Quantification. Nitrofural (furacilin) Structure and properties Physical properties of furatsilin

Pyatigorsk Medical and Pharmaceutical Institute Philosophy of State Budgetary Educational Institution of Higher Professional Education of Volgograd State Medical University of the Ministry of Health of the Russian FederationDepartment of Pharmaceutical ChemistryCoursework In pharmaceutical chemistry on the topic: “Validation assessment of methods for qualitative and quantitative analysis of furatsilin 0.002 with a solution of boric acid 2% 10 ml.” Executor: student of group 527 Mekhonoshin I.I.Supervisor:Makarova A.N.

Pyatigorsk, 2013

Content INTRODUCTION CHAPTER 1. General characteristics of furatsilin……… 1.1. General characteristics of furatsilin…… 1.2. Preparation and physical properties of furatsilin….. 1.3. Methods for identifying furacilin….. 1.4. Methods for quantitative determination of furatsilin.... 1.5. Pharmacological action, medical use and storage of furatsilin drugs...... CHAPTER 2. Development of methods for analyzing the drug furatsilin with sodium chloride..... 2.1. Validation assessment of methods for qualitative and quantitative analysis of drug ingredients according to the “Specificity” indicator……….. 2.2. Validation assessment of the method for the quantitative determination of furatsilin according to the “Linearity” indicator……………. 2.3. Validation assessment of the method for the quantitative determination of furatsilin according to the “Correctness” indicator……….. 2.4. Validation assessment of the method for the quantitative determination of furatsilin according to the “Precision” indicator……..

CONCLUSION…………………………….

REFERENCES……………………

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 emergence and strengthening 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 isolating the chemistry of furan compounds as derivatives of one of these parent cycles - furan. Historically, the first in the series of furan compounds was the synthesis in 1818 of pyroslitic acid during the pyrogenetic decomposition of mucus acid. The resulting liquid by-product was not studied, which delayed the discovery of furan by more than 50 years. Then follows the accidental discovery of furfural Dobereiner in 1832, while attempting 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 Stenhouse managed to determine its most important properties and derive an empirical formula. The production of furfural from bran dates back to the same time (1845) and the appearance of the name of this substance that has survived to this day - furfural, which was supposed to express the source of its production and external characteristics (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. Research has shown that among the numerous furan derivatives 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 5-nitrofuran derivatives were proposed for use in medical practice in the 50-60s. Then, due to the introduction into clinical practice of a large number of highly effective chemotherapeutic drugs in other classes of chemical substances, which exceeded the degree of activity of nitrofurans and had a number of advantages in terms of pharmacokinetic and toxicological characteristics, interest in the drugs in this group decreased. Nevertheless, nitrofurans are still used in medical practice.

Chapter 1. General characteristics of furatsilin.1.1. General characteristics of furatsilin.

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

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

1.2. Preparation and physical properties of furatsilin. 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, soluble in alkalis. The solution is yellow or colorless. Aqueous solutions lose their antimicrobial activity during long-term storage. The starting product for the synthesis of all drugs of the nitrofuran series is a very accessible substance - furfural, obtained from waste of various agricultural products (corn cobs, sunflower husks). The production of furatsilin is based on the nitration of furfural in a mixture of acetic anhydride and acetic acid. The resulting 5-nitrofurfural diacetate is hydrolyzed and the resulting 5-nitrofurfural is condensed with hydrochloric acid semicarbazide:

1.3. Methods for identifying furatsilin. To test authenticity, IR spectra of nitrofuran derivatives are used. They are pressed into tablets with potassium bromide and spectra are recorded in the region of 1900-1700 cm -1. The IR spectra must completely coincide with the IR spectra of the GSO. The IR spectrum of furatsilin has absorption bands at 971, 1020, 1205, 1250, 1587, 1784 cm -1. Chemical reactions used to identify furatsilin. The authenticity of furatsilin is determined by a color reaction with an aqueous solution of sodium hydroxide. Nitrofural, when using dilute solutions of alkalis, forms an acisol, colored orange-red: When furatsilin is heated in solutions of alkali metal hydroxides, the furan ring breaks and forms sodium carbonate, hydrazine and ammonia. The latter is detected by a change in color of wet red litmus paper:

Characteristic color reactions that allow 5-nitrofuran derivatives to be distinguished from each other are produced by an alcohol solution of potassium hydroxide in combination with acetone: nitrofural acquires a dark red color. Furacilin is also identified using the general reaction of formation 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% solution of sodium nitroprusside 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 environment. When a 1% solution of copper (II) sulfate, a few drops of pyridine and 3 ml of chloroform are added to a solution of nitrofurantoin (in a mixture of dimethylformamide and water), after shaking, the chloroform layer acquires a green color. Complex compounds of nitrofural and furazolidone under these conditions are not extracted 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 quantitative determination of furatsilin. 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 completion of the furatsilin oxidation process, the solution is acidified and the released excess iodine is titrated with sodium thiosulfate:
A known method for determining nitrofural bromatometric method, based on the oxidation of the hydrazine group in the presence of concentrated acids at a temperature of 80-90°C:
Furazidin-potassium is quantitatively determined acidimetrically by titrating with a 0.01 M solution of hydrochloric acid (bromothymol blue indicator). To establish the authenticity and quantitative determination of nitrofural, use UV spectra its 0.0006% solution in a mixture of dimethylformamide and 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 for 5-nitrofuran derivatives, since they are due to the presence of different electron-donating groups in position 2 of the furan ring. Quantitative spectrophotometric determination performed at 375 nm and content calculated using a nitrofural standard sample. The solvent for UV spectrophotometric determination can be a 50% solution of sulfuric acid, in which nitrofural has an absorption maximum at 227 nm. Also, quantitative determination of nitrofural can be carried 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 furatsilin drugs. Pharmacological action. It is an antibacterial substance that acts on various gram-positive and gram-negative bacteria (staphylococci, streptococci, dysentery bacillus, E. coli, Salmonella paratyphoid, causative agent of gas gangrene, etc.) It is used for the treatment and prevention of purulent-inflammatory processes, for bedsores and ulcers, burns II and III degree, to prepare the granulating surface for skin grafting and for the secondary suture, irrigate the wound with an aqueous solution of furatsilin and apply wet bandages; in case of osteomyelitis, after surgery the cavity is washed with an aqueous solution of furatsilin and a wet bandage is applied; for pleural empyema, the pus is sucked out and the pleural cavity is washed, followed by the introduction of 20 - 100 ml of an aqueous solution of furatsilin into the cavity. For anaerobic infection, in addition to conventional surgical intervention, the wound is treated with furatsilin; for chronic purulent otitis, an alcohol solution of furatsilin 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; to wash the maxillary (maxillary) and other paranasal sinuses, use an aqueous solution of furatsilin; for conjunctivitis and scrofulous eye diseases, an aqueous solution of furatsilin is instilled into the conjunctival sac; for blepharitis, the edges of the eyelids are lubricated with furatsilin ointment, and inside for the treatment of bacterial dysentery. Forms of release of the drug:

