MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
PHARMACOPOEIAL ARTICLE
Sulfanilamide FS.2.1.0038.15
Streptocide white Instead of GF X, Art. 633;
S ulfanilamidum instead of FS 42-2744-98
4-Aminobenzenesulfonamide
C6H8N2O2S M.m. 172.20
Contains at least 99.0% sulfonamide C6H8N2O2S in terms of dry matter.
Authenticity
- IR spectrum The infrared spectrum of the substance, taken in a disk with potassium bromide, in the frequency range from 4000 to 400 cm-1, according to the position of the absorption bands, should correspond to the pattern of the spectrum of sulfonamide (Appendix).
- UV spectrum. The ultraviolet absorption spectrum of a 0.0008% solution of the substance in a 0.01 M sodium hydroxide solution in the wavelength range from 220 to 330 nm should have an absorption maximum at 251 nm.
- UV spectrum. The ultraviolet absorption spectrum of a 0.015% solution of the substance in a 1 M solution of hydrochloric acid in the wavelength range from 220 to 320 nm should have absorption maxima at 264 nm, 271 nm, absorption minima at 241 nm, 268 nm and a shoulder in the range from 257 to 261 nm.
- Qualitative reaction. 0.05 g of the substance should give a characteristic reaction to primary aromatic amines (General Pharmacopoeia Monograph “General reactions to authenticity”).
Streptocide 300 mg No. 10 tab.
Instructions for medical use of the drug STREPTOCIDE Trade name Streptocide International nonproprietary name Sulfanilamide Dosage form Tablets 300 mg Composition 1 tablet contains the active substance: streptocide (sulfanilamide) 300 mg excipients: potato starch, talc. Description Tablets are white or almost white, in the form of solid, regular, round cylinders, the upper and lower surfaces of which are flat, the edges of the surfaces are beveled, with a scoring line on one side. Pharmacotherapeutic group Antimicrobial drugs for systemic use. Antibacterial drugs for systemic use. Sulfonamides and trimethoprim. Short-acting sulfonamides. Sulfanilamide. ATX code J01E B06. Pharmacological properties Pharmacokinetics When administered orally, it is quickly absorbed - the maximum concentration of streptocide in the blood is observed after 1-2 hours (within 4 hours it is indicated in the cerebrospinal fluid); a 50% reduction in maximum blood concentration occurs in less than 8 hours. Passes through histohematic, including blood-brain (BBB), placental barriers. Distributed throughout the tissues, after 4 hours it is found in the cerebrospinal fluid. In the liver it is acetylated with loss of antibacterial properties. Approximately 95% of the drug is excreted by the kidneys. Pharmacodynamics Streptocide disrupts the formation in microorganisms of so-called “germ factors” - folic, dehydrofolic acids, and other compounds containing para-aminobenzoic acid (PABA) in their molecules. As a result of the proximity of the structures of PABA and Streptocide, sulfanilamide, as a competitive acid antagonist, is included in the metabolic chain of microorganisms and disrupts metabolic processes in it, which leads to a bacteriostatic effect. Streptocide is a short-acting sulfonamide that has a bacteriostatic effect against streptococci, meningococci, pneumococci, gonococci, Escherichia coli, pathogens of toxoplasmosis and malaria. Does not affect anaerobic microorganisms. Indications for use - erysipelas - sore throat - wound infection Method of administration and dosage Take orally during or after meals with 150-200 ml of water. A single dose for adults and children over 12 years of age is 600 mg -1.2 g, the daily dose is 3-6 g. The daily dose is divided into 5 doses. Maximum doses for adults: single dose – 2 g, daily – 7 g. Single dose for children aged 6 to 12 years – 300-600 mg. The frequency of administration for children is 4-6 times a day. The maximum daily dose for children is 0.9-2.4 g. Before prescribing the drug to a patient, it is necessary to determine the sensitivity of the microflora to it that caused the disease in this patient. The duration of treatment is determined by the doctor individually, depending on the severity and course of the disease, the localization of the process, and the effectiveness of therapy. Side effects From the blood and lymphatic systems: leukopenia, agranulocytosis, aplastic anemia, thrombocytopenia, hypoprothrombinemia, eosinophilia, hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency. From the cardiovascular system: tachycardia, myocarditis. From the nervous system: headache; neurological reactions, including aseptic meningitis; ataxia; slight intracranial hypotension; convulsions; dizziness; drowsiness/insomnia; feeling tired; depression; peripheral or optic neuropathies; visual impairment; psychosis; depressed