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Prepare to lesson 13

June 24, 2024

Theme: Pharmaceutical analysis of phenols, aromatic carboxylic acids and their salts as drug substances: synthesis, properties, analysis, storage, action and use.

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. Can be one – two-and three- hydroxygroups. For example,

Phenol resorcinol pyrogallol

Depending on a relative positioning phenolic гидроксилов in molecules of two-and three-nuclear phenols, there can be various isomeasures (orto – meta-and pair-). For example:

Pyrocatechol resorcinol hydroquinine

(o-dioxybenzen) (m-dioxybenzen) (p-dioxybenzen)

Properties. The majority of phenols represents crystal substances with a strong characteristic smell. One-nuclear phenols badly растворимы in water, and two-nuclear, unlike one-nuclear, are well dissolved in water.

Chemical properties of phenols are caused, on the one hand, by presence in a molecule hydroxygroup with mobile atom of the Hydrogene, and with another – aromatic properties benzoic cycle.

1. Acid properties of phenols are expressed more strongly, than at spirits owing to interaction of electronic pair atom Оксигена of group withp-elektronami an aromatic ring. In connection with acid properties phenols are easily dissolved in solutions of alkalis. Therefore, unlike spirits which in usual conditions with alkalis do not react, phenols thus form salts – phenolates which in water strongly hydrolyze:

С₂Н₅ОН + NaOH ≠

С₆Н₅ОН + NaOH = С₆Н₅ОNa + H₂O

Underlining acid properties, phenol name carbolic acid. However acid properties are expressed so poorly, what even such weak acid as карбонатная Н₂СО₃, supersedes phenol from their salts (phenolates):

2С₆Н₅ОNa + H₂O + СО₂ = 2С₆Н₅ОН + Na₂СO₃

Therefore unlike acids, phenols do not co-operate with carbonates of alkaline metals.

2. The reactions of replacement caused by presence of an aromatic kernel, in orto – and para-position to phenolic hydroxyl: halogenatium (bromderivativs of phenols drop out in a deposit), nitration (nitrocompounds are painted in yellow colour), sulphonation, etc.

3. Reactions of condensation with aldehydes in the presence of sulphatic acid with formation aurin dyes.

Example – reaction with the Mark reactant (a mix of formaldehyde and concentrated Н₂SO₄):

aurin dye of red colour

4. A combination to diazonium salts in the alkaline environment with formation azo dye.

As a reactant usually take 0,1 % solution sulfanilic acid and 1 % solution nitrite sodium in the sour environment:

azo dye red colour

5. Formation of the painted complex compounds with salts of heavy metals, in particular with iron (ІІІ) chloride. The structure of formed complexes and their colour can be various: С₆Н₅ОFeCl₂; (С₆Н₅О) ₂FeCl;(С₆Н₅О) ₃Fe, etc.

All phenols react with iron(III) chloride solution to form a color compounds. Phenols with one hydroxy group form a violet compounds, phenols with two OH- groups – blue compounds, thymol does not react with iron chloride.

6. Oxidation of phenols (bromic water, lime chlorine) in the presence of ammonia with formation indophenol, painted in dark blue colour.

Phenol quinone quinone imide indophenol

Assay of phenols

More often quantitative definition of phenols spend bromatometry. With that end in view it is possible to use both a method direct, and back titration.

1. Bromatometry, direct titration. An investigated solution of phenol acidify HCl, add KBr and titrate with standard solution of KBrO₃ before disappearance of yellow colouring, characteristic bromine for surplus in reaction. As the indicator in this method use methyl orange which becomes colourless in a point of equivalence from surplus of bromine.

KBrO₃ + 5KBr + 6HCl = 3Br₂ + 6KCl + 3H₂O

2. Bromatometry, back titration, with iodometric finishing.

To an investigated solution add KBr, solution HCl and excess of standard solution KBrO₃.

KBrО₃ + 5KBr + 6HCl = 3Br₂ + 6KCl + 3H₂O

The part of bromine Br₂ reacts with phenol (see above), instead of the reacted bromine define by iodometry: add KI and allocated iodine I₂titrate with standard solution Na₂S₂O₃in the presence of starch (before disappearance of dark blue colouring):

Br₂ + 2KI = I₂ + 2KBr

I₂ + 2Na₂S₂O₃ = 2NaI + Na₂S₄O₆

Pharmacological action

Phenols show antiseptic action which is based on their ability to curtail fibers. Phenols possess bactericidal action, i.e. are capable to kill microorganisms or to create adverse conditions for their ability to live.

In medical practice apply: phenol, resorcinol, thymol, xeroformium, phenolphthalein, etc.

Phenols as drugs

Phenol

(Ph Eur monograph 0631)

C₆H₆O M.m. 4.1 108-95-2

Synthesis

1. 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 gas СО₂ 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.

2. A synthetic method from benzol.

a) Sulphonatoin of benzol by means of sulphatic acid Н₂SO₄ with formation benzolsulphoacid:

b) eutralization of a product by means of Са (OH) ₂ with formation calcium salts of benzolsulphoacid:

Surplus Ca(OH)₂eliminateby means of sulphatic acid:

Са (OH) ₂ + Н₂SO₄ = СаSO₄¯ + 2Н₂О

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) At processing of phenolate by sulphatic acid Н₂SO₄ obtain phenol:

The obtained product overtake and collect fraction which boils at 178–182 °C.

