dried in an oven at 105 ° C.

Quantitation. The quantitative determination of nitrofural is carried out in a place protected from bright light. Dissolve 60 mg of the substance in dimethylformamide and dilute the resulting solution with water to 500 ml. A 5 ml aliquot is diluted to 100 ml with water. A solution of a standard sample of nitrofural is prepared in the same way. Take electronic spectra of both solutions and measure the absorbance at a wavelength of 375 nm. Calculate the content of nitrofural in the substance according to the formula:

where Cx and Cst- concentration, Ax and Ast- light absorption of solutions of the analyte and the standard sample.

Laboratory work

Theme: Furacilin analysis in tablets. ...

Purpose of work: Learn to analyze some indicators

furacilin tablets according to DFU.

Name: Furacilin tablets 0.02 g

Tabulettae Furacilini 0.02

Composition for one tablet: Furacilin 0.02 g

Sodium chloride 0.8 g

Main active ingredient: Furacilin Nitrofuralum

5- nitrofurfural semicarbazone

C6H6N4O4 M. m. 198.14

1. Description

Tablets are yellow or greenish-yellow in color.

2. Average weight of tablets and deviation of individual tablets from average weight.

A glass or polymer weighing bottle of known weight is taken and the average weight of the tablets is set by weighing 20 tablets together with an accuracy of 0.001 g and calculated by the formula:

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where: https://pandia.ru/text/80/224/images/image006_51.gif "width =" 20 "height =" 27 src = "> is the average weight of tablets, g.

Format the results in the form of a table:

	mi		Δ mi, %

Deviation in the mass of individual tablets for tablets weighing 0.3 g and more is allowed within ± 5% of the average weight of the tablets.

Only two tablets can have deviations from the average weight, exceeding the indicated limits, but not more than twice.

3. Authenticity

Theoretical part

Being a derivative of 5-natrofuran, furacilin forms an orange-red acisol with an aqueous solution of sodium hydroxide.

When heated in a sodium hydroxide solution, the furan cycle breaks down and sodium carbonate, hydrazine and ammonia are formed. The presence of ammonia is detected by a discoloration of the wet litmus paper.

Nitrogen "href =" / text / category / azot / "rel =" bookmark "> nitric acid and 0.5 cm3 of argentum nitrate solution, a white curdled precipitate is formed.

3. Quantification

Theoretical basis

To determine the content of medicinal substances in tablets, a certain mass of powder of crushed tablets should be taken. To obtain an average sample, it is necessary to grind at least 20 tablets and take an exact sample from this mixture.

The quantitative determination of furacilin in the preparation is performed by the iodometric method based on the oxidation of the preparation with iodine in an alkaline medium. Previously, to improve the solubility of the drug, the mixture is heated. A titrated iodine solution in an alkaline medium forms hypoiodide:

Hypoiodide oxidizes furacilin to 5-nitrofurfural:

At the end of the oxidation process, the solution is acidified and the liberated excess of iodine is titrated with sodium thiosulfate:

Analysis progress.

About 0.8 g (accurately weighed) of the powder of crushed tablets is placed in a volumetric flask with a capacity of 100 cm3, 70 cm3 of water is added and dissolved in a water bath at 70 - 80 ° C until a clear solution is obtained.

The solution is cooled and made up to the mark with water and mixed.

In a conical flask with a capacity of 50 cm3, 5 cm5 of iodine solution with a molar equivalent concentration of 0.01 mol / dm3 is placed, 0.1 cm3 of NaOH solution and 5 cm3 of the prepared solution of the drug are added.

After 1-2 minutes, 2 cm3 of diluted sulfuric acid is added to the solution and the released iodine is titrated from the microburette with a sodium thiosulfate solution with a molar equivalent concentration of 0.01 mol / dm3 in the presence of a starch indicator.

Calculations

where is the volume of iodine solution added to the solution, cm3;

Sodium thiosulfate solution used for titration, cm3;

VTO – volume of a volumetric flask in which the preparation is diluted, cm3

V1 – an aliquot of the drug solution, cm3;

m Is the mass of the preparation taken for analysis, g.

0,0004954 – mass of С6Н6N4O4, in grams, which corresponds to 1 cm3 of iodine solution with an equivalent molar concentration of 0.01 mol / dm3;

The mass of the main substance in one tablet should be 0.018 - 0.022 g, calculate it by the formula:

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5. H2SO4 diluted.

6. A solution of iodine with a molar equivalent concentration of 0.01 mol / dm3.

7. A solution of Na2S2O3 with a molar equivalent concentration of 0.01 mol / dm3.

8. Conical flasks, 50 cm3.

9. Volumetric flasks per 100 cm3

10. Pipettes, 1.2 and 5 cm3.

11. Microburette.

Preparation of solutions for analyzes:

1. Sodium hydroxide solution. Dissolve 100 g of sodium hydroxide in water and dilute with water to 1. The solution is allowed to settle and the clear liquid is drained. Store in bottles with rubber stoppers.