state; paresthesia. From the respiratory system: pulmonary infiltrates, fibrosing alveolitis. From the digestive tract: thirst, dry mouth, dyspepsia, nausea, vomiting, diarrhea, anorexia, pancreatitis, pseudomembranous colitis. From the hepatobiliary system: increased activity of liver enzymes (ALT, AST, alkaline phosphatase), cholestatic hepatitis, hepatonecrosis, hepatomegaly, jaundice, cholestasis. From the urinary system: change in the color of urine (rich yellow-brown color), crystalluria with an acidic urine reaction; Nephrotoxic reactions are possible: interstitial nephritis, tubular necrosis, renal failure, hematuria, shock kidney with anuria. From the skin and subcutaneous tissue: skin hyperemia, skin rash (including erythematous-squamous, papular), itching, urticaria, allergic dermatitis, photosensitivity, exfoliative dermatitis, erythema nodosum, cyanosis. Allergic reactions: toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, systemic lupus erythematosus, serum syndrome, anaphylactic reactions, Quincke's edema, runny nose. General disorders: drug-induced fever, pain in the right hypochondrium and lower back. Other: difficulty breathing, periarteritis nodosa, hypothyroidism, hypoglycemia. In isolated cases, the development of hypothyroidism is possible. Contraindications - Individual sensitivity to sulfonamides, sulfone or other components of the drug; - a history of severe toxic-allergic reactions to sulfonamides; - inhibition of bone marrow blood formation; - decompensated heart failure; - diseases of the hematopoietic system; - anemia; - leukopenia; - Graves' disease; - kidney and liver diseases (nephrosis, nephritis, liver failure, severe renal failure, acute hepatitis); - hyperthyroidism; - congenital deficiency of glucose-6-phosphate dehydrogenase; - azotemia; - porphyria; - children under 6 years old; - women during lactation and pregnancy. Drug interactions When used simultaneously: – with non-steroidal anti-inflammatory drugs, sulfonylurea derivatives, antithrombotic agents, vitamin K antagonists – the effect of these drugs is enhanced; – with folic acid, bactericidal antibiotics (including penicillins, cephalosporins) – the effectiveness of sulfonamides is reduced; – with bactericidal antibiotics, oral contraceptives – the effect of these drugs is reduced; – with PAS and barbiturates – the activity of sulfonamides increases; – with erythromycin, lincomycin, tetracycline – antibacterial activity is mutually enhanced, the spectrum of action is expanded; – with rifampicin, streptomycin, monomycin, kanamycin, gentamicin, oxyquinoline derivatives (nitroxoline) – the antibacterial effect of the drugs does not change; – with nalidixic acid (nevigramon) – antagonism is sometimes observed; – with chloramphenicol, nitrofurans – the total effect is reduced; – with drugs containing PABA esters (novocaine, anesthesin, dikamine), – the antibacterial activity of sulfonamides is inactivated. Sulfonamides are not prescribed simultaneously with hexamethylenetetramine (urotropine), with antidiabetic drugs (sulfonylurea derivatives), with definin, neodicoumarin and other indirect anticoagulants. Streptocide may enhance the effect and/or toxicity of methotrexate as a result of displacing it from protein binding and/or weakening its metabolism. When used simultaneously with other drugs that cause bone marrow suppression, hemolysis, or hepatotoxicity, there may be a risk of developing toxic effects. Concomitant use with methenamine (urotropine) is not recommended due to the increased risk of developing crystalluria due to acidic urine. Phenylbutazone (butadione), salicylates and indomethacin can displace sulfonamides from binding to plasma proteins, thereby increasing their concentration in the blood. When used together with para-aminosalicylic acid and barbiturates, the activity of sulfonamides increases; with chloramphenicol – the risk of developing agranulocytosis increases; with drugs containing para-aminobenzoic acid esters (novocaine, anestezin, dicaine), the antibacterial activity of sulfonamide is inactivated. Special instructions When treating with the drug, it is necessary to systematically monitor renal function and peripheral blood parameters, blood glucose levels. During long-term treatment with the drug, it is necessary to periodically conduct blood tests (biochemical and general blood tests). Prescribing the drug in insufficient doses or premature discontinuation of the drug may increase the resistance of microorganisms to sulfonamides. Sulfonamides should not be used to treat infections caused by group A beta-hemolytic streptococcus, since they do not lead to its eradication and, as a result, cannot prevent complications such as rheumatism