Sodium benzoate authenticity. Alkaloids -purine caffeine, caffeine-sodium benzoate, theophylline, aminophylline, theobromine. The solution of the setting substance is prepared in the same way as for the preparation of the titrant solution according to the exact weighed portion.
Authenticity.
Caffeine-sodium benzoate
Coffeinum natrio-benzoicum
Receiving. Interaction aqueous solutions sodium benzoate and caffeine, the resulting solution is evaporated until a dry powder is formed.
1. reactions to caffeine after isolation with alkali and chloroform.
2. Reaction to benzoate ion with ferric trichloride forms a flesh-colored precipitate.
3. the drug gives a reaction characteristic of the sodium ion.
1.determination of caffeine by the iodometric method after precipitation from the preparation with an acid in the form of a caffeine base, the caffeine content should be 38 - 40% in terms of dry matter.
An exact sample of the drug is dissolved in water, diluted sulfuric acid and 0.1 M iodine solution are added, after settling for 15 minutes, the solution is filtered and the excess iodine in the filtrate is titrated with 0.1 M sodium thiosulfate solution, at the end of the titration, a starch solution is added.
I 2 + 2Na 2 S 2 O 3 = 2NaI + Na 2 S 4 O 6
UCH = 1/4; back titration formula
2. In another sample, the amount of sodium benzoate is determined by the neutralization method. Titration is carried out in the presence of an ether, which extracts the liberated benzoic acid.
An exact weighed portion of the drug is dissolved in water, ether, a mixed indicator (methyl orange and methylene blue) are added and titrated with a 0.5 M solution of hydrochloric acid until the appearance of the lilac color of the water layer
Sodium benzoate should be 58 - 62%.
Storage. in a well-closed container.
Application. Central nervous system stimulant, cardiotonic agent.
Forms of release. Solutions for injection 10, 20%, tablets 0.1; 0.2.
Cm. Study guide for intra-pharmacy control: concentrated solution of caffeine-sodium benzoate 10%; solutions for internal use- a solution of sodium bromide and caffeine-sodium benzoate; infusion of adonis herb, caffeine sodium benzoate and sodium bromide; intra-pharmaceutical preparation and packaging (mixture) of the composition: infusion of rhizomes and valerian roots, caffeine sodium benzoate, magnesium sulfate, sodium bromide, peppermint tincture.
Contains not less than 38.0% and not more than 42.0% of caffeine and not less than 58.0% and not more than 62.0% of sodium benzoate in terms of dry matter.
Description. White crystalline powder. Hygroscopic.
Solubility. Easily soluble in water, soluble in glacial acetic acid, moderately soluble in alcohol 95%.
Authenticity. 1. IR spectrum. Infrared spectrum of the substance residue obtained in the test “Quantification. Caffeine ", taken in a disk with potassium bromide, in the region from 4000 to 400 cm -1 according to the position of absorption bands should correspond to the spectrum of a standard sample of caffeine.
2. Qualitative response. Dissolve 0.5 g of the substance in 3 ml of water, add 1 ml of 10% sodium hydroxide solution, 10 ml of chloroform and shake for 1-2 minutes. The chloroform solution is filtered through an anhydrous sodium sulfate filter and the chloroform is evaporated in a water bath. The residue gives the authenticity reactions indicated in the article "Caffeine anhydrous", and after drying at 80 ° to constant weight has a melting point of 234 - 237 °.
3. Qualitative response. A solution of a substance of 1: 100 gives a characteristic reaction to benzoates.
4. Qualitative response. The substance gives a characteristic reaction B to sodium.
* The clarity of the solution. A solution of 0.5 g of the substance in 10 ml of water should be transparent and should not cloud or precipitate when heated in a closed test tube in a boiling water bath for 30 minutes. (OFS "Transparency and turbidity of liquids").
* The color of the solution. The solution obtained in the test "The clarity of the solution" must be colorless (CFC "Degree of color of liquids", method 2).