Aerosol.

Solution for external use 0.02% (aqueous).

Solution for external use 0.066% (alcohol).

Tablets of 0.02 g for preparing 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-closed container. Protects from light and moisture.

CHAPTER 2. Development of methods for analyzing the drug furatsilin with boric acid 2.1. Validation assessment of methods for qualitative and quantitative analysis of drug ingredients according to the “Specificity” indicator. The specificity of the method should be understood as the ability to reliably determine the analyzed compound in the presence of other components of the sample. To determine specificity, we prepare 3 model mixtures: 1) both ingredients as prescribed; 2) only the first ingredient as prescribed; 3) only the second ingredient as prescribed. Next, a validation assessment of the qualitative analysis of each of the ingredients of the medicinal product was carried out according to the “specificity” indicator. To establish specificity, it is necessary to ensure that there is no positive effect of the reaction to concomitant substances.

Methodology for qualitative analysis of furatsilin: Add 2 drops of sodium hydroxide solution to 0.5 ml of the test solution - an orange-red color appears

Methodology for qualitative analysis of boric acid: Evaporate 5 drops of the medicine to dryness, add 1 ml of 95% alcohol and set it on fire. The flame turns green.

In model mixture No. 1, which contains both ingredients according to the prescription (furacilin and boric acid), qualitative reactions prove the authenticity of each component of the drug. In model mixture No. 2, containing only furatsilin, using qualitative reactions to the second component (boric acid), the absence of an analytical effect in the first component is confirmed. In model mixture No. 3, containing only boric acid, qualitative reactions to the first component (furacilin) confirm the absence of an analytical effect for 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 quantitative determination of furatsilin:

Furacilin solution 0.02%, 1 ml of the test solution is added to a 50 ml volumetric flask, 20 ml of water, 5 ml of 1 M sodium hydroxide solution are added, the volume of the solution is adjusted to the mark with water, stirred and

20 min measure the optical density of the solution (Ax) 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) furatsilin RSO solution (Ast). The content of furatsilin (X) as a percentage is calculated using the formula

Boric acid. Add 3 ml of phenolphthalein-neutralized glycerin to 0.5 ml of the drug and titrate with shaking with 0.1 M sodium hydroxide solution until pink coloration occurs.

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

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

2.2. Validation assessment of the method for the quantitative determination of furatsilin according to the “Linearity” indicator. The linearity of the technique 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 is characterized by 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 the titrant is not consumed during the control experiment, then the calibration graph takes the form of a straight line emerging from the origin of coordinates and having a slope equal to 1. The main characteristic of linearity is the correlation coefficient - a measure of the relationship between the measured phenomena. The correlation coefficient (denoted “r”) is calculated using a special formula:

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

To check linearity, 5 experimental points were taken. Accurately weighed portions of furatsilin (0.02 g) were used, placed in a 100 ml volumetric flask, dissolved in 10 ml of dimethylformamide, cooled, the volume of the solution was adjusted to the mark with water, mixed and solutions were prepared from them so that the concentration of furatsilin in the solutions was 0.0004 %, 0.0003%, 0.0004%, 0.0005%, 0.0006%. The optical density of each solution was measured using 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 - Results of optical density measurements.

Vml
C %

Furacilin concentration in solution %

Based on the data obtained, a calibration graph of the dependence of optical density on concentration was constructed.

Figure 1 - Calibration graph of the dependence of optical density on furatsilin concentration. Based on the data obtained, the coefficient of the linearity equation and the correlation coefficient were calculated. y = 606 x + 0,0046 r = 0,9863 Conclusion: For this sample, 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 assessment of the method for the quantitative determination of furatsilin and boric acid according to the “Correctness” indicator. Right analytical technique is the degree of closeness of experimental results to the true value over the entire measurement range. The main factor determining correctness is the value of systematic error. To determine the correctness, we prepare 3 samples: - the first (low concentration) - the second (medium concentration) - the third (high concentration) Solution A1. Precisely weighed portions of furatsilin (0.01 g) and boric acid (1.0 g) were placed in a 100 ml volumetric flask, dissolved in 30 ml of water while heating, and after cooling, adjusted to the mark with water. Solution A2. Precisely weighed portions of furatsilin (0.02 g) and boric acid (2.0 g) were placed in a 100 ml volumetric flask, dissolved in 30 ml of water while heating, and after cooling, adjusted to the mark with water. Solution A 3. Accurately weighed portions of furatsilin (0.03 g) and boric acid (3.0) were placed in a 100 ml volumetric flask, dissolved in 30 ml of water while heating, and after cooling, adjusted to the mark with water. Next, 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 - Results of establishing a quantitative determination method based on the “correctness” indicator

		Found, g



2(medium)
2(medium)
2(medium)
3(upper)
3(upper)
3(upper)

SD = = 0.92;

T= = 2,14.