and glomerulonephritis. The drug should be prescribed with caution to patients with chronic heart failure, liver disease and impaired renal function. Streptocide should be prescribed with caution to patients with severe allergic diseases or bronchial asthma, with diseases of the blood system. If signs of a hypersensitivity reaction appear, the drug should be discontinued. In case of renal failure, accumulation of sulfonamide and its metabolites in the body is possible, which can lead to the development of a toxic effect. Sulfonamides, including streptocide, should be used with caution in patients with diabetes mellitus, since sulfonamides can affect blood sugar levels. High doses of sulfonamides have a hypoglycemic effect. Since sulfonamides are bacteriostatic and not bactericidal drugs, a full course of therapy is necessary to avoid relapse of infection and the development of persistent forms of microorganisms. Given the similarity of the chemical structure, sulfonamides should not be used in people with hypersensitivity to furosemide, thiazide diuretics, carbonic anhydrase inhibitors and sulfonylureas. Patients need to drink enough fluids to avoid crystalluria and the development of urolithiasis. In elderly patients, there is an increased risk of developing severe adverse reactions from the skin, inhibition of blood formation, and thrombocytopenic purpura (the latter, especially in combination with thiazide diuretics). Prescribing the drug to patients over 65 years of age should be avoided due to the increased risk of severe adverse reactions. It is recommended to avoid exposure to direct sunlight and artificial ultraviolet irradiation, given the possibility of developing photosensitivity when using sulfonamides. During treatment, it is necessary to adhere to the dosage regimen, apply the recommended dose at intervals of 24 hours, without skipping doses of the drug. If a dose is missed, do not double the next dose. If the signs of the disease do not begin to disappear or, conversely, the health condition worsens or adverse events occur, it is necessary to stop using the drug and consult a doctor about the possibility of further use of the drug. Children Do not use in children under 6 years of age. Use during pregnancy or breastfeeding During pregnancy or breastfeeding, the drug is contraindicated. If treatment with the drug is necessary, breastfeeding should be stopped. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms Until the individual reaction to the drug is determined, you should refrain from driving vehicles or operating other mechanisms, since during treatment with sulfonamides, adverse reactions from the nervous system such as dizziness, convulsions, ataxia are possible , drowsiness, depression, psychosis. Overdose Possible increased side effects. In case of an overdose, anorexia (lack of appetite), nausea, vomiting, colicky pain, headache, drowsiness, dizziness, and fainting may occur. With long-term use, fever, hematuria, crystalluria, cyanosis, tachycardia, paresthesia, diarrhea, cholestasis, renal failure with anuria, toxic hepatitis, leukopenia, agranulocytosis are possible. Treatment. In case of overdose, it is recommended to consult a doctor. Treatment is symptomatic. Before providing medical care, rinse the stomach with a 2% sodium bicarbonate solution and take a suspension of activated charcoal or other enterosorbents. Drinking large amounts of fluid, forced diuresis, and hemodialysis are indicated. Release form and packaging 10 tablets are placed in a blister pack made of polyvinyl chloride film and aluminum foil. Contour cell packaging, together with instructions for medical use in the state and Russian languages, are placed in boxes made of chrome-ersatz recycled or boxed cardboard or in boxes made of corrugated cardboard. The number of instructions in a group package is included in the number of packages. Storage conditions Store in original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children. Shelf life: 5 years. Do not use after the expiration date. Conditions for dispensing from pharmacies By prescription Manufacturer/Packager PJSC “Lubnyfarm”, Ukraine, 37500, Poltava region, Lubny, st. Barvinkova, 16. Owner of the registration certificate of PJSC "Lubnyfarm", Ukraine, 37500, Poltava region, Lubny, st. Barvinkova, 16. Name, address and contact details of the organization on the territory of the Republic of Kazakhstan that accepts claims (suggestions) on the quality of medicines from consumers and is responsible for post-registration monitoring of the safety of the medicine: Pharmaline LLP, 050016, Almaty, st. Shamieva, 11,
Related impurities
Determination is carried out by thin layer chromatography (TLC).