Acidity or alkalinity. 0.25 g of the preparation is dissolved in 5 ml of freshly boiled and cooled water and 0.1 ml of 1% phenolphthalein solution is added. The solution should not turn pink. A pink color should appear on the addition of no more than 0.15 ml of 0.05 M sodium hydroxide solution.
Loss on drying. Not more than 5.0% (OFS "Loss in mass on drying", method 1). About 0.5 g (accurately weighed) of the substance is dried at a temperature of 80 ± 2 ºС.
Easily charring substances. 0.3 g of the substance is dissolved in 3 ml of concentrated sulfuric acid. The color of the solution should not be more intense than the standard B 5 (General Pharmacopoeia Monograph "Color Degree of Liquids", method 2). For a substance intended for production drugs for parenteral administration, this solution should be colorless.
Sulfates. Not more than 0.02% (OFS "Sulfates", method 1). 0.5 g of the substance is dissolved in 5 ml of water, 5 ml of 95% alcohol are added.
Chlorides. Not more than 0.02% (OFS "Chlorides"). 0.1 g of the substance is dissolved in 5 ml of water, 5 ml of 95% alcohol are added.
Heavy metals. Not more than 0.001% (OFS "Heavy Metals"). 1.0 g of the drug is dissolved in 10 ml of water.
Residual organic solvents. In accordance with the General Pharmacopoeia Monograph “Residual organic solvents”.
* Pyrogenicity. The substance must be pyrogen-free (OFS "Pyrogenicity"). Test dose: 10 mg of the substance in 1 ml of 0.9% sodium chloride solution per 1 kg of rabbit weight.
Microbiological purity... In accordance with the General Pharmacopoeia Monograph "Microbiological purity".
Quantitation. 1. Sodium benzoate. About 0.3 g (accurately weighed) of the substance, previously dried to constant weight, is dissolved in 2 ml of chloroform, 40 ml of acetic anhydride are added and titrated with a 0.1 M solution of perchloric acid in methanol to the first equivalence point determined potentiometrically (OFS "Potentiometric titration").
A control experiment is carried out in parallel.
1 ml of 0.1 M solution of perchloric acid in methanol corresponds to 14.41 mg of sodium benzoate C 8 H 10 N 4 O 2.
2. Caffeine. Continue titration from the first to the second equivalence point, determined potentiometrically (OFS "Potentiometric titration").
Authenticity Reactions to Benzoate
Qualitative reaction to sodium cation
Sodium dyes the colorless burner flame yellow.
Problem number 7
For the production of "Bitter tincture" the enterprise purchased a batch of medicinal plant products "Three-leaf watch leaf" weighing 2160 kg (net), packed in fabric bales weighing 40 kg (net). Traces of smudges were found on three bales. To confirm the quality of raw materials, samples were taken and analyzed.
· What regulatory documents are guided by during the acceptance and testing of samples?
· Calculate the sample size.
· How are the average and analytical sample masses determined? What is the quartering method?
THREE-LEAVED WATCH LEAVES - FOLIA MENYANTHIDIS TRIFOLIATAE
Three-leaf watch - Menyanthestrifoliata
Rotational watch family - Menyanthaceae
Conclusion on the quality of raw materials:
According to GF XI - numerical indicators for whole raw materials: the sum of flavonoids in terms of rutin is not less than 1%; humidity not more than 14%; total ash no more than 10%; yellowed, blackened and brown leaves no more than 5%.
When carrying out the acceptance and testing of samples, OFS 420013-03 "Rules for the acceptance of medicinal plant raw materials and sampling methods" are guided, and the analysis of samples is carried out in accordance with the State Pharmacopoeia of the XI edition.
The sample size is calculated for intact product items, and three bales with traces of smudges are opened and analyzed separately.
The sample size is calculated according to table No. 1.
2160/40 = 54 (bales) the sample size is 10% of the transport units of the lot, i.e. 6 bales.