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

2.4. Validation assessment of the method for the quantitative determination of furatsilin according to the “Precision” indicator Precision(reproducibility) is a characteristic of random scattering. Essentially it is a measure of the sum of random errors. When establishing precision, it should be borne in mind that this characteristic has 3 levels: - repeatability (convergence); - intermediate precision (in-laboratory reproducibility); - interlaboratory reproducibility. For the purposes of pharmaceutical analysis, 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 no regulatory document sets a lower limit for precision and it is determined by the analysis method used: SD = ; RSD = × 100%. Method of quantitative determination. To determine precision, we prepare a model solution of furatsilin with boric acid No. 2. To do this, we took precise weighed portions of furatsilin (0.02 g) and boric acid (0.9 g), placed them in a 100 ml volumetric flask, dissolved them in 30 ml of water while heating, and after cooling brought them up to the mark with water. Three parallel titrations were carried out at three concentration levels (9 determinations). Definition No. 1. Three parallel titrations were carried out, measuring 1 ml of drug each time. Definition No. 2. Three parallel titrations were carried out, measuring 2 ml of drug each time. Definition No. 3. Three parallel titrations were carried out, measuring 3 ml of drug each time. Calculation of boric acid content (g) is carried out using the following formula: ; We enter all the data obtained into table No. 3. Table 3 - Results of establishing a quantitative determination method according to the “precision” indicator.

Nitrofuran derivatives

1. 3-part.
ethylene oxide	ethylene sulfide	ethylenimine
2. 5-membered.
furan	thiophene	pyrrole
3. 5-membered with several heteroatoms.
pyrazole	imidazole	1,3-thiazole	thiazolidine	Oxazole-1,3
1,2,3-oxadiazole	1,3,7-thiadiazole	1,2,4-thiadiazole	1,2,3,4-tetrazole
4. 6-membered.
α-pyran	g-pyran	tetra-hydropyran	pyridine	piperidine
5. 6-membered with several heteroatoms.
pyridazine	pyrimidine	pyrazine	piperazine	1,3,5-triazine	dioxin
thiazine	oxazine	morpholine
7. 7-membered.
azepine	1,2-diazepine

Authenticity:

1. As a group reaction to the nitrofuran group in the molecules of these compounds, a reaction with alkali solutions is typical. The nature of the color depends on the structure of the substituent in position 2. For some compounds it appears only in a strongly alkaline environment or when heated, for others - in the cold. It is assumed that the color is caused by the opening of the furan ring with the formation of a strongly colored anion:

2. In addition, to distinguish one drug from another, a reaction with an alcoholic solution of alkali in various organic solvents is recommended. Most often they take acetone or dimethylformamide, in which nitrofurans dissolve very well. Depending on the concentration of the test drug in the organic solvent and the amount of alkali added, the colors change in accordance with the nature of each drug.

3. Also, a group reaction is the formation of ammonia when their alkaline solutions are treated with zinc dust.

Na 2 CO 3 + HCl àCO 2

N 2 H 4 + N,N-diethylaminobenzaldehyde à azo dye (red in H+).

4. Reaction of the silver mirror.

2OH + reduced form 2Ag¯ + oxidized form - NH 4 + + 3NH 3 + H 2 O

5. With Fehling's reagent:

The reagent is a mixture of equal volumes of Fehling's solution 1 (CuSO 4 + trace H 2 SO 4 - a transparent bluish liquid) and Fehling's solution 2 (Seignette's salt - sodium potassium tartrate in an alkali solution).

Fehling's reagent itself is a transparent liquid of bright blue color, a complex of copper salts (the formula below is according to Tatyana Yuryevna Ilyina; Sergey Nikolaevich Trusov imagines a complex of copper with potassium sodium tartrate somewhat differently - in his opinion, copper binds via alcohol hydroxyls only with one molecule of tartaric acid).

When the aldehyde is added and boiled in a water bath, a red-brown precipitate forms.

Aldehyde + Fehling complex + KOH + 3NaOH CuOH + acidic Potassium tartaric acid + acidic Sodium tartaric acid + acid from aldehyde + 2H 2 O

2CuOH à Cu 2 O + H 2 O

Copper hydroxide 1 is yellowish in color, very unstable and quickly decomposes to a brick-red oxide.

6. With Nessler's reagent:

RCHO + K 2 + 3KOH à Hg¯ + RCOOK + 4KI + 2H 2 O

7. As specific reactions for drugs of the nitrofuran series, one can use their ability to form colored or poorly soluble complexes with salts of heavy metals in aqueous solutions: CuSO 4, AgNO 3, Co(NO) 2, etc.

9. You can use different types of chromatography and characterize each of the drugs based on the Rf value.

Quantification:

1. Since all drugs of the nitrofuran series give colored solutions with alkali solutions, colorimetric methods can be used as a general method of quantitative determination. For this purpose, a solution is prepared from an accurately weighed portion of the drug, treated with 1N. alkali solution and after some time measure the optical density of the solution using a photoelectrocolorimeter. Under the same conditions, the specific absorption rate of a standard sample of the drug is determined and then the percentage of the drug is calculated using the appropriate formula. GF10 recommends determining furadonin and furazolidone using this method (GF10 p. 322).