Test solution. 0.1 g of the substance is dissolved in 10 ml of a mixture of 96% alcohol - 25% concentrated ammonia solution (9:1).
Reference solution. 0.25 ml of the test solution is placed in a 50 ml volumetric flask, the volume of the solution is adjusted to the mark with a mixture of 96% alcohol - 25% concentrated ammonia solution (9:1) and stirred.
The shelf life of the solution is 7 days.
Sulfanilic acid standard solution. 0.1 g of sulfanilic acid (4-aminobenzenesulfonic acid) is dissolved in 70 ml of a mixture of 96% alcohol - 25% concentrated ammonia solution (9:1) in a 100 ml volumetric flask, adjust the volume of the solution to the mark with the same mixture of solvents and mix.
The shelf life of the solution is 7 days.
0.5 ml of the resulting solution is placed in a 10 ml volumetric flask, the volume of the solution is adjusted to the mark with a mixture of 96% alcohol - 25% concentrated ammonia solution (9:1) and stirred.
The solution is used freshly prepared.
On the starting line of the plate (pre-washed with acetone) with a layer of silica gel 60 F254, 0.01 ml of the test solution (100 μg of sulfanilamide) is applied to point A, next to point B 0.01 ml of the reference solution (0.5 μg of sulfanilamide) is applied, and 0.01 ml of the test solution and a solution of a standard sample of sulfanilic acid (100 μg of sulfanilamide and 0.5 μg of sulfanilic acid) are applied to point B.
The plate with the applied samples is dried in air for 10 minutes, placed in a chamber with a mixture of solvents: a concentrated solution of 25% ammonia - methanol - chloroform (3:9:16) and chromatographed using the ascending method. When the front of the mobile phase has passed about 80 - 90% of the length of the plate from the starting line, it is removed from the chamber, dried until traces of solvents are removed and viewed in UV light at a wavelength of 254 nm.
On chromatogram A (test solution), in addition to the main spot, the presence of one additional spot is allowed, which in size and intensity of absorption should not exceed the spot on chromatogram B (no more than 0.5%).
The results of the analysis are considered reliable if 2 clear separate spots are observed on chromatogram B.
Streptocide (sulfanilamide)
CAS number:
63-74-1
Gross formula:
C6H8N2O2S
Appearance:
solid, white or almost white crystalline powder.
Chemical name and synonyms:
Sulfanilamide, 4-Aminobenzenesulfonamide
Physico-chemical properties:
Molecular weight 172.20 Density 1.08 Melting point 164-167 ° C Solubility in water 7.5 g / l at 25 ºC Combustion products: these products are carbon oxides (CO, CO2), nitrogen oxides (NO, NO2...).
Description:
Streptocide is a white crystallized powder, odorless, with a bitter taste. It is slightly soluble in water, ethanol, methanol, ether and acetone, but is highly soluble in boiling water, glycerin, hydrochloric acid (HCl), Natrii hydroxidum (sodium hydroxide) and Kalii hydroxide (potassium hydroxide) solution, insoluble in chloroform, ether, benzene, petroleum ether.
Streptocide (sulfonamide) is an organic sulfur compound, structurally similar to p-aminobenzoic acid (PABA) and has the antibacterial property of inhibiting the synthesis of folic acid in the bacterial cell, which ultimately leads to cell death.
When Ernest Fournoux of the Pasteur Institute showed that sulfonamide is an active metabolite after the breakdown of a substance called Prontosil in the body, he opened a new chapter in the field of medicinal chemistry. Prontosil is a dye that was produced by German manufacturers of the chemical concern IG Farben. Prontosil was found to inhibit the growth of streptococci in mice. When the company doctor, Gerhard Domagk's daughter, contracted an infection, her life was saved by an oral dose of Prontosil. Although this was a desperate measure, it not only ensured her recovery, but also ensured that Domagk received the Nobel Prize in Medicine or Physiology. The discovery of the effectiveness of sulfonamide led to the search for similar compounds. The goal of the search was usually to reduce the natural toxicity of the parent substance while improving the drug effect.
Doctor of Divinity Woods at one time discovered that the activity of sulfonamide in microorganisms is competitively overcome by para-aminobenzoic acid (PABA), with which there is a structural similarity. In these organisms, PABA is an important substance in the biosynthesis of folic acid. They die when given sulfonamide because they can no longer produce enough folic acid, which itself is important for cell division. The human body is essentially unaffected because folic acid is obtained from the diet.
Application:
Streptocide is mainly used for traumatic infections caused by hemolytic streptococcus, staphylococcus and local wound infections. It has the lower toxicity of all sulfide drugs and can be used in small doses by infants and pregnant women. Sulfanilamide is the main component for the production of sulfate drugs (sulfamidine, pyrimidine and sulfamethoxazole, sulfamethoxytriazine, etc.).
In veterinary medicine, it is actively used as an ingredient in many antibiotic drugs for the treatment of bacterial infections of small domestic and farm animals. It has an antibacterial effect on hemolytic streptococcus (Streptococcus pyogenes) - a streptococcal gram-positive bacterium, Neisseria meningitidis or meningococcus - a gram-negative diplococcus that can lead to meningitis; Staphylococcus aureus is a staphylococcal gram-positive bacterium that is the cause of many infectious diseases, affecting the skin and internal organs and other gram-positive and gram-negative bacteria.
Receipt:
There are several ways to obtain streptocide.
1. Acetyl aniline is used as the starting material. Acetanilide reacts with chlorosulfonic acid at 40-50°C and then slowly cooled, added to water to decompose the acid, and the precipitate is dried and filtered to obtain acetaminophen chloride and ammoniated, ammonia temperature is controlled at 40-45°C, hydrolysis, acidification.
2. Method with mixed diphenylurea.
The condensation of aniline and urea is monophenylurea and diphenylurea (called mixed urea), which is obtained from chlorosulfonated, aminated, hydrolysis, acid precipitation. The reaction procedure is as follows.
(1) Condensate the condensate of aniline hydrochloride and urea at a temperature of 101 ~ 110 C for 3-4 hours to obtain mixed diphenylurea.
(2) Chlorosulfonated perchloric acid is pressed into a sulfonated pot while stirring and cooling. When the temperature drops below 10 C, mixed phenylurea is added evenly with constant stirring, the reaction temperature is increased, the addition is completed at 46 ~ 50 C, isolated and stirred for 2 hours, cooled to a temperature below 10 C, water is added to decompose the acid. Controlling that the decomposition temperature does not exceed 15 C, after adding water, continue stirring for 20 minutes, then wash with water by precipitation to obtain mixed phenylurea.
(3) Ammoniated 2% aqueous ammonia is placed in an ammonia bath, cooled to 25°C, stirred and added to the phenylurea mixture, control the temperature at 40°C, isolate and react for 3 hours to obtain ammonia liquid.
(4) Hydrolysis and neutralization. The amide is heated to 90°C, 3% alkali is added, continued heating to 108-112°C, hydrolyzed for 5 hours and transferred to a pot for crystallization, hydrochloric acid is added to neutralize the crystals, then cooled to 20°C, crystallized, filtered , washed with water, dried products.
Effect on the body:
The activity of the antibiotic is to interfere with the synthesis of nucleic acid necessary for pathogenic microbes, making it difficult for bacteria to feed and stopping vital activity and reproduction, having the effect of suppressing the inhibition of hemolytic streptococcus, staphylococcus and meningococcus. The route of administration of streptocide is oral; it is easily absorbed from the gastrointestinal tract, can penetrate through the blood-brain barrier into brain tissue and through the placental barrier into the fetus. Rapid excretion then occurs, mainly excreted in the form of metabolites via the kidneys.
Toxicological data:
Oral (LD50): Acute toxicity: 3900 mg/kg [Rat].
When administered orally, 3000 mg/kg [mouse].
Oral administration, mouse: LD50 = 3 g/kg;
Oral administration, rabbit: LD50 = 1300 mg/kg;
Inhalation (LC50): Acute toxicity: 255 ppm 4 hours [Rat].
quantitation
The determination is carried out in accordance with the requirements of the General Pharmacopoeia Monograph "Nitritometry" using about 0.25 g (exactly weighed) of the substance.
When visually indicating the titration end point, tropeolin 00 mixed with methylene blue is used as an internal indicator.
At the same time, a control experiment is carried out.
1 ml of 0.1 M sodium nitrite solution corresponds to 17.22 mg of sulfonamide C6H8N2O2S.