2. HNO3 diluted. Mix 1 part of nitric acid and 1 part of water.

3. AgNO3 solution. Dissolve 20 g of argentum nitrate in water and dilute to 1 with water.

4. H2 SO4 divorced. Concentrated sulfuric acid - 1 part, water - 5 parts. Measure the water into a porcelain or glass vessel and add acid to it little by little with stirring. The content of H2SO4 is 15.5 - 16.5%.

3. Starch solution. 1 g of starch is ground in a mortar with 5 ml of water until a homogeneous slurry is obtained and the mixture is slowly poured into 100 ml of boiling water with constant stirring. Boil for 2-3 minutes until a slightly opalescent liquid is obtained. The shelf life of the solution is 2-3 days.

Self-study questions(in writing)

1. Give the formula of 5-nitrofuran, a derivative of which is furacilin. What class of organic substances does this compound belong to?

2. In what other dosage forms is furacilin used?

Literature:

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0,02% - 200,0

Characteristics of the finished product

Furacilin solution 0.02% with sodium chloride 0.9% is sterile.

Composition

Furacilin 0.2 g

Sodium chloride 0.2 g

Water for injection up to 1 l

Transparent yellow liquid, pH = 5.2-6.8 odorless.

The drug for sterility and the absence of mechanical impurities must meet the requirements specified in Art. GF XI, no. 2, p. 140.

The drug is produced in 200 and 400 ml bottles in bottles for blood and blood substitutes, sealed with rubber stoppers 25P, IR-21 for rolling with aluminum caps.

The drug is stored at room temperature (not higher than 25 ° C) in a place protected from light. Expiration date 1 month.

They are used in neurosurgical operations, for the treatment of wounds and cavities after operations, for purulent processes, instillations of the bladder, etc.

Authenticity

1. Add 2-3 drops of sodium hydroxide to 0.5 ml of solution. A bright red color appears.

5-nitrofurfural semicarbazone

2. To 0.5 ml of solution add 2-3 drops of diluted nitric acid and silver nitrate solution. A white curdled precipitate is formed, soluble in ammonia solution (chlorides).

3. A graphite stick is moistened with a solution and brought into a colorless flame. The flame turns yellow (sodium).

quantitation

Method: IODOMETRY, in alkaline medium, back titration, E = 1/4 M.m.

Place 2 ml of 0.01 N iodine solution in a 50 ml flask with a ground stopper, add 2 drops of sodium hydroxide solution (until iodine is discolored), 2 ml (0.02%) or 5 ml (0.01%) of the analyzed solution, close with a stopper, mix and leave for 2 minutes in a dark place.

Then add 2 ml of diluted sulfuric acid and the released iodine is titrated from a microburette with 0.01 N sodium thiosulfate (indicator is starch). A control experiment is carried out in parallel. 1 ml of 0.01 N iodine solution corresponds to 0.0004954 g of furacilin.

Determination of pH

The determination is carried out using a pH meter or RIFAN indicator paper.

Protocol No. 3

Aseptic unit. Organization of work in aseptic conditions.

Asepsis includes a number of successive measures that complement each other, and a mistake made in one link of this series negates all the work done and subsequent work.

1. Preseptic (gateway) - designed to prepare personnel for work.

2. Aseptic - is intended for the preparation of dosage forms.

3. Hardware - it is equipped with autoclaves, sterilizers, devices that allow receiving water for injection.

Requirements for the premises. The production of medicines under aseptic conditions is carried out in "clean" rooms, in which the air purity is standardized by the content of microbial and mechanical particles.

The aseptic unit is usually located away from sources of contamination with microorganisms (patient service room, washing, filling, sanitary unit).

In rooms for the preparation of medicines under aseptic conditions, the walls should be painted with oil paint or lined with light tiles, and there should be no protrusions, cornices, cracks. The ceilings are painted with glue or water-based paint. The floors are covered with linoleum or rails with compulsory welding of seams. Doors and windows must fit tightly and have no gaps.

The aseptic unit is equipped with supply and exhaust ventilation with a predominance of air supply over the exhaust. To reduce microbial contamination, it is recommended to install air purifiers that provide effective air purification by filtration through ultrafine fiber filters and ultraviolet radiation.

For air disinfection in the aseptic unit, unshielded bactericidal irradiators are installed: wall-mounted BN-150), ceiling (OBP-300), mobile beacon type BPE-450); bactericidal lamps BUV-25, BUV-30, BUV-60 based on a power of 2-2.5 W per 1 m 3 of the room volume, which are switched on for 1-2 hours before starting work in the absence of people. Switch: I of these irradiators should be located in front of the entrance to the room, interlocked with a light board "Do not enter, the bactericidal irradiator is on". The entrance to the room where the unshielded germicidal lamp is turned on is allowed only after it has been turned off, a long stay in the specified room - only 15 minutes after the unshielded germicidal lamp is turned off.