2. For drugs containing a hydrazine group in their molecule that can be oxidized, the iodometric method is recommended (for example, furatsilin).

Reverse iodometry in an alkaline environment. NH 2 -NH 2 is released, reacts with I 2 /OH -

2NaIO + N 2 H 4 à N 2 + NaI + 2H 2 O

NaI + NaIO excess + H 2 SO 4 + H 2 0 à I 2 + Na 2 SO 4 + H 2 O

f=1/4. Similarly, for such preparations, the bromatometric method can be used.

3. According to the specific absorption rate E.

4. Using standard solutions.

5. By chromatography methods (TLC).

Application: broad-spectrum bactericidal properties furatsilin 1:5000 – rinsing, washing purulent wounds.

Storage: in well-closed dark glass jars, in a cool place, protected from light. According to list B.

Furacilinum - Furacilin.

5-Nitrofurfural semicarbazone.

Description: Yellow or greenish-yellow finely crystalline powder with a bitter taste.

Solubility: Very slightly soluble in water, slightly soluble in alcohol, soluble in alkalis.

Authenticity:

Furacilin gives all the reactions characteristic of drugs of the nitrofuran series (see above).

A reaction (non-pharmacopoeial) has been described for furatsilin, which distinguishes it from all other drugs of the nitrofuran series - this is a reaction with resorcinol in a hydrochloric acid environment. When the reaction mixture is heated and subsequently alkalized, fluorescence is observed, which intensifies when isoamyl alcohol is added (no chemicals needed).

Quantification:

Using the reverse iodometry method: a sample of the drug is dissolved in water when heated in a water bath. For better solubility, sodium chloride is added. Then an excess of titrated iodine solution and 0.1 ml of NaOH solution are added to a certain amount of this solution.

Oxidative decomposition of the hydrazine group to nitrogen occurs:

In an alkaline environment, iodine can react with alkali and produce hypoiodides:

I 2 + 2NaOH à NaI + NaIO + H 2 O

When sulfuric acid is added, iodine is released, which, together with the excess titrated solution of I2, is titrated with sodium thiosulfate:

NaI + NaIO + H 2 SO 4 à I 2 + Na 2 SO 4 + H 2 O

I 2 + 2Na 2 S 2 O 3 à 2NaI + Na 2 S 4 O 6

Impurities:

GF10 allows: chlorides, sulfates, heavy metals, and arsenic within the standard.

The drug may contain an impurity semicarbazide, which is determined with Fehling's solution. Since this impurity is unacceptable in the preparation, when adding Fehling’s reagent and heating, a red precipitate of cuprous oxide should not form.

Storage: List B. In well-closed dark glass jars in a cool place, protected from light.

Application: Prescribed externally for the treatment and prevention of purulent-inflammatory processes and internally for the treatment of bacterial dysentery.

Release form: powder; tablets of 0.1 g for oral administration and 0.02 g for - preparation of a solution (for external use), 0.2% ointment.

Furadoninum (Furadonin)

N-(5-Nitro-2-furfurylidene)-1-aminohydantoin.

Description: Yellow or orange-yellow crystalline powder, bitter in taste.

Solubility: Practically insoluble in water and alcohol.

Authenticity:

1. With an alkali solution, a dark red color is observed.

2. When the drug is dissolved in a freshly prepared solution of dimethylformamide, a yellow color appears, which when adding 2 drops of 1 N. alcohol solution, KOH turns brown-yellow.

Quantification:

According to GF10, it is determined photoelectrocolorimetrically (GF10 p. 322).

Storage: in a dry place, protected from light.

Application: The drug is effective in the treatment of urinary tract infections. Indications: pyelitis, pyelonephritis, cystitis, urethritis. It is also used to prevent infections during urological operations, cystoscopy, catheterization, etc.

Release form: tablets of 0.05 g, tablets of furadonin, soluble in the intestines, 0.1 g of yellow tablets with an orange or greenish tint with a score; tablets, soluble in the intestines, 0.03 g for children.

Furazolidonum (Furazolidone)

N - (5-Nitro-2-furfurylidene) - 3-aminooxazolidone-2.

Description: Yellow or greenish-yellow powder, odorless, slightly bitter taste.

Solubility: Practically insoluble in water, very little in alcohol.

Authenticity.

Furacilinum - Furacilin.

5-Nitrofurfural semicarbazone.

Description: Yellow or greenish-yellow fine-crystalline powder with a bitter taste.

Solubility: Very slightly soluble in water, slightly soluble in alcohol, soluble in alkalis.

Authenticity:

Furacilin gives all the reactions characteristic of drugs of the nitrofuran series (see above).

A reaction (non-pharmacopoeial) has been described for furatsilin, which distinguishes it from all other drugs of the nitrofuran series - a reaction with resorcinol in a hydrochloric acid environment. When the reaction mixture is heated and subsequently alkalized, fluorescence is observed, which intensifies when isoamyl alcohol is added (no chemicals required).

Quantification:

Using the reverse iodometry method: a sample of the drug is dissolved in water when heated in a water bath. For better solubility, sodium chloride is added. Next, an excess of titrated iodine solution and 0.1 ml of NaOH solution are added to a certain amount of this solution.

Oxidative decomposition of the hydrazine group to nitrogen occurs:

In an alkaline environment, iodine can react with alkali and produce hypoiodides:

I 2 + 2NaOH à NaI + NaIO + H 2 O

When sulfuric acid is added, iodine is released, which, together with the excess titrated solution of I2, is titrated with sodium thiosulfate:

NaI + NaIO + H 2 SO 4 à I 2 + Na 2 SO 4 + H 2 O

I 2 + 2Na 2 S 2 O 3 à 2NaI + Na 2 S 4 O 6

Impurities:

GF10 allows: chlorides, sulfates, heavy metals, and arsenic within the standard.

