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LECTURE № 7

LECTURE № 7 Aromatic compounds as drugs ( p- Aminophenol derivatives, quinones, phenols). Acids of aromatic series, their salts, esters and amides as drug substances associate prof. Mosula L. M. The Plan 1. Derivatives of p- aminophenol as drug.

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LECTURE № 7

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  1. LECTURE № 7 Aromatic compounds as drugs (p-Aminophenol derivatives, quinones, phenols). Acids of aromatic series, their salts, esters and amides as drug substances associate prof. Mosula L. M.

  2. The Plan • 1. Derivatives ofp-aminophenol as drug. • 2. Quinones, which are used in medicine. • 3. Phenols as drugs. • 4. Aromatic acids and their salts, which are used in medicine. • 5. Esters of aromatic acids as drugs. • 6. Amides of aromatic acids and their derivatives, which are used in medicine.

  3. p-Aminophenol derivatives • The hydroxilated (o, m, p), better known as the aminophenols, are quite interesting from the standpoint of being considerably less toxic than aniline. The para-compounds (C-3) is of particular interast from two standpoint: namely it is the metabolic product of aniline, and it is the least toxic of the three possible aminophenols. It also possesses a strong antipyretic and analgesic action. However, it is too toxic to serve as a drug, and for this reason, there were numerous modifications attempted. • One of the first was acetylation of the amine group to provide N-acetyl-p-aminophenol (acetaminophenol), a producr that retained a good measure of the desired activities. Another approach to the detoxication of p-aminophenol was the atherification of the phenolic group. The best known of these are anisidine(C-9) and phenetidine (C-10), which are the methyl and ethyl ethers, respectively. However, it becomes apparent that a free amino group in these compounds, although promoting a strong antipyretic action, was also conducive to methemoglobin formation. The only exception to the preceding was for compounds in which a carboxyl group or sulfonic acid group had been substituted on the benzene nucleus. In these compounds, however, the antipyretic activity also had disappeared. The foregoing consideration led to the preparation of the alkyl ethers of N-acetyl-p-aminophenol of which the ethyl ether was the best and is known as phenacetin (C-11). The methyl and propyl homologues were undesirable from the standpoint of causing emesis, salivation, diuresis and other reactions. Alkylation of the nitrogen with a methyl group has a potentiating effect on the analgesic action, but, unfortunately, has a highly irritant action on mucous membranes.

  4. Paracetamol • General Notices • Paracetamolum • СН3СОNHC6H4OH • C8H9NO2 М m. = 151,2 g/mol • The chemical name: N - (4-hydroxiphenyl) • p-acetaminophenol. • Content • 99.0 per cent to 101.0 per cent (dried substance).

  5. Obtaining1. Nitrosation of phenol with the next reduction and aceetylation:

  6. CHARACTERS • Appearance • White, crystalline powder. • Solubility • Sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. • IDENTIFICATION • First identificationA, C. • Second identificationA, B, D, E.

  7. A. Melting point(2.2.14): 168 °C to 172 °C. • B. UV-spectroscopy. Dissolve 0.1 g in methanol R and dilute to 100.0 ml with the same solvent. To 1.0 ml of the solution add 0.5 ml of a 10.3 g/l solution of hydrochloric acid R and dilute to 100.0 ml with methanol R. Protect the solution from bright light and immediately measure the absorbance (2.2.25) at the absorption maximum at 249 nm. The specific absorbance at the maximum is 860 to 980. • C.Infrared absorption spectrophotometry(2.2.24). • PreparationDiscs. • Comparisonparacetamol CRS.

  8. D.Indophenol test after acid hydrolysis(for a primary aromatic amino group).To 0.1 g add 1 ml of hydrochloric acid R, heat to boiling for 3 min, add 1 ml of water R and cool in an ice bath. No precipitate is formed. Add 0.05 ml of a 4.9 g/l solution of potassium dichromate R. A violet colour develops which does not change to red(difference from Phenacetinum).