In the presence of personnel, shielded bactericidal irradiators can be operated, which are installed at a height of 1.8-2 m, at the rate of 1 W per 1 m 3 of the room, provided that directed radiation to people in the room is excluded.

Since ultraviolet irradiators form toxic products (ozone and nitrogen oxides) in the air, ventilation must be turned on during their operation.

All equipment and furniture brought into the aseptic unit are pretreated with napkins moistened with a disinfectant solution (1% chloramine B solution, 0.75% chloramine B solution with 0.5% detergent, 3% hydrogen peroxide solution with 0.5% detergent funds). Storing unused equipment in the aseptic unit is strictly prohibited. The aseptic unit is cleaned at least once a shift using disinfectants.

General cleaning of the aseptic unit is carried out once a week. At the same time, the premises are, if possible, freed from equipment, walls, doors, floors are washed and disinfected. After disinfection, it is irradiated with ultraviolet light.

Before entering the aseptic unit, there should be rubber mats, which are moistened with a disinfectant solution once per shift. The aseptic unit is separated from other premises of the pharmacy by air locks.

Personnel requirements . Individuals involved in the preparation of medicines under aseptic conditions must observe strict rules of personal hygiene. When entering the gateway, they must put on special shoes, wash their hands with soap and a brush, put on a sterile gown, a 4-layer gauze bandage, a hat (while carefully removing the hair), shoe covers. The best is the use of a helmet and overalls. The gauze bandage should be changed every 4 hours. After putting on sterile technological clothing, the personnel should rinse their hands with water for injection and treat them with a disinfectant solution of ethyl alcohol 80%, a solution of chlorhexidine bigluconate in 70% ethyl alcohol or a 0.5% solution of chloramine B (in the absence of other substances). It is prohibited to enter from the airlock to the room for preparation and packaging of medicines under aseptic conditions in non-sterile sanitary clothes. It is also forbidden to go outside the aseptic unit wearing sterile sanitary clothing.

Sanitary clothes, gowns, gauze, textile products, cotton wool are sterilized in bixes in steam sterilizers at a temperature of 132 ° C for 20 minutes or at 120 ° C for 45 minutes and stored in closed boxes for no more than 3 days. Shoes are disinfected outside and stored in airlocks before and after work. Persons with infectious diseases, open wounds on the skin, carriers of pathogenic microflora should not be allowed to work until their complete recovery.

STERILIZATION

Sterilization (or de-feeding)- it is the process of complete destruction of microorganisms and their spores in medicinal substances, dosage forms, dishes, auxiliary materials, instruments and apparatus.

The term "sterilization" comes from lat. sterilis, which means sterile. Sterility is achieved by observing asepsis and using sterilization methods in accordance with the requirements of the State Federal University "Methods and Conditions of Sterilization", previously in the State Fund XI - article "Sterilization".

When choosing the method and duration of sterilization, it is necessary to take into account the properties, volume or weight of the materials to be sterilized.

Sterilization methods can be divided into: physical, mechanical, chemical.

Physical methods of sterilization. These include: thermal, or heat, sterilization, ultraviolet sterilization, radiation sterilization, sterilization by high-frequency currents.

Of the listed methods, in the conditions of pharmacies, thermal sterilization is used, as well as sterilization with ultraviolet rays. Other methods of sterilization in pharmacies have not yet found application.

Thermal sterilization. With this method of sterilization, the death of microorganisms occurs under the influence of high temperature due to the coagulation of proteins and the destruction of enzymes of microorganisms. The most widely used sterilization in pharmacy practice is dry heat and steam.

Steam sterilization under pressure is carried out in steam sterilizers (autoclaves) of various designs. The most convenient are those steam sterilizers in which the preset pressure and temperature are automatically maintained, and the possibility of drying auxiliary material (cotton wool, filter paper, gauze, etc.) after sterilization is also provided (Table 31). Currently, sterilizers such as VK-15, VK-30 (Fig. 137), GP-280, etc. are widely used. In the practice of hospital pharmacies, sterilizers such as GP-400, GPD-280 can also be used \ and GPS-500, which are similar in structure and principle of operation to the GP-280 sterilizer.

In CRA No. 3, a VK-75 autoclave sterilizer is used. Vertical steam sterilizers VK-ZO and VK-75 differ in the capacity of the sterilization chamber. They consist of a housing with a sterilization and water vapor chambers, a cover, a casing, electric heating elements, an electrical panel, an electrocontact manometer, a pressure gauge, an ejector, a safety valve, a water indicator and a pipeline with valves. The sterilization and water vapor chambers are combined into a single welded structure, but functionally separated, as a result of which it is possible to shut off the steam flow into the sterilization chamber during loading and unloading of the autoclave, as well as to automatically maintain the working pressure in the water vapor chamber for subsequent sterilization. Both chambers are made of stainless steel. The maximum steam pressure in the sterilization chamber is 0.25 MPa. Both sterilizers operate on a 220/380 V three-phase alternating current network.