The drug must contain an admixture semicarbazide, which is determined with Fehling's solution. Since this impurity is unacceptable in the preparation, when adding Fehling’s reagent and heating, a red precipitate of cuprous oxide should not form.

Storage: List B. In well-closed dark glass jars in a cool place, protected from light.

Application: Prescribed externally for the treatment and prevention of purulent-inflammatory processes and internally for the treatment of bacterial dysentery.

Release form: powder; tablets of 0.1 g for oral administration and 0.02 g for - preparation of a solution (for external use), 0.2% ointment.

Furadoninum (Furadonin)

N-(5-Nitro-2-furfurylidene)-1-aminohydantoin.

Description: Yellow or orange-yellow crystalline powder, bitter in taste.

Solubility

Authenticity:

1. With an alkali solution, a dark red color is observed.

2. When the drug is dissolved in a freshly prepared solution of dimethylformamide, a yellow color appears, and when 2 drops of 1 N are added. alcohol solution, KOH turns brown-yellow.

Quantification:

According to GF10, it is determined photoelectrocolorimetrically (GF10 p. 322).

Storage: in a dry place, protected from light.

Furazolidonum (Furazolidone)

N - (5-Nitro-2-furfurylidene) - 3-aminooxazolidone-2.

Description: Yellow or greenish-yellow powder, odorless, slightly bitter taste.

Solubility: Practically insoluble in water, very little in alcohol.

Authenticity:

1. When heated with an alkali solution, a brown color is observed, which is due to the presence of an easily hydrolyzed oxazolidone ring in the furazolidone molecule. The addition of alkali causes the ring to rupture to form a water-soluble colored compound:

2. When the drug is dissolved in the or. solvents and the addition of an alcoholic alkali solution, a violet color appears. When the concentration changes, the color changes.

Quantification:

GF10 prescribes the use of the photocolorimetry method (GF10 p. 322).

Storage

Application: Effective against gram-positive and gram-negative bacteria. At the same time, it has anti-Trichomonas activity. The drug is also effective for giardiasis. Of the pathogens of intestinal infections, the most sensitive to furazolidone are the pathogens of dysentery, typhoid fever and paratyphoid fever. Has a relatively weak effect on pathogens of purulent and anaerobic infections. One of the positive features of furazolidone is that resistance of microorganisms to it develops slowly.

Release form: tablets of 0.05 g in a package of 20 pieces.

Furaginum (Furagin)

N-(5-Nitro-2-furyl)-allylideneaminohydantoin.

Description: Yellow or orange-yellow finely crystalline powder, odorless, bitter taste.

Solubility: Practically insoluble in water and alcohol.

Storage: List B. In a dry place, protected from light.

Application: Use internally and topically. It is prescribed orally mainly for diseases of the urinary tract (acute and chronic pyelonephritis, cystitis, urethritis, infections after surgical interventions on the genitourinary system, etc.).

Release form: powder; tablets of 0.05 g in a package of 100 pieces.

Furacilinum - Furacilin. - concept and types. Classification and features of the category "Furacilinum - Furacilin." 2017, 2018.

Instructions

on the preparation and quality control of furatsilin solution 0.02% for external use in pharmacies.

1. Characteristics of the finished product

Furacilin solution 0.02% for external use.

The drug is a 0.02% solution of furatsilin in a 0.9% sodium chloride solution.

Furacilina 0.2 g.

Sodium chloride 9.0 g.

Purified water 1 liter.

Yellow or greenish-yellow liquid, odorless.

They are produced in bottles of different capacities, sealed with rubber stoppers for rolling in aluminum caps.

Store the drug at room temperature, shelf life is 1 month.

Furacilin solutions are used as an external antibacterial agent.

The quality of the solution must comply with the requirements of GPC Art. 295.

2. Characteristics of raw materials and materials

Table 1

Name of raw materials, intermediate products

Regulatory and technical documentation

Qualification

I. Raw materials

Purified water

Furacilin

Sodium chloride

II. Materials

Medical gauze

Medical cotton wool

Laboratory filter paper

Universal indicator paper

Cotton fabrics of the calico group

Cotton belting

Silk Toile

Aluminum caps

Rubber plugs

Parchment

Glass bottles

Measuring glassware for preparing solutions, etc.

GF X st. 74

GF X st. 295

GF X st. 426

Hygroscopic

Filtering

Art. 12008 100% natural silk

3. Description of the technological process

The technological process for the production of furatsilin solution consists of 6 stages:

1. Preparatory work

2. Preparation of the solution

3. Filtration and packaging of the solution

4. Sterilization of the solution

5. Control of finished products

6. Design

Stage 1. Preparatory work

1.1. Preparation of the premises, personnel, auxiliary materials, equipment, container closures is carried out in accordance with the current order of the Ministry of Health and Social Protection of the PMR.

Auxiliary material, vessels for preparing solutions, volumetric flasks, cylinders, funnels, glass filters, container closures (rubber stopper containers) are processed and sterilized in accordance with the current “Instructions for the preparation of solution for injection in pharmacies.”

Aluminum caps are soaked for 15 minutes in a 1-2% solution of detergents, heated to 70-80°C, washed, then the solution is drained, and the caps are washed with running tap water.

Clean caps are dried in bins in air sterilizers.

1.2 Preparation of raw materials.

To obtain solutions of furatsilin, use furatsilin corresponding to GF X st. 295.

Gross formula of furatsilin C6H6N4O4 M.m. 198.14

Stage 2. Preparation of the solution

A solution of furatsilin is prepared by the mass-volume method. Measure 1000 ml into a heat-resistant glass flask. purified water, add 9.0 grams of sodium chloride and 0.2 grams of furatsilin. The contents of the flask are heated until furatsilin is completely dissolved and filtered into a bottle.