  9. E. It gives the reaction of acetyl (2.3.1). Heat over a naked flame. • About 15 mg test substances place in a test tube in length about 180 mm and external diameter 18 mm and add 0,15 ml of phosphoric acid R. Close test tube by means of stopper, through which 10 mm which contains water R are passed a small test tube the in length about 100 mm and in external diameter and carries out a refrigerator role. On an external surface of a smaller test tube place 1 drop of lanthanum nitrate solution R. If substance rather easily hydrolyzes, the device place on 5 mines at a water heater, then take out a smaller test tube. For substances, which it is difficult hydrolyzes, a mix slowly heat up on an open flame to boiling. A drop remove, mix on a porcelain plate about 0,05 ml of 0,01 M. iodine solution. On drop edge put 0,05 ml of ammonia diluted solution R2; through 1–2 mines in a junction of two drops there is a dark blue colouring which amplifies and remains during a short time interval. • La (NO3) 3 + 2CH3COOK + NH4OH = LaOH (CH3COO) 2 + NH4NO3 + 2 KNO3 • LaOH (CH3COO) 2 + I2 = LaOH (CH3COO) 2 I2 • Dark blue colouring

  10. Other reactions of identification1. SPU. Formation azo dye (identification of a primary aromatic amino group after acid hydrolysis). The examinee a solution acidifyHCl diluted R, add 0,2 ml of solution sodium nitrite R NaNO2 a and through 1–2 mines add 1 ml of a solution -naphthol; there is an intensive orange or red colouring and, as a rule, the precipitate of the same colour is formed. orange or red

  11. 2. Formation azo dye from diazonium salts(identification phenolic hydroxyl).At interaction with diazonium salts occurs azocoupling in o-position from OH-group to formation azo dye of red colour: azo dye of red colour

  12. 3. Interaction with solution of iron (III) chloride(presence phenolic hydroxyl). 0,1 g a drug shake up about 10 ml of water and add some drops of a solution FeCl3; there is a blue-violet colouring: • СН3СОNHC6H4OH + FeCl3 = СН3СОNHC6H4OFeCl2 + HCl • blue-violet • 4. Acid hydrolysis with the next identification of acetic acid.0,1 g drug cautiously boil about 2 mlof sulphatic aciddiluted H2SO4 during 2 mines; there is a smell acetic acid CН3CООН: • СН3СОNHC6H4OH + НОН = H2NC6H4OН + СН3СООH TESTS Related substances Liquid chromatography (2.2.29). Prepare the solutions immediately before use. Heavy metals (2.4.8) Maximum 20 ppm. Loss on drying (2.2.32) Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 °C. Sulphated ash (2.4.14) Maximum 0.1 per cent, determined on 1.0 g.

  13. ASSAYCeriumetry, direct titration Dissolve 0.300 g in a mixture of 10 ml of water R and 30 ml of dilute sulphuric acid R. Boil under a reflux condenser for 1 h, cool and dilute to 100.0 ml with water R. To 20.0 ml of the solution add 40 ml of water R, 40 g of ice, 15 ml of dilute hydrochloric acid R and 0.1 ml of ferroin R. Titrate with 0.1 M cerium sulphate until a greenish-yellow colour is obtained. Carry out a blank titration. Еm (C8H9NO2) = M. m./2 1 ml of 0.1 M cerium sulphate is equivalent to 7.56 mg of C8H9NO2.