From each opened product unit, 3 point samples of the same mass are taken, they are mixed and a combined sample is obtained, from which the average sample is taken by the quartering method according to table No. 2 (400.0), which are packed and sent to the center for drug control and certification , there it is divided by the quartering method into 3 analytical samples:
the first (weighing 200.0) determines the authenticity, grinding and content of impurities;
the second (weighing 25.0) determines the moisture content;
the third (weight 150.0) determines the ash content and active ingredients.
The State Pharmacopoeia requires the determination of the amount of flavonoids in terms of rutin in the leaves of the trefoil (according to the State Pharmacopoeia XI edition, not less than 1%).
The quality control department of a pharmaceutical enterprise for the manufacture of tablets received the substance "Rutin" of several series for quality assessment. In one series, the readings of the optical density when determining the impurity of quercetin exceeded the regulated norm.
· Justify the reasons for the change in the content of the impurity.
· Give the chemical formula of this substance, its Latin and rational names.
· List it physically - Chemical properties and the normative indicators due to these properties.
· Suggest methods for the qualitative and quantitative determination of rutin, write the reaction equations.
Rutinum - Rutin
3-Rutinoside quercetin; 3-rhamnoglycosyl-3,5,7,3 ", 4" -pentaoxflavone
In the composition of rutin there are chemical groups: By its chemical structure, rutoside is a glycoside. The sugar part (disaccharide of rutinose) includes D-glucose and L-rhamnose. Aglycone - quercetin, refers to flavanoids containing chroman (dihydrobenzopyran) core quercetin
1.phenolic hydroxyls.
Description. Greenish-yellow fine-crystalline powder, odorless and tasteless. Solubility. Practically insoluble in water, slightly soluble in 95% alcohol, hardly soluble in boiling alcohol, practically insoluble in acid solutions, in ether,
Analysis of Routine. 1. The IR spectrum must completely match the spectrum of the standard. 2. UV spectrum of 0.002% solution of the drug in absolute alcohol has a max at 259 and 362.5 nm. Due to the aromatic system of quercetin.
Chemical reactions: 1) a glycosidic bond is godrolysis, and then a color reaction with sodium hydroxide solution (yellow-orange color), the color is due to the conversion of the flavonoid into chalcone with the opening of the pyran ring.
2) The cyanine reaction occurs when rutin is exposed to magnesium powder and conc. hydrochloric acid in an alcoholic environment. based on the formation of colored pyrylium salts upon reduction of flavonoids with hydrogen, including rutin
3) the sugar part (glucose) is determined with the reactant. Fehling after hydrolysis.
Quantitative determination: Method –UV-spectrophotometry.
Determine the optical density of the solution on a spectrophotometer at wavelengths of 375 nm (D1) and 362.5 nm (D2) in a cuvette with a layer thickness of 1 cm.If the ratio D1 / D2 is within 0.875 ± 0.004, then the content of rutin in percent (X) calculated by the formula:
where 325.5 - specific indicator absorption E \% cm of pure rutin (anhydrous) in absolute alcohol at a wavelength of 362.5 nm; a - weight in grams. If the ratio D1 / D2 exceeds 0.879, then the percentage of rutin (X) is calculated by the formula:
3.In the conditions of a pharmacy:
Justify the rules for the introduction of alcohol-containing medicines in the manufacture of liquid dosage forms for indoor and outdoor use.
In the manufacture of LF, alcohol-containing LF are often introduced (tinctures, liquid extracts, elixirs, novogalenic (maximally purified drugs) alcohol solutions). Should be guided by the position of the order of the Ministry of Health and Social. Development of Russia No. 308 dated 21.10.97:
Alcohol solutions are prepared in a mass-volumetric way;
If a solution is prescribed in the prescription without specifying the concentration; provided in the ND with several drug concentrations, a solution of weak concentration should be dispensed (for example, a solution of boric acid 0.5%, 1%, 2%, 3%, 5% - dispense a 1% solution, iodine solution 1%, brilliant green 1%, etc.)
The dispensing rate of alcohol of accounting concentration in terms of weight is 50.0, if indicated for a special purpose - no more than 100.0.