Authenticity of furatsilin.

1. To 1 ml. add 3-4 drops of sodium hydroxide solution to the drug solution; an orange-red color is formed.

2. To 1ml. the drug is added 2 drops of 96% ethyl alcohol, 10% copper sulfate solution and 10% sodium hydroxide solution; A dark red color and precipitate are formed.

3. To 1 ml. add 2 drops of perhydrol and 30% sodium hydroxide solution; a pale yellow color is observed.

4. To 1ml. the drug is added 2 drops of 96% ethyl alcohol and 5% sodium nitroprusside solution; a red color and precipitate appear.

5. To 1 ml. add 2 drops of Nessler's reagent to the drug; a red-brown color and precipitate are formed.

Quantitative determination of furatsilin.

To 2 ml. 0.01 mol/dm3 iodine solution, add 2 drops of 10% sodium hydroxide solution (until the iodine becomes discolored) and 2 ml. furatsilin solution 0.02%, mix and leave for 2-3 minutes in a dark place. Then 2 ml is added to the solution. diluted sulfuric acid and the released iodine are titrated with 0.01 mol/dm3 sodium thiosulfate solution (the indicator is starch, which is added to the end of the titration).

In parallel, under the same conditions, titration is carried out without furatsilin. The difference between the number of milliliters of 0.01 mol/dm3 sodium thiosulfate solution used for the control titration and the test solution is multiplied by 0.0247 and the amount of furatsilin is found as a percentage.

1 ml. 0.01 mol/dm3 of iodine solution corresponds to 0.0004954 g of furatsilin.

Authenticity of sodium chloride.

1. The test mixture is applied to a graphite stick, pre-treated with diluted hydrochloric acid, and a colorless flame of a burner or alcohol lamp is introduced. In this case, the edges of the flame turn yellow (sodium ion).

1. To 1 ml. 0.5 ml of the drug is added. diluted nitric acid and 0.2-0.3 ml. silver nitrate solution; A cheesy precipitate forms, soluble in excess ammonia (chloride ion).

Quantitative determination of sodium chloride.

1. To 1 ml. add 2 ml of solution. water, 1-4 drops of potassium chromate solution and titrated with 0.1 mol/dm3 silver nitrate solution until an orange-yellow color.

1 ml. 0.1 mol/dm3 of silver nitrate solution corresponds to 0.00585 g of sodium chloride.

Stage 3. Filtration and packaging of the solution

3.1 Filtration, bottling, capping, primary control for the absence of mechanical contamination.

If the analysis result is satisfactory, the solution is filtered under the pressure of a liquid column or at a vacuum of 0.15-0.25 kg/cm2.

A silk toile is used for filtering.

Filtering the solution is combined with simultaneous pouring it into prepared sterile vials.

The bottles are sealed with stoppers and initial control of the solution is carried out for the absence of mechanical contamination in accordance with the current instructions for monitoring injection solutions manufactured in pharmacies for cleanliness from mechanical contamination.

If mechanical impurities are detected, the solution is filtered.

If the solution is filtered into a large container, then it is then poured into prepared sterile vials, sealed with sterile stoppers, after which primary control is carried out for the absence of mechanical contamination.

3.2. Capping with aluminum caps, marking.

Vessels with the solution are closed with metal caps using a rolling device, marked by inscription, stamping, using tokens, etc., then transferred for sterilization.

Stage 4. Sterilization of the solution

The solution in vials is sterilized in a steam sterilizer with saturated water vapor at an excess pressure of 0.11 MPa (1.1 kgf/cm2) and a temperature of 120°C. The solution in bottles with a capacity of up to 100 ml is sterilized for 8 minutes, from 100 ml to 500 ml. – 12 min.

To avoid rupture of the bottles, the autoclave should be unloaded no earlier than 20-30 minutes after the pressure inside the sterilization chamber becomes zero.

Stage 5. Control of finished products

The solution in the bottles is controlled for the absence of mechanical contamination (see clause 3.1.).

From each batch of 1 solution, 2 hours after cooling, a solution is taken for control. The solution is analyzed for color, transparency, qualitative and quantitative content of furatsilin in accordance with the methods outlined in the section “Stage 2”.

5.3. Braquerage.

The solution in the bottle is considered rejected if it does not comply with physicochemical parameters, contains visible mechanical impurities, is not sterile, does not have a seal, or does not have enough filling volume in the bottle (taking into account the requirements of clause 3.1.).

Stage 6. Registration

Bottles with solutions are prepared in accordance with the current rules for the registration of drugs in pharmacies.

Safety precautions

When preparing injection solutions, you should follow the rules of design, operation, technology (safety and industrial sanitation when working in pharmacies, and the operating and safety rules when working in autoclaves.

State University of Medicine and Pharmacy

them. N. Testemitanu

FACULTY OF PHARMACEUTICS

DEPARTMENT

PHARMACEUTICAL AND TOXICOLOGICAL CHEMISTRY

Medicinal substances derived from furan

^ Guidelines 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: Be able to analyze the quality of medicinal substances, furan derivatives in connection with the chemical structure that determines their preparation, methods of analysis, storage and use.
Targets

Based on literary data and analytical regulatory documentation (AND), learn to analyze medicinal substances of the studied groups through a comparative assessment of physical, physicochemical and chemical properties.
Be able to determine the quality of medicinal substances of the topic being studied in accordance with the requirements of the AED, with the preparation of the necessary documentation.

Topic study plan

One lesson is allocated to study the topic.
Class form

Independent preparation for performing target tasks;
Practical laboratory work;
Final control.