  14. STORAGE • Protected from light. • Action and use • Analgesic and antipyretic. • Preparations • Co-codamol Tablets • Effervescent Co-codamol Tablets • Co-dydramol Tablets • Co-proxamol Tablets • Paediatric Paracetamol Oral Solution • Paracetamol Oral Suspension • Paracetamol Suppositories • Paracetamol Tablets • Dispersible Paracetamol Tablets • Soluble Paracetamol Tablets

  15. Quinone derivatives • Vitamin K • The term vitamin K was applied to the vitamin isolated from alfalfa, and a similar principle from fishmeal was named vitamin K2. Vitamin K2 refers to a series of compounds called the menaquinones. These have a longer side chain with more unsaturation. Many other closely related compounds possess vitamin K activity. The synthetic compounds menadione and menadiol are referred to as vitamin K3 and K4. • Vitamin K is a naphthoquinone derivative containing diterpenoid units biosynthesized by the intermediate, geraylpyrophosphate.

  16. Numerous compounds have been tested for their antihemorrhagic activity, and significant biologic activity is manifested in compounds with the following structure when: 1. ring A is aromatic or hydroaromatic 2. ring A is not substituted 3. ring B is aromatic or hydroaromatic 4. R equals OH, CO, OR, OAc (the R in OR equals methyl or ethyl) 5. R’ equals methyl 6. R” equals H, sulfonic acid or an alkyl group containing ten or more carbon atoms. A double bond in the β, γ-position of this alkyl group enhances potency, whereas, if the double bound is further removed, it exerts no effect. Isoprenoid groups are more effective than straight chains. 7. R”’ equals H, OH, NH2, CO, OR, Ac (the R in OR equals methyl or ethyl). It is interesting that, if ring A is benzenoid, the introduction of sulfur in place of –CH=CH- in this ring in 2-methylnaphthoquinone permits the retention of some antihemorrhagic activity.

  17. Products: • Menadione (2-methyl-1,4-naphthoquinone; menaphthone; thyloquinone). • On a mole-for-mole basis, menadione is equal to vitamin K1 in activity and can be used as a complete substitute for this vitamin. It is effective orally, intravenously and intramuscularly. • Menadione Sodium Bisulfite (2-methyl-1,4-naphthoquinone sodium bisulfite; Hykinone, Vikasol) is prepared by adding a solution of sodium bisulfite to menadione. Menadione sodium bisulfite occurs as a white, crystalline, odorless powder. One gram of it dissolves in about 2 ml of water, and it is slightly soluble in alcohol. It decomposes in the presence of alkali to liberate the free quinone.

  18. Menadione Sodium Diphosphate (tetrasodium 2-methyl-1,4-naphthalenediol bis(dihydrogen phosphate); Synkayvite; Kappadione) is a white hygroscopic powder, very soluble in water, giving solutions that have a pH of 7 to 9. It is available in ampules for use subcutaneusly, intramuscularly, intravenously and in tablets for oral administration.

  19. Identification • A. Menadione Sodium Bisulfite and Menadione Sodium Diphosphate yield the reaction characteristic of sodium salts and burn with yellow flame. • B. Menadione Sodium Bisulfite reacts with concentrated sulphuric acid to form sulphur(IV) oxide. C. Destruction of Menadione Sodium Bisulfite in base medium to sodium sulphite and 2-methyl-1,4- naphthoquinone. 2-Methyl-1,4- naphthoquinone may be identified by its melting point (104-107*C). This reaction may be used for assay of vitamin K. For this reason reduce obtained 2-methyl-1,4- naphthoquinone to 1,4-dioxi-2-methylnaphtaline and titrate with 0.2N Ce(SO4)3 using a o-phenantroline as an indicator.

  20. Derivatives of phenols • Phenols are the derivatives of aromatic hydrocarbons containing in a molecule one or several hydroxygroups, which are directly connected with an aromatic ring.

  21. Phenolphthalein • (Ph Eur monograph 1584) • C20H14O4 318.377-09-8 • Action and use • Laxative. • DEFINITION • Phenolphthalein contains not less than 98.0 per cent and not more than the equivalent of 101.0 per cent of 3,3-bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one, calculated with reference to the dried substance.