In complex mixtures, alcohol-containing liquids should be added in ascending order of alcohol strength in order to avoid the formation of a sediment of DV.
Alcohol in the manufacture of extemporal drugs is measured by volume, and taken into account by weight in terms of 95 - 96%.
Prescription form No. 148, alcohol is on the PKU.
4. Focus on organizational and economic aspects:
What is the order of pricing, dispensing from the pharmacy and accounting ethyl alcohol, alcohol-containing dosage forms and factory-made alcohol tinctures?
1,3,7-trimethyl-xanthine monohydrate
Receiving:
2. Synthetic way
a) Traube synthesis (for theophylline and caffeine):
Description: White silky needle-like crystals or white crystalline powder of bitter taste, odorless.
Solubility: Let's slowly dissolve in water, LR in hot, TP in alcohol. Solutions are neutral.
Authenticity:
1. Murexid test (oxidation in an acidic medium with the destruction of the imidazole cycle):
2. GF - UV spectrum, 1 maximum;
3.reaction with I 2: when adding a solution of I 2 to caffeine, there should be no sediment or turbidity, however, if we acidify the solution, a brown precipitate Coff I 4 HI, soluble in NaOH, forms
Coff + I 2 à no reaction à (upon acidification) Coff I 4 HI¯, soluble in NaOH.
4. When tannin is added, a white precipitate is formed, which is soluble in an excess of the reagent.
NeHF:
1. MF - IR spectrum in comparison with the standard.
2.In alkaline environment the pyrimidine cycle is destroyed:
3. Reaction of azo coupling:
Purity:
1. Extraneous alkaloids are unacceptable. The solution of the drug should not give a precipitate with Mayer's reagent.
2. Theobromine and theophylline are unacceptable. TLC. Only 1 spot is allowed on the chromatogram.
3. Organic impurities with KH 2 SO 4 - must be transparent and colorless.
Quantitation:
1. Non-aqueous titration. The caffeine is dissolved in chloroform and acetic anhydride is added. The indicator is crystal violet, titrated to a yellow color.
2. Reverse iodometry (GF for caffeine-sodium benzoate):
Coff + I 2 + KI + H 2 SO 4 à Coff I 4 HI + KHSO 4
I 2 + 2Na 2 S 2 O 3 а Na 2 S 4 O 6 + 2NaI
Before titrating excess iodine, the precipitate must be filtered.
4. FEC (by the reaction of azo dye formation).
Storage: List B. In a well-closed container.
Application: Caffeine (and caffeine-sodium benzoate) is used for infectious and other diseases accompanied by depression of the central nervous system and of cardio-vascular system, with poisoning with drugs and other poisons that depress the central nervous system, with spasms of the cerebral vessels (with migraines, etc.), to increase mental and physical performance, to eliminate drowsiness. Caffeine is also used for enuresis in children.
1. Russian name of the medicinal product.
Sodium benzoate
Sodium benzoic acid
Sodium salt of benzoic acid
Sodium benzoate
2. Latin name drug.
Natrium benzoicum
3. Chemical formula indicating molar mass
Molar mass 144,11
4. Appearance
White crystalline powder, odorless or with a very faint odor, sweetish-salty taste.
5. Physical and chemical properties
Density: 1.44 g / cm3
Solubility.
Let's easily dissolve in water, it is difficult to dissolve in alcohol.
The transparency and color of the solution.
A solution of 1 g of the drug in 10 ml of freshly boiled and chilled water should be transparent and colorless.
Alkalinity and acidity.
A few drops of phenolphthalein solution are added to the resulting solution; the solution should remain colorless. A pink color should appear from the addition of no more than 0.75 ml of 0.05 N. caustic soda solution.
0.15 g of the drug is dissolved in 14 ml of water, add 1 ml of diluted nitric acid and filtered. 10 ml of the filtrate must withstand the test for chlorides (no more than 0.02% in the drug).
Dissolve 1.5 g of the preparation in 25 ml of water, add 5 ml of diluted hydrochloric acid and filter. 10 ml of the solution must withstand the test for sulfates (no more than 0.02% in the preparation).
10 ml of the same filtrate must withstand the test for heavy metals (no more than 0.001% in the preparation).
Weight loss on drying.
About 1.5 g of the preparation (accurately weighed) is dried at 100-105 to constant weight. Weight loss should not exceed 3%.
Humidity: no more than 2%.
Note. Sodium benzoate for cooking injection solutions must additionally pass the test for iron: a solution of 0.4 g of the drug in 10 ml of water must withstand the test for iron (no more than 0.0075% in the drug).
6. Methods of obtaining
Sodium benzoate is obtained by the reaction of the interaction of benzoic acid with a solution of sodium hydroxide or sodium carbonate:
a) with sodium hydroxide:
sodium benzoate chemical analysis
b) with sodium carbonate:
2+ Na 2 CO 3 2 + H 2 O + CO 2
7. Qualitative analysis
The drug gives the characteristic reaction to benzoates and reaction B to sodium.
Qualitative reaction to benzoates:
To 2 ml of neutral benzoate solution (0.01-0.02 g of benzoate ion) add 0.2 ml of ferric chloride solution; a pinkish-yellow precipitate is formed.
6C 6 H 5 COONa + 2FeCl 3 + 10H 2 O (C 6 H 5 COO) 3 Fe Fe (OH) 3 7H 2 O + 6NaCl + 3C 6 H 5 COOH
Qualitative reaction to sodium ions:
a) Dry reaction. Sodium salt added to a colorless flame turns it yellow.
b) With zinccuranyl acetate: (a yellow crystalline precipitate forms)
Na + + Zn [(UO 2) 3 (CH 3 COO) 8] + CH 3 COOH + 9H 2 O = NaZn [(UO 2) 3 (CH 3 COO) 9] 9H 2 O + H +
c) With a solution of picric acid (a yellow crystalline precipitate forms)
С 6 H 2 (NO 2) 3 OH + Na +> С 6 H 2 (NO 2) 3 ONa + H +
Authenticity determination method according to State Pharmacopoeia X:
0.25 g of the drug is dissolved in 5 ml of water, add 1 ml of nitric acid, the separated white crystals are filtered off, washed with water and dried in a desiccator over sulfuric acid until constant weight is reached. The temperature of the benzoic acid obtained is 120-124.5 ° C.
Reaction scheme:
C 6 H 5 COONa + HNO 3 C 6 H 5 COOH + NaNO 3
8. Quantitative analysis
About 1.5 g of the drug (accurately weighed) is dissolved in 20 ml of water in a flask with a ground stopper with a capacity of 250 ml, 45 ml of ether, 3-4 drops of a mixed indicator (1 ml of methyl orange solution and 1 ml of methylene blue solution) are added and titrated 0.5 n. solution of hydrochloric acid until a lilac color appears in the aqueous layer. At the end of the titration, shake well the contents of the flask.
1 ml 0.5 N. hydrochloric acid solution corresponds to 0.07205 g of sodium benzoate, which, in terms of dry matter, must be at least 99.0%.
9. Application
1. Preparation: Sodium benzoate
Pharmacological group: secretolytics and stimulants of the motor function of the respiratory tract.
As an expectorant - alone (per se) and as part combination drugs... When taken orally, it enhances the secretion of the mucous membrane of the respiratory tract.
2. Preparation: Caffeine-sodium benzoate
Pharmacological group: breathing stimulants, psychostimulants
Diseases accompanied by depression of the central nervous system, functions of the cardiovascular and respiratory systems (including drug poisoning, infectious diseases), spasms of cerebral vessels (including migraine), decreased mental and physical performance, drowsiness, enuresis in children, respiratory disorders (periodic breathing, idiopathic apnea) in newborns (including premature babies).
10. Storage conditions
In a well-sealed container, in a dry, dark place.