Information material

5-nitrofuran derivatives

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

Table 1

Medicines derived from 5-nitrofuran

Description, solubility

Nitrofuralum

Nitrofuralul (Furacilina)

5-nitrofurfural semicarbazone

Yellow or greenish-yellow, odorless, fine crystalline powder.

Very slightly soluble in water, slightly soluble in 95% alcohol, soluble in alkalis.

M r =198,14.

Nitrofurantoinum

Nitrofurantoină (Furadonină)

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

Yellow or orange-yellow, odorless, fine-crystalline powder.

Very slightly soluble in water, slightly soluble in 95% alcohol, slightly soluble in acetone.

M r =256,18.

Furazolidonum

Furazolidonă

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

Yellow or greenish-yellow, odorless, fine-crystalline powder.

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

M r =225,16.

Physico-chemical properties

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

Nitrofural (furatsilin) exhibits acidic properties in solutions (imide group) and is better soluble in alkalis than other drugs.

To establish authenticity and quantitative determination, UV spectra in various solvents (ethanol, dimethylformamide, etc.) are used.

Chemical properties and methods of analysis

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

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

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

nitrofurantoin (furadonin) dark red color
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 a salt:

furazolidone red-brown color
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 non-aqueous basic solvents (dimethylformamide - DFA) (Tables 2,3).
Table 2

^ Results of the reaction with an aqueous-alcoholic solution of potassium hydroxide

in a non-aqueous environment

^ Medicinal substance	Results of interaction with
^ Medicinal substance	solvent - DPA	DPA and hydroalcoholic KOH solution
Nitrofurantoin (furadonin)	yellow coloring	brown-yellow coloration
Furazolidone	yellow coloring	violet color, and the walls of the test tube are blue
Nitrofural (furacilin)	purple coloring	there is a violet-red color on the walls of the test tube

Table 3

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

Quantitative determination of 5-nitrofuran derivatives can be carried out using 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 cleavage. When subjected to severe exposure to alkali solutions, all 5-nitrofuran derivatives undergo rupture of the furan ring. Other transformations are individual for each drug, depending on the nature of the substituent. For example, when nitrofural (furatsilin) is heated in an alkali solution, hydrazine, sodium carbonate and ammonia are formed, which is detected by the blueness of wet red litmus paper:

Formation of hydrazones. All 5-nitrofuran derivatives, when reacted with phenylhydrazine or 2,4-nitrophenylhydrazine, give the corresponding hydrazones, which can be identified by their melting point. Thus, when solutions of drugs are boiled 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 C:

nitrofurantoin

5-nitro-2-furfurylidene-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 (furatsilin) is also hydrazine, an energetic reducing agent:

Quantification

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 solution of iodine in an alkaline medium forms hypoiodite:

Hypoiodite oxidizes nitrofural to 5-nitrofurfural:

After the nitrofural oxidation process is completed, the solution is acidified and the released excess iodine is titrated with sodium thiosulfate:

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

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 application 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 absorbed quite well from the gastrointestinal tract; their bioavailability ranges from 50 to 90-95%.
Nitrofural (furacillin) – locally, externally. Externally, in the form of aqueous 0.02% (1:5000) or alcoholic 0.066% (1:1500) solutions, irrigate the wounds and apply wet bandages.
Nitrofurantoin (furadonin)– for bacterial urinary tract infections (pyelitis, pyelonephritis , cystitis, urethritis), prevention of infections during urological operations or examinations (cystoscopy, catheterization, etc.).
Furazolidone - dysentery, paratyphoid fever, giardiasis, food toxic infections; Trichomonas colpitis, urethritis; infected wounds and burns.

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

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

furan benzofuran
In addition to the benzofuran ring, 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 heterocyclic grisan system:

grisan

Tablea 4

Medicinal drugs, 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"-methylgrisene-2"-dione-3,4"

White or white with a creamy tint, the finest crystalline powder with a weak specific odor.

Practically insoluble in water, slightly soluble in alcohol, acetone, easily soluble in dimethylformamide and methylene chloryl.

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, as well as TLC and HPLC methods, are used.

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

The presence of chloride ion in amiodarone is determined.

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

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

Amiodarone, unlike many antiarrhythmic drugs, simultaneously has a dual mechanism of action: antiarrhythmic and antianginal effects.

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

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

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

^ Questions for self-preparation of students

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

^ Practical laboratory work
Task 1 . Conduct a comparative assessment of the quality of medicinal substances according to the following indicators: “Description” and “Solubility”.

Present the data in the form of a table and give a conclusion on the conformity of quality according to these indicators.

Note: Solvents are used in accordance with AED requirements.

Task 2. Carry out a reaction between 5-nitrofuran derivatives and 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 must be neutral), poured into 3 test tubes and added 2-3 drops of solutions of copper sulfate (1st tube), cobalt chloride ( 2nd test tube) and silver nitrate (3rd test tube).

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

Task 3. Determine the authenticity of medicinal substances from the 5-nitrofuran group.

Nitrofural (Furacilin)

3.1.A . The UV spectrum of a drug solution prepared for quantitative determination in the range from 245 nm to 450 nm has an absorption maximum 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, detectable by the smell or by the blueness of wet red litmus paper added to the vapor of the boiling liquid.