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.

IDENTIFICATION

A. Oxidation of phenol by means of sodium hypochlorite solution in the presence of concentrated ammonia (indophenol’s reaction). 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

B. Reaction with a neutral iron (III) chloride solution (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.

C. Reaction with bromic 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.

Not pharmacopoeial reactions

1. 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

2. Interaction 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-nitrophenol p-nitrophenol

b) with HNO₃concentrated:

2,4,6-trinitrophenol

(yellow dye – picric acid)

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

aurin dye of red colour

TESTS

Solution S

Dissolve 1.0 g in water R and dilute to 15 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and not more intensely coloured than reference solution B₆ (2.2.2, Method II).

Acidity

To 2 ml of solution S add 0.05 ml of methyl orange solution R. The solution is yellow.

Freezing point (2.2.18)

Not less than 39.5 °C.

Residue on evaporation

Not more than 0.05 per cent, determined by evaporating 5.000 g to dryness on a water-bath and drying the residue at 100 °C to 105 °C for 1 h.

ASSAY

1. 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:

Not reacted bromine Br₂ reacts with KI with formation of iodine I₂:

Br₂ + 2KI = I₂ + 2KBr

The allocated iodine titrate 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^–

2S₂O₃^2– – 2е ® S₄O₆^2–

Е_m (C₆Н₆О) = М m./6; k (KBrO₃) = 6

1 ml of 0.0167 M bromide-bromate is equivalent to 1.569 mg of C₆H₆O.

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

Resorcinol

(Ph Eur monograph 0290)

C₆H₆O₂ M.m. = 110.1 108-46-3

Resorcinol (m-dihydroxybenzene, resorcin) is synthetically prepared.

Obtaining

Synthesis from benzol and H₂SO₄ with the subsequent fusion with alkali NaOH, and then acid action under the following scheme:

DEFINITION

Resorcinol contains not less than 98.5 per cent and not more than the equivalent of 101.0 per cent of benzene-1,3-diol, calculated with reference to the dried substance.

CHARACTERS

A colourless or slightly pinkish-grey, crystalline powder or crystals, turning red on exposure to light and air, very soluble in water and in alcohol.

IDENTIFICATION

A. Melting point (2.2.14): 109 °C to 112 °C.

B. Interaction with chloroform in the alkaline medium.Dissolve 0.1 g in 1 ml of water R, add 1 ml of strong sodium hydroxide solution R and 0.1 ml of chloroform R, heat and allow to cool. An intense, deep-red colour develops which becomes pale yellow on the addition of a slight excess of hydrochloric acid R.

C. Fusion with potassium hydrogen phthalate with formation fluoresceine in the alkaline medium (specific reaction). Thoroughly mix about 10 mg with about 10 mg of potassium hydrogen phthalate R, both finely powdered. Heat over a naked flame until an orange-yellow colour is obtained. Cool and add 1 ml of dilute sodium hydroxide solution R and 10 ml of water R and shake to dissolve. The solution shows an intense green fluorescence.

Technique in textbook. At heating of a substance with phthalic anhydride it is formed fusion (melt) yellow-orange colour. After dissolution fusion (melt) in solution NaOH appears intensively-green fluorescence (formation hydroxide fluoresceine).

green fluorescence

Other reactions of identification

Gives all reactions, characteristic for phenols (see phenol).

1. Reaction with iron (ІІІ) chloride

At addition to a water solution of a substance of solution FeCl₃ blue-violet colouring which at addition of a solution of ammonia NH₄OH passes in the brown-yellow is formed.

TESTS

Solution S

Dissolve 2.5 g in carbon dioxide-free water R and dilute to 25 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and not more intensely coloured than reference solution B₅ or R₅ (2.2.2, Method II) and remains so when heated in a water-bath for 5 min.

Acidity or alkalinity

To 10 ml of solution S add 0.05 ml of bromophenol blue solution R2. Not more than 0.05 ml of 0.1 M hydrochloric acid or 0.1 M sodium hydroxide is required to change the colour of the indicator.

Related substances

Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.

Test solution Dissolve 0.5 g of the substance to be examined in methanol R and dilute to 10 ml with the same solvent.

Reference solution Dilute 0.1 ml of the test solution to 20 ml with methanol R.

Apply separately to the plate 2 µl of each solution. Develop over a path of 15 cm using a mixture of 40 volumes of ethyl acetate R and 60 volumes of hexane R. Allow the plate to dry in air for 15 min and expose it to iodine vapour. Any spot in the chromatogram obtained with the test solution, apart from the principal spot, is not more intense than the spot in the chromatogram obtained with the reference solution (0.5 per cent).

Pyrocatechol

To 2 ml of solution S add 1 ml of ammonium molybdate solution R2 and mix. Any yellow colour in the solution is not more intense than that in a standard prepared at the same time in the same manner using 2 ml of a 0.1 g/l solution of pyrocatechol R.

Loss on drying (2.2.32)

Not more than 1.0 per cent, determined on 1.00 g of powdered substance by drying in a desiccator for 4 h.

Sulphated ash (2.4.14)

Not more than 0.1 per cent, determined on 1.0 g.

ASSAY

1. Bromatometry, back titration, with iodometric finishing

Dissolve 0.500 g in water R and dilute to 250.0 ml with the same solvent. To 25.0 ml of the solution in a ground-glass-stoppered flask add 1.0 g of potassium bromide R, 50.0 ml of 0.0167 M potassium bromate, 15 ml of chloroform R and 15.0 ml of hydrochloric acid R1. Stopper the flask, shake and allow to stand in the dark for 15 min, shaking occasionally. Add 10 ml of a 100 g/l solution of potassium iodide R, shake thoroughly, allow to stand for 5 min and titrate with 0.1 M sodium thiosulphate, using 1 ml of starch solution R as indicator.

Chemism it is possible to present such equations.

KBrO₃ + 5KBr + 6HCl = 3Br₂ + 6KCl + 3H₂O

Allocated bromine Br₂ reacts with resorcinol С₆Н₄(ОН)₂ with formation 2,4,6-tribromresocinol:

1 mol 6 equiv.

Not reacted bromine Br₂ reacts with KI with formation of iodine I₂:

Br₂ + 2KI = I₂ + 2KBr

The allocated iodine titrate by standard solution Na₂S₂O₃in the presence of starch before disappearance of dark blue colouring (add starch towards the end of titration):

I₂ + 2Na₂S₂O₃ = 2NaI + Na₂S₄O₆

I₂ + 2е ® 2I^–

2S₂O₃^2– – 2е ® S₄O₆^2–

SPU. In parallel spend control experience.

E_m (С₆Н₆О₂) =М. M./6; k (KBrO₃) = 6

1 ml of 0.0167 M potassium bromate is equivalent to 1.835 mg of C₆H₆O₂.

STORAGE

Store protected from light.

Ph Eur

Action and use

Keratolytic.

Ph Eur

Thymol

General Notices

(Ph Eur monograph 0791)

C₁₀H₁₄O M.m. 150.2 89-83-8

DEFINITION

Thymol is 5-methyl-2-(methylethyl)phenol.

Thymol (Isopropyl m-cresol)

Obtaining

1. Is obtained from oil of thyme by alkaline extraction followed by acidification.

2. A synthetic method from 3-metylphenol (m-cresol)

m-cresol isopropyl-m-cresol thymol

3. A synthetic method from p-isopropyltoluene (p-cymol)

CHARACTERS

Colourless crystals, very slightly soluble in water, very soluble in alcohol, freely soluble in essential oils and in fatty oils, sparingly soluble in glycerol. It dissolves in dilute solutions of alkali hydroxides.

IDENTIFICATION

First identification B.

Second identification A, C, D.

A. Melting point (2.2.14): 48 °C to 52 °C.

B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with thymol CRS.

C. Dissolve 0.2 g with heating in 2 ml of dilute sodium hydroxide solution R and add 0.2 ml of chloroform R. Heat on a water-bath. A violet colour develops.

D. Reaction with a mix concentrated H₂SO₄ and HNO₃ (specific reaction)

Dissolve about 2 mg in 1 ml of anhydrous acetic acid R. Add 0.15 ml of sulphuric acid R and 0.05 ml of nitric acid R. A bluish-green colour develops.

Gives all reactions of identification to phenols, except reaction with iron(ІІІ) chloride.

TESTS

Appearance of solution

Dissolve 1.0 g in 10 ml of dilute sodium hydroxide solution R. The solution is not more opalescent than reference suspension IV (2.2.1) and not more intensely coloured than reference solution R₆ (2.2.2, Method II).

Acidity

To 1.0 g in a 100 ml glass-stoppered conical flask add 20 ml of water R. Boil until dissolution is complete, cool and stopper the flask. Shake vigorously for 1 min. Add a few crystals of the substance to be examined to initiate crystallisation. Shake vigorously for 1 min and filter. To 5 ml of the filtrate, add 0.05 ml of methyl red solution R and 0.05 ml of 0.01 M sodium hydroxide. The solution is yellow.

Related substances

Examine by gas chromatography (2.2.28).

Test solution Dissolve 0.100 g in alcohol R and dilute to 10.0 ml with the same solvent.

Reference solution (a) Dilute 1 ml of the test solution to 100 ml with alcohol R.

Reference solution (b) Dilute 1 ml of reference solution (a) to 10 ml with alcohol R.

Reference solution (c) Dilute 5 ml of reference solution (b) to 10 ml with alcohol R.

The chromatography may be carried out using:

—a glass or steel column 4 m long and 2 mm in internal diameter packed with diatomaceous earth for gas chromatography R, impregnated with a mixture suitable for the separation of free fatty acids,

—nitrogen for chromatography R as the carrier gas at a flow rate of 30 ml/min,

—a flame-ionisation detector,

maintaining the temperature of the column at 80 °C, that of the injection port at 250 °C and that of the detector at 300 °C.

Inject 1 µl of each solution and, after 2 min, increase the temperature of the column to 240 °C at a rate of 8 °C/min and maintain at this temperature for 15 min. The test is not valid unless the peak in the chromatogram obtained with reference solution (b) has a signal-to-noise ratio not less than five. In the chromatogram obtained with the test solution, the sum of the areas of the peaks, apart from the principal peak, is not greater than the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent). Disregard any peak with an area less than that of the principal peak in the chromatogram obtained with reference solution (c).

Residue on evaporation

Evaporate 2.00 g on a water-bath and heat in an oven at 100 °C to 105 °C for 1 h. The residue weighs not more than 1.0 mg (0.05 per cent).

ASSAY

1. SPU. Bromatometry, back titration, with iodometric finishing

Shot of thymol dissolve in solution NaOH, add crystal KBr, excess HCl, 2–3 drops of the indicator methyl orange and at intensive shake up titrate by standard solution KBrO₃ before disappearance of pink colouring.

KBrO₃ + 5KBr + 6HCl = 3Br₂ + 6KCl + 3H₂O

1 mol 4 equivalent

The superfluous drop of bromine Br₂ (oxidizer) decolours the indicator the methyl orange.

E_m(C₁₀Н₁₄О) = М. м./4

STORAGE

Store protected from light.

Ph Eur

Action and use

Antimicrobial preservative; antiseptic.

Antiseptic, disinfectant and vermicidal agent.

Xeroformium SP X

Bismuthi tribromphenolas basicus

С₁₂Н₅Bi₃Br₆О₆M. m. = 1351,6 g/mol

Not less than 50,0 % and no more than 55,0 % Bi₂O₃

The chemical name: bismuth tribromophenol basic with bismuth oxide.

Obtaining

Synthetic method from phenol by means of bromination, interactions with alkali, and then with 10 % solution of bismuth nitrate:

Precipitate of xeroformium filter, wash out water and dry.

Properties

The description. A small amorphous powder of yellow colour with a weak original smell.

Solubility. It is practically insoluble in water, 95 % spirit, ether, chloroform. Decays at interaction with strong acids and alkalis.

Identification

1. Reactions for ions Bi^{3 +}

a) SPU. Reaction with solution of sodium sulphide (Na₂S) in chloride-acid medium. Test substance dissolve in chloride acid diluted R. Received solution boil during 1 minutes, cool and if it is necessary, filter. To a part of the received filtrate add water R; the white or light yellow precipitate BiOCl, which colour after addition of a solution of sodium sulphide Na₂S changes on brown (Bi₂S₃) is formed:

BiCl₃ + 2HOH ® BiOCl¯ + 2HCl

white

or light yellow

2Bi³⁺ + 3S^2– ® Bi₂S₃¯

brown

Another technique. Then shake up drug with water and a solution of sodium sulphide Na₂S appears black colouring:

2Bi³⁺ + 3S^2– ® Bi₂S₃¯

black

b) SPU. Reaction with thiourea in nitric-acid medium.

Investigated substance dissolve in HNO₃diluted, boil during 1 mines, cool and if it is necessary, filter. To a part of the received solution add a solution of thiourea; light-yellow-orange colouring is formed or the orange precipitate is formed. Then add a solution sodium fluoride; the solution does not become colourless within 30 minutes.

c) Not pharmacopoeial reaction. Interaction with solution KI

At addition to the acidified solution of drug of solution KI black precipitate BiI₃ , which is dissolved a lot of reactant with formation of complex salt K [BiI₄] is formed:

Bi³⁺ + 3I^– ® BiI₃¯

black

BiI₃ + KI = K[BiI₄]

2. Reaction with solution NaOH (for the rest tribromphenol)

Drug shake up with solution NaOH and filter. At acidifiing a filtrate by means of HCl it is allocated white precipitate of tribromphenol.

Precipitate filter, wash out water, dry up and identify by means of melting point (92)C).

Tests for cleanliness

1. Free tribromphenol (an inadmissible impurity)

Drug shake up from 95 % alcohol (in alcohol tribromphenol it is dissolved) and filter. At mixing of a filtrate with water the solution should remain transparent within 15 minutes In case of impurity presence alcoholic solution at dilution of water grows turbid.

2. Inadmissible impurity of Arsenic and Tellurium.

Assay

SPU. Chelatometry, direct titration, after a preliminary mineralization

Substance preliminary mineralized in flask by means of mix HNO₃ and HClO₄.

Direct titration warmed up to 70 °C an investigated solution by standard solution Na₂-EDTA in the medium of ammonia concentrated NH₄OH and presence of indicator mix xylenol orange (1 part of xylenol orange and 99 part KNO₃) before transition of colouring from pink-violet (complex BiInd) to yellow (colour of free indicator H₃Ind).

Chemism it is possible to present in the form of the equations:

Bi^{3 +} + H₃Ind BiInd + 3H ⁺

Calculation conduct on Bi₂O₃ which there should be 50,0–55,0 %.

Е_m= M. m. /2 Bi₂O₃

Storage

In dense corked container, protecting from action of a moisture and light.

Application. Astringent, drying and antiseptic.

Apply external in the form of a powder, dusting powder, ointment (3–10 %).

Aromatic acids and their derivatives

Aromatic acids and their salts

Aromatic acids – derivatives of aromatic hydrocarbons in which molecules in an aromatic kernel 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.

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.

Benzoic Acid

General Notices

(Ph Eur monograph 0066)

C₇H₆O₂ M.m.=122.1 65-95-0

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.

Obtaining

Now benzoic acid obtain several synthetic methods.

1. Toluene oxidation in the sulphatic-acid medium by means of MnO₂or K₂Cr₂O₇:

С₆Н₅СН₃ + 3MnO₂ + 3H₂SO₄ = С₆Н₅СООН + 3MnSO₄ + 4Н₂О

С₇Н₈ + 2Н₂О – 6е ® С₇Н₆О₂ + 6Н⁺

MnO₂ + 4Н⁺ + 2е ® Mn²⁺ + 2Н₂О

С₆Н₅СН₃ + 3MnO₂ + 6H⁺ ® С₆Н₅СООН + 3Mn²⁺ + 4Н₂О

2. Chlorination of toluene with the further hydrolysis benzenetrichloride:

3. Decarboxylation of phthalic acid, consisting of several stages.

a) Neutralization (saponification) phthalic acid by means of limy water Са (OH) ₂ with formation calcium phthalate:

b) Pyrolysis calcium phthalate at 330–350 °C with formation calcium benzoate (С₆Н₅СОО) ₂Са:

c) Interaction calcium benzoate with chloride acid HCl and formation benzoic acid:

(С₆Н₅СОО) ₂Са + 2HCl = 2С₆Н₅СООH + СаCl₂

The simplified record of process decarboxylation phthalic acid in the medium of limy water Са (OH) ₂ , which binds СО₂:

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

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

Dissolve 0.5 g with shaking in 5 ml of sulphuric acid R. After 5 min, the solution is not more intensely coloured than reference solution Y₅ (2.2.2, Method I).

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

All glassware used must be chloride-free and may be prepared by soaking overnight in a 500 g/l solution of nitric acid R, rinsed with water R and stored full of water R. It is recommended that glassware be reserved for this test.

Solution (a) Dissolve 6.7 g of the substance to be examined in a mixture of 40 ml of 1 M sodium hydroxide and 50 ml of alcohol R and dilute to 100.0 ml with water R. To 10.0 ml of this solution add 7.5 ml of dilute sodium hydroxide solution R and 0.125 g of nickel-aluminium alloy R and heat on a water-bath for 10 min. Allow to cool to room temperature, filter into a 25 ml volumetric flask and wash with three quantities, each of 2 ml, of alcohol R. Dilute the filtrate and washings to 25.0 ml with water R. This solution is used to prepare solution A.

Solution (b) In the same manner, prepare a similar solution without the substance to be examined. This solution is used to prepare solution B.

In four 25 ml volumetric flasks, place separately 10 ml of solution (a), 10 ml of solution (b), 10 ml of chloride standard solution (8 ppm Cl) R (used to prepare solution C) and 10 ml of water R. To each flask add 5 ml of ferric ammonium sulphate solution R5, mix and add dropwise and with swirling 2 ml of nitric acid R and 5 ml of mercuric thiocyanate solution R. Shake. Dilute the contents of each flask to 25.0 ml with water R and allow the solutions to stand in a water-bath at 20 °C for 15 min. Measure at 460 nm the absorbance (2.2.25) of solution A using solution B as the compensation liquid, and the absorbance of solution C using the solution obtained with 10 ml of water R as the compensation liquid. The absorbance of solution A is not greater than that of solution C (300 ppm).

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.

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

Е_m (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

Sodium benzoate

Ph Eur

General Notices

(Ph Eur monograph 0123)

C₇H₅NaO₂ M.m.=144.1 532-32-1

Ph Eur

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.

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).

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

Another reaction for benzoates:

a) with iron (ІІІ) chloride:

6C₆H₅COONa + 2FeCl₃+ 10H₂O = (C₆H₅COO)₃Fe×Fe(OH)₃×7H₂O¯ + 3C₆H₅COOH + 6NaCl

light-yellow

d) Not pharmacopoeial reaction. Reaction with solution AgNO₃:

C₆H₅COONa + AgNO₃ = C₆H₅COOAg¯ + NaNO₃

white

B. It gives reaction (a) of sodium (2.3.1).

а) Interaction with potassium hexahydroxostibat (V)

Na⁺ + [Sb(OH)₆]^– ® Na[Sb(OH)₆]

white

Another reaction for Na⁺:

b) Reaction with methoxyphenylacetic acid reagent

white

c) N. Pirochemical reaction. The salt of Sodium moistened with HCl R and brought in a colourless flame, paints it in yellow colour:

Na⁺ + hn ® *Na⁺ ® Na⁺ + hn₁

TESTS

Solution S

Dissolve 10.0 g in carbon dioxide-free water R and dilute to 100 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and not more intensely coloured than reference solution Y₆ (2.2.2, Method II).

Acidity or alkalinity

To 10 ml of solution S add 10 ml of carbon dioxide-free water R and 0.2 ml of phenolphthalein solution R. Not more than 0.2 ml of 0.1 M sodium hydroxide or 0.1 M hydrochloric acid is required to change the colour of the indicator.

Halogenated compounds

To 20.0 ml of solution S add 5 ml of water R and dilute to 50.0 ml with alcohol R (test solution).

Determination of ionised chlorine

In three 25 ml volumetric flasks, prepare the following solutions.

Solution (a) To 4.0 ml of the test solution add 3 ml of dilute sodium hydroxide solution R and 3 ml of alcohol R. This solution is used to prepare solution A.

Solution (b) To 3 ml of dilute sodium hydroxide solution R add 2 ml of water R and 5 ml of alcohol R. This solution is used to prepare solution B.

Solution (c) To 4.0 ml of chloride standard solution (8 ppm Cl) R add 6.0 ml of water R. This solution is used to prepare solution C.

In a fourth 25 ml volumetric flask, place 10 ml of water R. To each flask add 5 ml of ferric ammonium sulphate solution R5, mix and add dropwise and with swirling 2 ml of nitric acid R and 5 ml of mercuric thiocyanate solution R. Shake. Dilute the contents of each flask to 25.0 ml with water R and allow the solutions to stand in a water-bath at 20 °C for 15 min. Measure at 460 nm in a 2 cm cell the absorbance (2.2.25) of solution A using solution B as the compensation liquid, and the absorbance of solution C using the solution obtained with 10 ml of water R as the compensation liquid. The absorbance of solution A is not greater than that of solution C (200 ppm).

Determination of total chlorine

Solution (a) To 10.0 ml of the test solution add 7.5 ml of dilute sodium hydroxide solution R and 0.125 g of nickel-aluminium alloy R and heat on a water-bath for 10 min. Allow to cool to room temperature, filter into a 25 ml volumetric flask and wash the filter with 3 quantities, each of 2 ml, of alcohol R (a slight precipitate may form that disappears on acidification). Dilute the filtrate and washings to 25.0 ml with water R. This solution is used to prepare solution A.

Solution (b) In the same manner, prepare a similar solution replacing the test solution by a mixture of 5 ml of alcohol R and 5 ml of water R. This solution is used to prepare solution B.

Solution (c) To 6.0 ml of chloride standard solution (8 ppm Cl) R add 4.0 ml of water R. This solution is used to prepare solution C.

In four 25 ml volumetric flasks, place separately 10 ml of solution (a), 10 ml of solution (b), 10 ml of solution (c) and 10 ml of water R. To each flask add 5 ml of ferric ammonium sulphate solution R5, mix and add dropwise and with swirling 2 ml of nitric acid R and 5 ml of mercuric thiocyanate solution R. Shake. Dilute the contents of each flask to 25.0 ml with water R and allow the solutions to stand in a water-bath at 20 °C for 15 min. Measure at 460 nm in a 2 cm cell the absorbance (2.2.25) of solution A using solution B as the compensation liquid, and the absorbance of solution C using the solution obtained with 10 ml of water R as the compensation liquid. The absorbance of solution A is not greater than that of solution C (300 ppm).

Heavy metals (2.4.8)

2.0 g complies with limit test C for heavy metals (10 ppm). Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.

Loss on drying (2.2.32)

Not more than 2.0 per cent, determined on 1.00 g by drying in an oven at 100 °C to 105 °C.

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.

Chemism it is possible to present in two stages:

C₆H₅COONa + СН₃СООН ® C₆H₅COONaН⁺×СН₃СОО^–

protogenic solvent

СН₃СООН + HClO₄ = СН₃СООН₂⁺×ClO₄^–

acid

Summarising these equations, we will receive expression:

C₆H₅COONaН⁺×СН₃СОО^–+ СН₃СООН₂⁺×ClO₄^– = NaClO₄ + C₆H₅COOН + 2СН₃СООН

In a general view chemism it is possible to present the equation:

C₆H₅COONa + HClO₄ = NaClO₄ + C₆H₅COOH

Е_m(C₆H₅COONa) = М. м.

1 ml of 0.1 M perchloric acid is equivalent to 14.41 mg of C₇H₅NaO₂.

Storage

In 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.

Salicylic Acid

General Notices

(Ph Eur monograph 0366)

C₇H₆O₃ M.m. = 138.1 69-72-7

Chemical name: o-Hydroxybenzoic acid

DEFINITION

Salicylic acid contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of 2-hydroxybenzenecarboxylic acid, calculated with reference to the dried substance.

Obtaining

Interaction sodium phenolate with carbonic gas at temperature 125 °C (Kolbe-Schmidt’s method):

C₆H₅ONa + CO₂ C₆H₄(OH)COONa C₆H₄(OH)COOH + NaCl

Reaction spend in an autoclave under the pressure of 6 atm. Thus there is an intramolecular regrouping. For clarification a preparation recrystallized from water.

CHARACTERS

A white, crystalline powder or white or colourless, acicular crystals, slightly soluble in water, freely soluble in ethanol (96 per cent), sparingly soluble in methylene chloride.

IDENTIFICATION

First identification A, B.

Second identification A, C.

A. Melting point(2.2.14): 158 °C to 161 °C.

B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with salicylic acid CRS.

C. Dissolve about 30 mg in 5 ml of 0.05 M sodium hydroxide, neutralise if necessary and dilute to 20 ml with water R. 1 ml of the solution gives reaction (a) of salicylates (2.3.1).

1. SPU. Reaction with solution of iron (ІІІ) chloride. To water solution of drug add 1 drop of solution FeCl₃; there is a blue-violet colouring which disappears from addition of several drops of diluted HCl and does not disappear from addition of several drops of diluted CH₃COOH.

2. SPU. Decarboxylation of drug. At drug heating above 160 °C with sodium carbonate (sodium citrate, dry sodium acetate, for the sublimation prevention) feels a phenol smell:

Phenol

3 SPU. Decarboxylation at heating with conc. H₂SO₄:

Са(ОН)₂ + СО₂ = CaCO₃¯

lime water turbidity

Not pharmacopoeial reaction.

4. Formation aurin dye with the Marki’s reagent. At addition to a substance Marki’s reagent (a solution of formaldehyde НСНО in sulphatic acid concentrated H₂SO₄) it is formed aurin dye of red colour:

aurin dye of red colour

TESTS

Solution S

Dissolve 2.5 g in 50 ml of boiling distilled water R, cool and filter.

Appearance of solution

Dissolve 1 g in 10 ml of ethanol (96 per cent) R. The solution is clear (2.2.1) and colourless (2.2.2, Method II).

Related substances

Liquid chromatography(2.2.29).

Test solution Dissolve 0.50 g of the substance to be examined in the mobile phase and dilute to 100.0 ml with the mobile phase.

Reference solution (a) Dissolve 10 mg of phenol R in the mobile phase and dilute to 100.0 ml with the mobile phase.

Reference solution (b) Dissolve 5 mg of salicylic acid impurity B CRS in the mobile phase and dilute to 20.0 ml with the mobile phase.

Reference solution (c) Dissolve 50 mg of 4-hydroxybenzoic acid R in the mobile phase and dilute to 100.0 ml with the mobile phase.

Reference solution (d) Dilute 1.0 ml of reference solution (a) to 10.0 ml with the mobile phase.

Reference solution (e) Dilute a mixture of 1.0 ml of each of reference solutions (a), (b) and (c) to 10.0 ml with the mobile phase.

Reference solution (f) Dilute a mixture of 0.1 ml of each of reference solutions (a), (b) and (c) to 10.0 ml with the mobile phase.

The chromatographic procedure may be carried out using:

—a stainless steel column 0.15 m long and 4.6 mm in internal diameter packed with non-deactivated octadecylsilyl silica gel for chromatography R (5 µm),

—as mobile phase at a flow rate of 0.5 ml/min a mixture of 1 volume of glacial acetic acid R, 40 volumes of methanol R and 60 volumes of water R,

—as detector a spectrophotometer set at 270 nm.

Inject 10 µl of reference solutions (d) and (e). When the chromatograms are recorded in the prescribed conditions, the retention times relative to phenol are: 4-hydroxybenzoic acid about 0.70 and 4-hydroxyisophthalic acid about 0.90. Adjust the sensitivity of the system so that the height of the principal peak in the chromatogram obtained with reference solution (f) is at least 70 per cent of the full scale of the recorder. The test is not valid unless: in the chromatogram obtained with reference solution (e), the third peak corresponds to the phenol peak in the chromatogram obtained with reference solution (d) and the resolution between the peaks corresponding to 4-hydroxyisophthalic acid and to phenol is at least 1.0. If this resolution is not obtained adjust the quantity of acetic acid in the mobile phase.

Inject 10 µl of the test solution and 10 µl of reference solution (f). In the chromatogram obtained with the test solution: the areas of the peaks due to 4-hydroxybenzoic acid, 4-hydroxyisophthalic acid and phenol are not greater than the areas of the corresponding peaks in the chromatogram obtained with reference solution (f) (0.1 per cent for 4-hydroxybenzoic acid; 0.05 per cent for 4-hydroxyisophthalic acid and 0.02 per cent for phenol).

In the chromatogram obtained with the test solution: the area of any peak, apart from the principal peak and the peaks due to 4-hydroxybenzoic acid, 4-hydroxyisophthalic acid and phenol, is not greater than that of the peak due to 4-hydroxyisophthalic acid in the chromatogram obtained with reference solution (f) (0.05 per cent); the sum of the areas of all the peaks, apart from the principal peak, is not greater than twice the area of the peak due to 4-hydroxybenzoic acid in the chromatogram obtained with reference solution (f) (0.2 per cent). Disregard any peak with an area less than 0.01 times that of the principal peak in the chromatogram obtained with reference solution (f).

Chlorides (2.4.4)

10 ml of solution S diluted to 15 ml with water R complies with the limit test for chlorides (100 ppm).

Sulphates

Not more than 200 ppm. Dissolve 1.0 g in 5 ml of dimethylformamide R and add 4 ml of water R. Mix thoroughly. Add 0.2 ml of dilute hydrochloric acid R and 0.5 ml of a 25 per cent m/m solution of barium chloride R. After 15 min any opalescence in the solution is not more intense than that in a standard prepared as follows: to 2 ml of sulphate standard solution (100 ppm SO₄) R add 0.2 ml of dilute hydrochloric acid R, 0.5 ml of a 25 per cent m/m solution of barium chloride R, 3 ml of water R and 5 ml of dimethylformamide R.

Heavy metals (2.4.8)

Dissolve 2.0 g in 15 ml of ethanol (96 per cent) R and add 5 ml of water R. 12 ml of the solution complies with limit test B for heavy metals (20 ppm). Prepare the reference solution using lead standard solution (2 ppm Pb) prepared by diluting lead standard solution (100 ppm Pb) R with a mixture of 5 volumes of water R and 15 volumes of ethanol (96 per cent) R.

Loss on drying(2.2.32)

Not more than 0.5 per cent, determined on 1.000 g by drying in a desiccator.

Sulphated ash(2.4.14)

Not more than 0.1 per cent, determined on 2.0 g.

IMPURITIES

A. R = H: 4-hydroxybenzoic acid,

B. R = CO₂H: 4-hydroxyisophthalic acid,

C. phenol.

ASSAY

SPU. Alkalimetry, direct titration in the medium of neutralised on phenolphthalein alcohol. Dissolve 0.120 g in 30 ml of ethanol (96 per cent) R and add 20 ml of water R. Titrate with 0.1 M sodium hydroxide, using 0.1 ml of phenol red solution R as indicator (SPU – indicator phenolphthalein and titrate before pink colouring).

Е_m (С₇Н₆О₃) = М m.

1 ml of 0.1 M sodium hydroxide is equivalent to 13.81 mg of C₇H₆O₃.

STORAGE

Protected from light.

Action and use

Keratolytic.

Preparations

Salicylic Acid Collodion

Salicylic Acid Ointment

Coal Tar and Salicylic Acid Ointment

Zinc and Salicylic Acid Paste

Salicylic Acid Ointment

DEFINITION

Salicylic Acid Ointment contains 2% w/w of Salicylic Acid in a suitable water-emulsifying basis.

Extemporaneous preparation

The following formula and directions apply.

Salicylic Acid, finely sifted

20 g

Wool Alcohols Ointment

980 g

Melt the Wool Alcohols Ointment, gradually add the Salicylic Acid and stir until cold.

The ointment complies with the requirements stated under Topical Semi-solid Preparations and with the following requirements.

Content of salicylic acid, C₇H₆O₃

1.9 to 2.1% w/w.

IDENTIFICATION

Shake 1 g with 10 ml of water , filter and add to the filtrate iron(III) chloride solution R1; an intense reddish violet colour is produced which persists on the addition of 6M acetic acid. Add 2M hydrochloric acid; the colour disappears and a white, crystalline precipitate is produced.

ASSAY

Dissolve 10 g in a mixture of 20 ml of ethanol (96%), previously neutralised to phenol red solution, and 20 ml of ether and titrate with 0.1M sodium hydroxide VS using phenol red solution as indicator. Each ml of 0.1M sodium hydroxide VS is equivalent to 13.81 mg of C₇H₆O₃.

Sodium salicylate

(Ph Eur monograph 0413)

Natrii salicylas

Natrium salicylicum

C₆H₄COONa

C₇H₅NaO₃ M.m. = 160.1 54-21-7

Chemical name: 2-hydroxybenzenecarboxylate, sodium salt of о–oxybenzoic acid.

DEFINITION

Sodium salicylate contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of sodium 2-hydroxybenzenecarboxylate, calculated with reference to the dried substance.

Obtaining

Neutralisation of salicylic acid by equivalent quantity of sodium hydrocarbonate NaHCO₃ or sodium hydroxide NaOH.

НОC₆H₄COOH + NaHCO₃ = НОC₆H₄COONa + CO₂ + H₂O

CHARACTERS

A white, crystalline powder or small, colourless crystals or shiny flakes, freely soluble in water, sparingly soluble in alcohol.

IDENTIFICATION

First identification A, C.

Second identification B, C.

A. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with sodium salicylate CRS.

B. Solution S (see Tests) gives the reactions of salicylates (2.3.1).

1. Reaction with solution of iron (ІІІ) chloride. To water solution of drug add 1 drop of solution FeCl₃; there is a violet colouring which does not disappear after addition of CH₃COOH R.

2. Definition of melting point (must be 158 °C to 161 °C) of salicylic acid, after interaction of sodium salicylate with HCl R:

НОC₆H₄COONa + HCl = НОC₆H₄COOH + NaCl

Not pharmacopoeial reaction.

Formation aurin dye with the Marki’s reagent. At addition to a substance Marki’s reagent (a solution of formaldehyde НСНО in sulphatic acid concentrated H₂SO₄) it is formed aurin dye of red colour (see salicylic acid).

C. It gives reaction (b) of sodium (2.3.1).

b) Reaction with methoxyphenylacetic acid reagent

white

TESTS

Solution S

Dissolve 5.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to 50 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and not more intensely coloured than reference solution BY₆ (2.2.2, Method II).

Acidity

To 20 ml of solution S add 0.1 ml of phenol red solution R. The solution is yellow. Not more than 2.0 ml of 0.01 M sodium hydroxide is required to change the colour of the indicator to reddish-violet.

Chlorides (2.4.4)

To 5 ml of solution S add 5 ml of water R and 10 ml of dilute nitric acid R and filter. 10 ml of the filtrate diluted to 15 ml with water R complies with the limit test for chlorides (200 ppm).

Sulphates (2.4.13)

2.5 ml of solution S diluted to 15 ml with distilled water R complies with the limit test for sulphates (600 ppm).

Heavy metals (2.4.8)

Dissolve 1.6 g in 16 ml of a mixture of 5 volumes of water R and 10 volumes of alcohol R. 12 ml of the solution complies with limit test B for heavy metals (20 ppm). Prepare the standard using lead standard solution (2 ppm Pb) prepared by diluting lead standard solution (100 ppm Pb) R with a mixture of 5 volumes of water R and 10 volumes of alcohol R.

Loss on drying (2.2.32)

Not more than 0.5 per cent, determined on 1.00 g by drying in an oven at 100 °C to 105 °C.

ASSAY

Acidimetry, non-aqueous titration (determining the end-point potentiometrically)

Dissolve 0.130 g in 30 ml of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

HOC₆H₄COONa + СН₃СООН ® HOC₆H₄COONaН⁺×СН₃СОО^–