  22. Phenol • (Ph Eur monograph 0631) • C6H6O M.m. 4.1108-95-2

  23. Obtaining • From coal pitch • At processing of coal pitch receive various products (oils), including phenol. With that end in view process alkali; phenolate С6Н5ОNa which we will well dissolve in water is formed and easily separates from insoluble impurity in water and other components of coal pitch: • С6Н5ОН + NaОН = С6Н5ОNa + Н2О • The received solution of phenolate process carbonic gasСО2 or the diluted mineral acid, for example, HCl. Thus receive phenol which is partially dissolved in water: • С6Н5ОNa + Н2О + СО2 = С6Н5ОН + NaНСО3 • С6Н5ОNa + HCl = С6Н5ОН + NaCl • The received product overtake and collect fraction which boils at 180–200 C.

  24. 2. A synthetic methodfrom benzol. • a) Sulphonatoin of benzolby means of sulphatic acidН2SO4 with formation benzolsulphoacid: b) eutralizationof a product by means of Са (OH) 2 with formation calcium salts of benzolsulphoacid: Surplus Ca(OH)2 eliminate by means of sulphatic acid: Са (OH) 2 + Н2SO4 = СаSO4 + 2Н2О

  25. c) After filtering a filtrate process of solution sodium carbonate Na2CO3; it is formed sodium salt of benzolsulphoacid: d) The received solution evaporate and alloy with alkali NaOH; sodium phenolate is formed: e) Atprocessing of phenolate by sulphatic acidН2SO4 obtain phenol: The obtained product overtake and collect fraction which boils at 178–182 C.

  26. 2. Synthesis from benzene chloride: • С6Н5Сl + НOH С6Н5ОH + HCl • 3.Synthesis from benzolsulphoacid: • С6Н5SO3H + 2NaOH С6Н5ОNa + NaHSO3 + H2O • С6Н5ОNa + HCl С6Н5ОH + NaCl • DEFINITION • Phenol contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of C6H6O. • CHARACTERS • Colourless or faintly pink or faintly yellowish crystals or crystalline masses, deliquescent, soluble in water, very soluble in alcohol, in glycerol and in methylene chloride.

  27. IDENTIFICATION • A.Oxidation of phenol by means of sodium hypochlorite (NAClO) solution in the presence of concentrated ammonia(indophenol test).Dissolve 0.5 g in 2 ml of concentrated ammonia R. The substance dissolves completely. Dilute to about 100 ml with water R. To 2 ml of the dilute solution add 0.05 ml of strong sodium hypochlorite solution R. A blue colour develops and becomes progressively more intense. blue colour

  28. B.Reaction with a neutral iron (III) chloridesolution(reaction for phenolic hydroxyl).To 1 ml of solution S (see Tests) add 10 ml of water R and 0.1 ml of iron (III) chloride(ferric chloride) solution R1. A violet colour is produced which disappears on addition of 5 ml of 2-propanol R. This reaction it is possible to distinguish a solution of phenol from a solution of salicylic acid (phenolic acid); in this case colouring remains at presence of acetic acid.

  29. C.Reaction with bromine water (Br2)(reaction for benzene ring). To 1 ml of solution S add 10 ml of water R and 1 ml of bromine water R. A pale-yellow precipitate is formed. • 2,4,6-tribromphenol • pale-yellow precipitate • D. SPU. IR-spectroscopy. The IR-spectrum of absorption of substance solution in ССl4 for should correspond to reference spectrum SPU of phenol.

  30. Not pharmacopoeial reactions • Formation azo dye with diazonium salts.The alkaline solution of phenol with diazonium salts forms azo dyes durk red or orange-red colour. Azocoupling proceeds, basically, in para-position to OH-group (substitute of І sorts) and if this position is occupied replacement occurs in ortho-position: dark red or orange-red colour

  31. Reaction with nitric acid • At interaction with HNO3 (depending on its concentration and quantity) can be formed mononitro-derivatives (orto - or para-) or 2,4,6-trinitrophenol (yellow dye – picric acid): • a) with 20 % solution HNO3: o-nitrophenolp-nitrophenol b) withHNO3 concentrated: 2,4,6-trinitrophenol (yellow dye – picric acid)

  32. 3. Reaction with the Marki reagent (solution of formaldehydeНСНО in conc. sulphatic acid H2SO4); it is formed aurin dyeof red colour. • aurin dye of red colour

  33. ASSAY • Bromatometry, back titration, with iodometric finishing • Dissolve 2.000 g in water R and dilute to 1000.0 ml with the same solvent. Transfer 25.0 ml of the solution to a ground-glass-stoppered flask and add 50.0 ml of 0.0167 M bromide-bromate and 5 ml of hydrochloric acid R, close the flask, allow to stand with occasional swirling for 30 min and then allow to stand for a further 15 min. Add 5 ml of a 200 g/l solution of potassium iodide R, shake and titrate with 0.1 M sodium thiosulphate until a faint yellow colour remains. Add 0.5 ml of starch solution R and 10 ml of chloroform R and continue the titration with vigorous shaking. • Carry out a blank titration. • Chemism it is possible to present by means of such equations: • KBrO3 + 5KBr + 6HCl = 3Br2 + 6KCl + 3H2O • Allocated bromine Br2 reacts with phenol С6Н5ОН with formation of a white precipitate 2,4,6-tribromphenol:

  34. Not reacted bromine Br2 reacts with KI with formation of iodine I2: • Br2 + 2KI = I2 + 2KBr • The allocated iodinetitrate by standard solution Na2S2O3 in the presence of the indicator of starch and solvent of chloroform before disappearance of dark blue colouring (add starch towards the end of titration): • I2 + 2Na2S2O3 = 2NaI + Na2S4O6 • I2 + 2е 2I– • 2S2O32– – 2е S4O62– • Еm (C6Н6О) = М m./6; k (KBrO3) = 6 1 ml of 0.0167 M bromide-bromate is equivalent to 1.569 mg of C6H6O.

  35. STORAGE • Store in an airtight container , protected from light. • Action and use • Antiseptic; antimicrobial preservative; antipruritic. • Preparations • Aqueous Phenol Injection • Oily Phenol Injection • Phenol • Ph Eur • and Glycerol Injection

  36. Aromatic acids and their derivatives • Aromatic acids and their salts • Aromatic acids – derivatives of aromatic hydrocarbons in which molecules in an aromatic ring one or several atoms of the Hydrogene are substituted on carboxyl group – СООН. • Properties. Aromatic acids – crystal substances, usually a little soluble in water and well soluble in organic solvents (spirit, benzene, chloroform). Constants of their acidity a little more than at fat acids. In particular, benzoic acid С6Н5СООН is a little stronger acid in comparison with СН3СООН, that speaks effect of linking of group –СООН with С6Н5-ring. Possess the general chemical properties, characteristic for carbopxylic acids: form salts, anhydrides, halogenanhydride, esters, amides, etc.

  37. Pharmacological action and medical application. Introduction carboxyl group – СООН in a molecule of aromatic hydrocarbon lowers toxicity of conpound and simultaneously causes occurrence of cauterising, irritating action on tisue. Apply aromatic acids as antiseptic, and their salts – as carriers specific anions. The best solubility of salts in water reduces irritating action. • Benzioc acid in an organism easily react with amino acid glycol with formation hyppuric acid, which quantity testifies to a functional condition of a liver. • In medical practice apply benzoic and salicylic acids, and also their salts: sodium benzoate and sodium salicylate.

  38. Benzoic Acid • General Notices • (Ph Eur monograph 0066) • C7H6O2M.m.=122.165-95-0 • DEFINITION • Benzoic acid contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of benzenecarboxylic acid. • Benzoic acid and its esters occur naturally in gum benzoin and in Peru and tolu balsams. It is found as a white crystalline solid that slowly sublimes at room temperature and is steam distillable. It is slightly soluble in water, but more soluble in alcohol and other polar organic solvents.

  39. Obtaining • Now benzoic acid obtain several synthetic methods. • 1. Toluene oxidation in the sulphatic-acid medium by means of MnO2 or K2Cr2O7: • С6Н5СН3 + 3MnO2 + 3H2SO4 = С6Н5СООН + 3MnSO4 + 4Н2О • С7Н8 + 2Н2О – 6е  С7Н6О2 + 6Н+ • MnO2 + 4Н+ + 2е  Mn2+ + 2Н2О • С6Н5СН3 + 3MnO2 + 6H+  С6Н5СООН + 3Mn2+ + 4Н2О2. • 2. Chlorination of toluene with the further hydrolysis benzenetrichloride:

  40. CHARACTERS • A white, crystalline powder or colourless crystals, odourless or with a very slight characteristic odour, slightly soluble in water, soluble in boiling water, freely soluble in alcohol and in fatty oils. • IDENTIFICATION • A. Melting point (2.2.14): 121 °C to 124 °C. • B. Solution S (see Tests) gives reaction (a) of benzoates (2.3.1). • a) Reaction with iron (ІІІ) chloride • To 1 ml of the solution specified in separate article, add 0,5 ml solution of iron (ІІІ) chloride R1; the light-yellow precipitate, soluble in ether R is formed. • C6H5COOH + NaOH = C6H5COONa + H2O • 6C6H5COONa + 2FeCl3 + 10H2O = (C6H5COO)3FeFe(OH)37H2O + 3C6H5COOH + 6NaCl light-yellow

  41. SPU. Preparation sublimation • Some crystals of the crushed drug moisten with sulphatic acid R, cautiously heat up a test tube bottom; on test tube walls white touch C6H5COOH is formed. • Not pharmacopoeial reaction. Reaction with solution AgNO3 • C6H5COOH + AgNO3 = C6H5COOAg + HNO3 • white • TESTS • Solution S • Dissolve 5.0 g in alcohol R and dilute to 100 ml with the same solvent. • Appearance of solution • Solution S is clear (2.2.1) and colourless (2.2.2, Method II). • Carbonisable substances

  42. Oxidisable substances • Dissolve 0.2 g in 10 ml of boiling water R. Cool, shake and filter. To the filtrate add 1 ml of dilute sulphuric acid R and 0.2 ml of 0.02 M potassium permanganate. After 5 min, the solution is still coloured pink. • Halogenated compounds and halides. • Heavy metals (2.4.8) • 12 ml of solution S complies with limit test B for heavy metals (10 ppm). Prepare the standard using a mixture of 5 ml of lead standard solution (1 ppm Pb) R and 5 ml of alcohol R. • Sulphated ash (2.4.14) • Not more than 0.1 per cent, determined on 1.0 g.

  43. ASSAY • Alkalimetry in alcohol solution, direct titration • Dissolve 0.200 g in 20 ml of alcohol R and titrate with 0.1 M sodium hydroxide, using 0.1 ml of phenol red solution R as indicator, until the colour changes from yellow to violet-red. • C6H5COOH + NaOH = C6H5COONa + H2O • Еm(C6H5COOH) = М m. • 1 ml of 0.1 M sodium hydroxide is equivalent to 12.21 mg of C7H6O2. • Storage • In dense corked container, protecting from action of a moisture and light. • Action and use • Antimicrobial preservative. • Benzoic acid is employed externally as an antiseptic in lotions, ointment and mouthwashes. It is more effective as a preservative in foods and pharmaceutic products at low pH. When used as a preservative in emulsions, its effectiveness depends upon both pH and distribution into the two phases. • Preparations • Compound Benzoic Acid Ointment • Benzoic Acid Solution

  44. Sodium benzoate • Ph Eur • General Notice • (Ph Eur monograph 0123) • C7H5NaO2M.m.=144.1532-32-1 • DEFINITION • Sodium benzoate contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of sodium benzenecarboxylate, calculated with reference to the dried substance.

  45. Obtaining • Dissolution of benzoic acid in a hot solution of sodium carbonate Na2CO3. • 2С6H5COOH + Na2CO3 = 2С6H5COONa + H2O + CO2 • The received solution condenses before the crystallisation, the allocated crystals filter and dry up. • CHARACTERS • A white, crystalline or granular powder or flakes, slightly hygroscopic, freely soluble in water, sparingly soluble in alcohol (90 per cent V/V).

  46. IDENTIFICATION • A. It gives reactions (b) and (c) of benzoates(2.3.1). • b) Sublimation of benzoic acid. Some crystals of the crushed drug moisten with sulphatic acid R, cautiously heat up a test tube bottom; on test tube walls white touch C6H5COOH is formed. • 2C6H5COONa + H2SO4 = 2C6H5COOH + Na2SO4 • c) Definition of melting point (must be 121 °C to 124 °C) of benzoic acid, after interaction drug with chloride acid. • To drug solution add HCl R; the precipitate which after recrystallization from warm water R and drying in vacuum has melting point (121 °C to 124 °C) is formed. • C6H5COONa + HCl = C6H5COOH + NaCl

  47. ASSAY • Acidimetry,non-agueous titration • Dissolve 0.250 g in 20 ml of anhydrous acetic acid R, heating to 50 °C if necessary. Cool. Using 0.05 ml of naphtholbenzein solution R as indicator, titrate with 0.1 M perchloric acid until a green colour is obtained. • C6H5COONa + HClO4 = NaClO4 + C6H5COOH • Еm(C6H5COONa) = М. m. • Storage • In the dense corked container, protecting from action of a moisture and light. • Action and use • Expectorant. • It is used as a preservative in acidic liquid preparations in which benzoic acid is released. • Preparations • Powder, mixture.

  48. Esters of aromatic carboxylic acids • Methyl Salicylate • General Notices • (Ph Eur monograph 0230) • C8H8O3 M.m. = 152.1 • Chemical name: methyl salicylate, methyl 2-hydroxybenzoate, methyl ester of 2-oxybenzoic acid, methyl ester of salicylic acid. • DEFINITION • Methyl salicylate contains not less than 99.0 per cent m/m and not more than the equivalent of 100.5 per cent m/m of methyl 2-hydroxybenzoate.

  49. CHARACTERS • A colourless or slightly yellow liquid, very slightly soluble in water, miscible with alcohol and with fatty and essential oils. • IDENTIFICATION A. Heat 0.25 ml with 2 ml of dilute sodium hydroxide solution R on a water-bath for 5 min. Add 3 ml of dilute sulphuric acid R. A crystalline precipitate is formed. Filter. The precipitate, washed with water R and dried at 100 °C to 105 °C, melts (2.2.14) at 156 °C to 161 °C. • HOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2O • NaOC6H4COONa + 2HCl = HOC6H4COOH + 2NaCl It is possible to confirm formation of salicylic acid with reaction with the Marki reagent; it is formed aurin dye of red colour . B. To 10 ml of a saturated solution add 0.05 ml of iron (III) chloride (ferric chloride) solution R1. A violet colour develops. • СН3ОСОС6Н4ОН + FeCl3 = СН3ОСОС6Н4ОFeCl2 + HCl • violet colour

  50. ASSAY • Acidimetry after alkaline hydrolysis, back titration • HOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2O • excess • NaOC6H4COONa + HCl = HOC6H4COONa + 2NaCl • T • 2NaOH + 2HCl = 2NaCl + 2H2O • rest • Еm(C8H8O3) = М. м./2 • STORAGE • Store protected from light. • Action and use • Counter-irritant. • Preparations • Methyl Salicylate Liniment • Methyl Salicylate Ointment

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