^ 3.2. Nitrofurantoin (Furadonin)

3.2.A. The UV spectrum of the drug solution 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.B. 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 adding two drops of a 1 mol/l solution of sodium hydroxide in 50% alcohol turns into brown-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.B. 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 solution is diluted with water to 10 ml; a yellow color appears. After adding a few drops of a 1 mol/l solution of potassium hydroxide in 50% alcohol, the color of the solution does not change.
3.4. Griseofulvin

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

3.4.B. 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 quantitative determination of drugs.
^ 4.1. Nitrofural (furacilin)

4.1.A. Iodometric determination. About 0.1 g of the drug (exactly weighed) is placed in a 500 ml volumetric flask, 4 g of sodium chloride, 300 ml of water are added and dissolved by heating to 70-80 0 C in a water bath. The cooled solution is brought to the mark with water and mixed (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, 2 ml of diluted sulfuric acid is added to the solution and the released iodine is titrated from a microburette with 0.01 mol/l sodium thiosulfate solution (starch as indicator).

At the same time, a control experiment is carried out.

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

4.1.B. Photocolorimetric determination. About 0.02 g of the drug (exactly 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 adjusted to the mark with water.

To 0.5 ml of the resulting solution add 7.5 ml of water, 2 ml of 0.1 mol/l sodium hydroxide solution and mix. 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 furatsilin and the optical density (A c t) is measured.

4.1.C. Spectrophotometric determination. About 0.75 g of the drug (exactly weighed) is placed in a 250 ml volumetric flask and dissolved in 30 ml of dimethylformamide. Fill the volume of the solution with water to the mark and mix. 5 ml of the resulting solution is placed in a 250 ml volumetric flask. Fill the volume of the solution with water to the mark and mix. The optical density of the resulting solution is measured using 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 optical density of a standard sample of nitrofural is measured.

Where A, A st– optical density of the test and standard solutions, respectively;

a, a st – weight of the drug and standard, respectively, g;

4.2.A. Photocolorimetric determination. About 0.1 g of the drug (exactly weighed) is placed in a 100 ml volumetric flask, about 50 ml of water and 2.5 ml of 1 mol/l sodium hydroxide solution are added, dissolved with stirring, the volume of the solution is adjusted to the mark with water and mixed well. 0.6 ml of the resulting solution is placed in a 100 ml volumetric flask, the volume of the solution is adjusted to the mark with water, and exactly 20 minutes later, counting from the moment of adding 1 mol/l sodium hydroxide solution, the optical density of the resulting solution is determined using a photoelectrocolorimeter 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 rate) of a standard sample, determined under the same conditions;

4.2.B. Non-aqueous titration . About 0.4 g of the drug (exactly 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 the color turns 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 in the preparation must be no less than 99% and no more than 101.0%.

4.2.C. Spectrophotometric determination. About 0.120 g of the drug (exactly weighed) is placed in a 1000 ml volumetric flask and dissolved in 50 ml of dimethylformamide. Fill the volume of the solution with water to the mark. 5 ml of the resulting solution is placed in a 100 ml volumetric flask. Adjust 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.

The sodium acetate solution indicated above is used as a control solution.

Where A– optical density of the test solution;

765 – specific absorption (specific absorption rate) (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 (exactly weighed) is placed in a 50 ml volumetric flask, 30 ml of dimethylformamide is added. After dissolving the drug, add 2 ml of a 0.05 mol/l alcohol solution of potassium hydroxide, stir, cool to 20 0 C, adjust the volume of the solution to the mark with dimethylformamide and mix. 0.6 ml of the resulting solution is placed in a 100 ml volumetric flask, the volume of the solution is adjusted to the mark with water and exactly 20 minutes later, counting from the moment of adding 0.05 mol/l alcohol solution of potassium hydroxide, the optical density of the resulting solution is measured using a photoelectrocolorimeter 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 rate 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 (exactly weighed) is dissolved in absolute alcohol in a 200 ml volumetric flask, the volume of the solution is adjusted to the mark with absolute alcohol and mixed.

2 ml of the resulting solution is transferred to a 100 ml flask, the volume of the solution is adjusted 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 C 17 H 17 ClO 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)	^ Determining the authenticity of medicinal substances: methodology (reaction conditions, analytical effect); chemistry of reactions (for analyzed substances)	^ Quantification: methodology, chemistry of reactions for chemical methods of analysis or the basic principles of the method for physicochemical methods of analysis; formula for calculating the quantitative content of the active substance; assessment of the quality of the analyzed substance based on the results obtained

Final control

Testing theoretical knowledge on self-study issues and final assignments.
Checking students' performance of practical work.

Final tasks

Write the structural formulas, Latin, Romanian and chemical names of medicinal substances derived from 5-nitrofuran.
Describe the physical and chemical properties of 5-nitrofuran derivative preparations. The significance of these properties in assessing their quality.
Give a general scheme for preparing preparations of 5-nitrofuran derivatives. For what purpose is acetylation or the formation of oximes carried out before the nitration of furfural?
Specify the amino derivatives condensed with 5-nitrofurfural in the synthesis of medicinal substances derived from 5-nitrofuran.
Write the structural formulas of nitrofuran, nitrofuratoin and furazolidone. Identify common functional groups in their structure.
Indicate the structural fragments responsible for the color of preparations of 5-nitrofuran derivatives.
Give the chemical properties of 5-nitrofuran derivatives that underlie 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 of nitrofural.
Calculate the volume of 0.01 mol/l sodium thiosulfate solution used to titrate an excess of 0.01 mol/l iodine solution according to the method described in paragraph 4.1.A. for the quantitative determination of nitrofural. If the sample weight of the drug is 0.1081 g, the percentage of the drug is 99.8%.
When quantitatively determining furadonin using the ADI (clause 4.2.A), it was found that A = 0.466; A 1cm 1% = 750; a= 0.1017. Determine whether the content (%) of furadonin meets the requirements of the AED?

Literature

Lecture notes.
Babilev F.V. Chimie farmaceutică, Chişinău: Universitas, 1994.- 675 rub.
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Equipment and reagents on the topic “Medicinal substances, furan derivatives”
Medicinal substances: