LECTUTE LECTUTE № № 99

Theme: Theme: Chlorderivatives of benzene Chlorderivatives of benzene sulfonamide as drugs. Sulphamides with sulfonamide as drugs. Sulphamides with

antidiabetic and diuretic effect. antidiabetic and diuretic effect. Sulfanilamide and its derivatives with Sulfanilamide and its derivatives with five-five-membered and six-membered membered and six-membered heterocyclic heterocyclic

substituents. Biseptol.substituents. Biseptol.

Associate prof. Mosula L.M. Associate prof. Mosula L.M.

Derivatives of benzenesulphonic acidDerivatives of benzenesulphonic acid Sulphatic acidSulphatic acid – – HH22SOSO4 4 HOHO––SOSO2–2–OH HOOH HO––SOSO33HH BBenzenesulphonic acidenzenesulphonic acid ( (sulphobenzoic sulphobenzoic acid) – product of substotution of acid) – product of substotution of

one group in a molecule of sulphatic acid on one group in a molecule of sulphatic acid on benzene ring –benzene ring –СС66НН5:5: СС66НН5–SO2–OH5–SO2–OH СС66НН5–SO3H Graphic formula: 5–SO3H Graphic formula:

Introduction Introduction sulphonic groupsulphonic group–SO3H in aromatic ring gives to substance –SO3H in aromatic ring gives to substance of acid of acid propertiesproperties, , promotespromotes its solubility in waterits solubility in water and and lowers toxicitylowers toxicity. .

BBenzenesulphonic acidenzenesulphonic acid forms series of derivatives, among which there forms series of derivatives, among which there are important drugs – are important drugs – derivativesderivatives of amides of amides (chloramines, pentosept (pantocidum)) (chloramines, pentosept (pantocidum)) andand alkyl ureides alkyl ureides (chlorpropamide, tolbutamide (butamidum), carbutamide, (chlorpropamide, tolbutamide (butamidum), carbutamide, glibenclamide)glibenclamide)..

SO2OH

SO2NH2

SO2R NCl

R1

Chlorderivatives of amides benzenesulphonic acid

Amide of benzenesulphonic acid: С6Н5–SO2–NH2

Chlorderivatives of amides benzenesulphonic acid have the general formula

:

Where R – H, COOH R1 – Na, Cl

Substitution of one or two atoms of the Substitution of one or two atoms of the Hydrogene in benzene sulphonamide Hydrogene in benzene sulphonamide group to Chlorine leads to formation of group to Chlorine leads to formation of labile compounds – labile compounds – chloramines,chloramines, which which easily decay with allocation of "easily decay with allocation of "active active chlorinechlorine” which shows oxidising properties. ” which shows oxidising properties. Therefore chloramine have Therefore chloramine have antiseptic and antiseptic and disinfectantdisinfectant properties. properties.

Are known various chloramine.Are known various chloramine.

1. 1. ChloramineChloramine and and dichloramine (dichloramine (the letter the letter B mean, that initial raw materials for B mean, that initial raw materials for

SO2 NCl

Na

SO2 NCl

Cl

2. 2. Chloramine Chloramine ТТ and and dichloramine dichloramine ТТ (letter (letter ТТ means, that initial raw means, that initial raw materials for synthesis is materials for synthesis is toluene, it is developed toluene, it is developed abroad).abroad).

Chloramine Chloramine ТТ

dichloramine dichloramine ТТ

DichloramineDichloramine have larger have larger of active chlorine.of active chlorine.

SO2 NCl

Na

H3C

SO2 NCl

Cl

H3C

The essence of action The essence of action chloraminechloramine consists that consists that they in the water medium hydrolyze with formation they in the water medium hydrolyze with formation HClO, which shows HClO, which shows strong oxidising propertiesstrong oxidising properties at at the expense of the expense of oxygen disintegrationoxygen disintegration::

HClO HClO HCl + HCl + OO 2HClO 2HClO 2HCl + 2HCl + O2O2 Or allocation of "Or allocation of "active chlorineactive chlorine” Cl2:” Cl2: 22HOCl HOCl ClCl22 + Н2 + Н2OO22 ClCl22 + Н2 + Н2OO + О + О oror 4HOCl 4HOCl 2 2Cl2Cl2 + 2 + 2НН22O + O + ОО22 Similar action have Similar action have hypochloriteshypochlorites, for , for

example, example, sodiumsodium hypochloritehypochlorite NaClO which in NaClO which in water hydrolyzes to water hydrolyzes to hypochlorite acidhypochlorite acid::

NaClO + NaClO + НОННОН Na NaОНОН + + НСНСlOlO But But advantageadvantage chloramines chloramines beforebefore

hypochlorites hypochlorites consists that they do not form some consists that they do not form some alkali Naalkali NaОНОН, which corrodes a wound surface., which corrodes a wound surface.

Chloramine T Chloramine T    Chloramine; the sodium salt of N- Chloramine; the sodium salt of N-chlorotoluene-p-sulphonamide; C7H7ClNNaO2S,3H2O chlorotoluene-p-sulphonamide; C7H7ClNNaO2S,3H2O = 281.7 = 281.7

General reagent grade of commerce.General reagent grade of commerce.

Chloramine TChloramine T SPU SPU

ССhloraminumhloraminum C7H7ClNNaO2S, 3H20C7H7ClNNaO2S, 3H20 ММ

m. = 281,7 g/molm. = 281,7 g/mol

S

CH3

NCl

ONaO

S

CH3

O

NO

. 3H2O . 3H2O

Na

Cl

The chemical name: sodium salt of The chemical name: sodium salt of N-N-chlorotoluene-chlorotoluene-pp-sulphonamide, sodium -sulphonamide, sodium NN--chlor-4-methylbenzol-sulphoneimide trihydrate, chlor-4-methylbenzol-sulphoneimide trihydrate, NN-chlorobenzene sulphonamide-sodium -chlorobenzene sulphonamide-sodium trihydrate.trihydrate.

Chloramine contains not less than 98,0 % and Chloramine contains not less than 98,0 % and no more than 103,0 % of sodium salt of no more than 103,0 % of sodium salt of N-N-chlorotoluene-chlorotoluene-pp-sulphonamide trihydrate.-sulphonamide trihydrate.

PropertiesProperties

The description. SPU.The description. SPU. A crystal powder white A crystal powder white абоабо white colour with a white colour with a yellowish shade.yellowish shade.

Solubility.Solubility. Freely soluble in Freely soluble in water Rwater R, soluble in , soluble in 96 % alcohol R96 % alcohol R, it is practically , it is practically insoluble in insoluble in ether R.ether R.

On air On air chloraminechloramine decays under the influence of decays under the influence of carbonic gascarbonic gas СОСО2 and it is 2 and it is audible has begun to smell chlorine (audible has begun to smell chlorine (ІІ) oxide Cl2O:) oxide Cl2O:

S

CH3

NCl

ONaO

+ 2CO2 + 3H2O

S

CH3

NH2

OO

+ 2NaHCO3 + Cl2O

At fast heating chloramine decays with explosion and flash.

IdentificationIdentification A. Hydrolisis of chloramine and action of a water solution on A. Hydrolisis of chloramine and action of a water solution on

indicatorsindicators. . 1 g of chloramine1 g of chloramine place in a conic flask with volume place in a conic flask with volume of 50 mlof 50 ml and and

dissolve in dissolve in waterwater, , free from free from СОСО2, 2, R R and lead up volume of solution the and lead up volume of solution the same solvent to same solvent to 20 ml20 ml. The received solution paints . The received solution paints red litmus paper R red litmus paper R in in dark bluedark blue colour, and then gradually colour, and then gradually decoloursdecolours it. it.

It is possible to confirm occurring processes with such equations. Water It is possible to confirm occurring processes with such equations. Water solutions of solutions of chloraminechloramine have alkaline reaction ( have alkaline reaction (рНрН = 8,0–10,0), = 8,0–10,0), because in water the because in water the chloraminechloramine partially hydrolyzes with formation partially hydrolyzes with formation of of alkalialkali NaOH: NaOH:

H3C–H3C–СС66НН4–SO–N4–SO–NССl–ONa + HOH l–ONa + HOH H3C– H3C–СС66НН4–SO2–NH2 + Na4–SO2–NH2 + NaССlOlO NaClO + NaClO + НОННОН Na NaОНОН + + НСНСlOlO Therefore Therefore the litmus paperthe litmus paper in water solution of in water solution of chloraminechloramine is painted in is painted in

dark blue colourdark blue colour, and , and phenolphthalein becamesphenolphthalein becames crimson colouringcrimson colouring.. The further The further decolouration of litmus paperdecolouration of litmus paper is possible explaines oxidising is possible explaines oxidising

properties properties НСНСlO, in particular, its lO, in particular, its acid acid and and chloric decay chloric decay (disintegration)(disintegration)::

2HClO 2HClO 2HCl + 2HCl + O2O2 4HOCl 4HOCl 2 2Cl2Cl2 + 2 + 2НН22O + O + ОО22

B. To 10 ml of solution S (substance solution in B. To 10 ml of solution S (substance solution in waterwater, , free from free from СОСО2, 2, RR) add 10 ml solution of) add 10 ml solution of hydrogene peroxyde diluted R hydrogene peroxyde diluted R НН22ОО2; 2; the white precipitate,the white precipitate, which is dissolved at heating, is formed. The which is dissolved at heating, is formed. The received hot solution filter, cool. The formed white crystals, which received hot solution filter, cool. The formed white crystals, which washed out and have been dried up at temperature from 100 washed out and have been dried up at temperature from 100 C to C to 105 105 C, should have melting point 137 C, should have melting point 137 C - 140 C - 140 C. C.

C. Calcination of chloramine in crucible and revealing in filtrate of C. Calcination of chloramine in crucible and revealing in filtrate of chlorides-ions. chlorides-ions.

1 g substance place in a porcelain crucible, calcinate, 1 g substance place in a porcelain crucible, calcinate, adhering to adhering to safety measures from firesafety measures from fire. The rest dissolve in 10 ml . The rest dissolve in 10 ml of water Rof water R and and filter. The received filtrate gives reaction (a) for chlorides-ions: filter. The received filtrate gives reaction (a) for chlorides-ions: reaction with solution reaction with solution ofof AgNO3 in the medium of AgNO3 in the medium of diluteddiluted HNO3. HNO3.

The received filtrate acidify by The received filtrate acidify by diluted diluted HNO3 HNO3 R R and add some drops and add some drops of solution AgNO3of solution AgNO3 R1 R1; ; white curdled precipitate white curdled precipitate AgCl, which is AgCl, which is insoluble in nitric acid, but insoluble in nitric acid, but freely soluble infreely soluble in ammonia solution R*ammonia solution R* is formed:is formed:

CL - + Ag + → AgCl ↓ CL - + Ag + → AgCl ↓ white curdled precipitatewhite curdled precipitate *For the salts of organic bases solubility test of formed precipitate *For the salts of organic bases solubility test of formed precipitate

AgCl spend after filterings and washings of precipitate by water.AgCl spend after filterings and washings of precipitate by water.

AgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2OAgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2OAt addition HNO3 At addition HNO3 white precipitate white precipitate AgCl again drops AgCl again drops

out:out:[Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3[Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3

D. Calcination of chloramine in crucible and revealing D. Calcination of chloramine in crucible and revealing in filtrate of sulphates-ions: reaction with solution in filtrate of sulphates-ions: reaction with solution of of barium chloridebarium chloride BaCl2 in the medium of BaCl2 in the medium of diluted diluted HCl. HCl. To 5 ml of the filtrate received in test C, add 1 ml To 5 ml of the filtrate received in test C, add 1 ml of of

diluted diluted HClHCl R R and 1 ml and 1 ml solution of barium chloride R1solution of barium chloride R1; ; the white precipitatethe white precipitate is formed: is formed:

SO42– + Ba2+ SO42– + Ba2+ BaSO4 BaSO4 white precipitate white precipitate

The precipitate is insoluble in mineral acids, alkalis.The precipitate is insoluble in mineral acids, alkalis.

E. Calcination of chloramine in crucible and revealing in filtrate of E. Calcination of chloramine in crucible and revealing in filtrate of Sodium- ions (reaction b): interaction with Sodium- ions (reaction b): interaction with methoxyphenylacetic acid methoxyphenylacetic acid

reagentreagent (solution of (solution of methoxyphenylacetic acidmethoxyphenylacetic acid in solution of tetramethyl in solution of tetramethyl hydroxide and ethanol); form hydroxide and ethanol); form white crystalline precipitatewhite crystalline precipitate, soluble in an , soluble in an

ammonia solution:ammonia solution:

CH

O

C

O

OHCH3

CH34NOH C

H

O

C

O

CH3 ON(CH3)4

+

CH

O

C

O

O

CH3

CH

O

C

O

CH3

Na

ONa

+ +

whitewhite

Other reactionOther reaction 1. Reaction with solution of potassium iodide in the presence of 1. Reaction with solution of potassium iodide in the presence of

chloroform (identification of chlorine – product of chloric chloroform (identification of chlorine – product of chloric disintegration)disintegration)..

At acidifying of substance solution by means of At acidifying of substance solution by means of diluteddiluted HCl - allocates HCl - allocates chlorinechlorine Cl2 (chloric disintegration): Cl2 (chloric disintegration):

At interaction of Cl2 with solution KI in the presence of At interaction of Cl2 with solution KI in the presence of chloroform chloroform free free iodine I2 is allocated and chloroformic layer becomes iodine I2 is allocated and chloroformic layer becomes violet colouringviolet colouring::

Cl2 + 2KI = 2KCl + I2Cl2 + 2KI = 2KCl + I2

S

CH3

NCl

ONaO

2HCl

SO2NH2

CH3

Cl2+ ++ NaCl;

Tests 1. A solution transparency. Solution S (substance solution in water, free from СО2, R) on degree turbidity should not exceed the standard ІІ. 2. Chromaticity of solution. Solution S should be transparent and colourless. 3. рН solution S. From 8,0 to 10,0. 4. Ortho-derivatives. 5. The rest, insoluble in ethanol. Weight of the dry rest should not exceed 20 mg (2 %).

AssayAssay Iodometry, substitute titrationIodometry, substitute titration Nearby 0,125 g (exact shot) substance place in conic flask with Nearby 0,125 g (exact shot) substance place in conic flask with

capacity of 250 ml with the ground in glass stopper, dissolve in capacity of 250 ml with the ground in glass stopper, dissolve in 100 ml 100 ml of water Rof water R, add 1 g of KI , add 1 g of KI R R and 5 ml and 5 ml of sulphatic acid of sulphatic acid diluted Rdiluted R H2SO4, maintain during 3 mines and titrate with H2SO4, maintain during 3 mines and titrate with 0,1 M 0,1 M solution of sodium thiosulphatesolution of sodium thiosulphate Na2S2O3, using as the indicator Na2S2O3, using as the indicator 1 ml1 ml of starch solution R of starch solution R..

S

CH3

NCl

ONaO

H2SO4

SO2NH2

CH3

Cl2+ ++2 Na2SO42

Cl2 + 2KI → I2 + 2KCl;I2 + 2Na2S2O3 → 2NaI + Na2S4O6.

Еm (C7H7ClNNaO2S, 3H20) = М m./2

StorageStorage In air-tight container, at protecting from light, a dry and In air-tight container, at protecting from light, a dry and

cool place, at temperature 8 cool place, at temperature 8 C-15 C-15 C.C. Action and use. External antiseptic and deodorant.Action and use. External antiseptic and deodorant. Apply to treatment of the infected wounds (1,5–2 % Apply to treatment of the infected wounds (1,5–2 %

solutions – washing of wounds, wetting of tampons and solutions – washing of wounds, wetting of tampons and napkins), disinfection of hands (0,25–0,5 % solution), napkins), disinfection of hands (0,25–0,5 % solution), processings of nonmetallic toolkit, disinfecting of processings of nonmetallic toolkit, disinfecting of subjects of care by patients (1–3 % solution), at a subjects of care by patients (1–3 % solution), at a tubercular infection (5 % solution).tubercular infection (5 % solution).

For disinfection sometimes use For disinfection sometimes use the "activated" the "activated" chloramine solutions: addition of ammonia NH3, chloramine solutions: addition of ammonia NH3, sulphate ammonium (NH4) 2SO4 or ammonium chloride sulphate ammonium (NH4) 2SO4 or ammonium chloride NH4Cl strengthens bactericidal properties of solutions.NH4Cl strengthens bactericidal properties of solutions.

Pantocidum Pantocidum SP SP ХХ

C SO2

O

HO

N

Cl

Cl

Pantosept*HalazoneC7H5Cl2NO4S М m. = 270,09 g/mol Not less than 50 % of active

chlorineThe chemical name: N-dichlor-p-carboxy-benzene-

sulphonamide, p-dichlorsulphoaminebenzoic acid. Pantosept is derivative of dichloramine.

Properties Properties The description. The description. A white powder with a A white powder with a

weak smell of chlorine.weak smell of chlorine. Solubility.Solubility. Slightly soluble in water and Slightly soluble in water and

the diluted acids, freely soluble in solutions the diluted acids, freely soluble in solutions of caustic and carbonic alkalis. of caustic and carbonic alkalis.

Sodium salt of pantocidum is freely Sodium salt of pantocidum is freely soluble in water. Therefore tablets of soluble in water. Therefore tablets of pantocidum always contain 50 % of pantocidum always contain 50 % of anhydrous sodium carbonate.anhydrous sodium carbonate.

IdentificationIdentification A. Hydrolisis of A. Hydrolisis of pantocidumpantocidum and action of water solution on(with) and action of water solution on(with)

indicatorsindicators. . To 1 g of To 1 g of pantocidum pantocidum 10 ml10 ml of of waterwater and and 2 drops2 drops of alkaline solution of of alkaline solution of

methyl red. methyl red. The liquid is painted in The liquid is painted in red colourred colour and further and further becomes becomes colourlesscolourless..

It is possible to confirm occurring processes with such equations. Water It is possible to confirm occurring processes with such equations. Water solutions solutions of of pantocidum have acid reaction because hydrolisis*:pantocidum have acid reaction because hydrolisis*:

C SO2

O

HO

N

Cl

Cl

+ 2H2O C SO2

O

HO

N

H

H

+ 2HClO

2HCl O2

Therefore alkaline solution of methyl red is painted in red colour (acid medium). The further decolouration of methyl red is possible explaines oxidation properties

of hypochlorite acid НСlO, in particular, its acid and chloric disintegration (decay):2HClO 2HCl + O24HOCl 2Cl2 + 2Н2O + О2

*It is necessary to notice, that because of bad solubility of pantocidum in water hydrolysis goes slowly.

2. Reaction with solution of potassium iodide 2. Reaction with solution of potassium iodide in the presence of chloroform (identification in the presence of chloroform (identification of chlorine – product of chloric of chlorine – product of chloric disintegration)disintegration)..

At acidifying of substance solution by means of At acidifying of substance solution by means of diluteddiluted HCl - allocates HCl - allocates chlorinechlorine Cl2 (chloric Cl2 (chloric disintegration):disintegration):

C SO2

O

HO

N

Cl

Cl

+ 2HCl C SO2

O

HO

N

H

H

+ 2Cl2

At interaction of Cl2 with solution KI in the presence of chloroform free iodine I2 is allocated and chloroformic layer becomes violet colouring:

Cl2 + 2KI = 2KCl + I2

TestsTests The general impurity of heavy metals, Arsenic – within standards.The general impurity of heavy metals, Arsenic – within standards. Sulphatic ashes from 0,5 g of pantocidum should not exceed 0,5 %.Sulphatic ashes from 0,5 g of pantocidum should not exceed 0,5 %.

Assay. Assay. Iodometry, substitute titrationIodometry, substitute titration Nearby 0,2 Nearby 0,2 гг g (exact shot) substance dissolve in mix (80 ml of g (exact shot) substance dissolve in mix (80 ml of water water

and 10 ml and 10 ml solution of solution of NaOH), add 15 ml NaOH), add 15 ml solution of solution of KI and 15 ml KI and 15 ml of of diluted sulphatic acid diluted sulphatic acid H2SO4. Allocated iodine I2 titrate with H2SO4. Allocated iodine I2 titrate with 0,1 M 0,1 M solution of sodium thiosulphatesolution of sodium thiosulphate Na2S2O3, using as indicator 1 ml Na2S2O3, using as indicator 1 ml of of starch solution R.starch solution R.

C SO2

O

HO

N

Cl

Cl

+ 2H2O C SO2

O

HO

N

H

H

+ 2HClO

4HOCl 2Cl2 + 2Н2O + О2 Cl2 + 2KI 2KCl + I2

I2 + 2Na2S2O3 → 2NaI + Na2S4O6Em = М m. Cl2/2

StorageStorage In dense corked containers, at protecting from light, a In dense corked containers, at protecting from light, a

dry and cool place dry and cool place (not to admit decomposition of (not to admit decomposition of drugdrug and reduction of the maintenance of active chlorine).and reduction of the maintenance of active chlorine).

Action and use. An active antiseptic.Action and use. An active antiseptic. Apply mainly Apply mainly to water disinfectingto water disinfecting (the weak smell of (the weak smell of

chlorine) therefore is audible, using chlorine) therefore is audible, using the tablets the tablets containing pantocidum 0,0082 g, sodium carbonate containing pantocidum 0,0082 g, sodium carbonate anhydrous Na2CO3 0,0036 g and sodium chloride NaCl anhydrous Na2CO3 0,0036 g and sodium chloride NaCl 0,1082 g. One tablet contains 3 mg of active chlorine. To 0,1082 g. One tablet contains 3 mg of active chlorine. To water disinfecting apply 1 tablet of pantocidum for 0,5–water disinfecting apply 1 tablet of pantocidum for 0,5–0,75 l of water, and at strong water infection on the 0,75 l of water, and at strong water infection on the same volume of water use - 2 tablets. Disinfecting same volume of water use - 2 tablets. Disinfecting occurs within 15 minutes.occurs within 15 minutes.

Use Use пантоцидпантоцид also also for disinfection of handsfor disinfection of hands (1–1,5 % (1–1,5 % solutions), syringings and processing of wounds (0,1–solutions), syringings and processing of wounds (0,1–0,5 % solutions).0,5 % solutions).

Alkyl ureides derivatives of Alkyl ureides derivatives of benzenesulphonic acidsbenzenesulphonic acids

Benzenesulphonic acid Benzenesulphonic acid – С6Н5–– С6Н5–

SOSO22OHOHSO2OH

Urea (carbamide) – amide of carbonate acid Н2СО3 H2N C

O

NH2

Ureides – N-acyl-derivatives of urea:R C

O

HN C NH2

O

Alkyl ureides of benzenesulphonic acids: SO2R NH C

O

NH R1

Alkyl ureides of benzenesulphonic acid reduces of sugar level in blood and because used to diabetum treatment ІІ type (achrestic diabetes). It is known more than 15 thousand sulfamides with hypoglycemic action, among which the important place occupy sulfanilureas and their derivatives (Chlorpropamide, Tolbutamide, Carbutamide, Glibenclamide).

ChlorpropamideChlorpropamide

(Ph Eur monograph 1087)(Ph Eur monograph 1087) Chlorpropamidum Chlorpropamidum

C10H13ClN2O3S М m. = 276,74 g/mol The chemical name: N - (p-chlorobenzenesulphonyl)-N '-propylureas,

1-[(4-chlorophenyl)sulphonyl]-3-propylurea. DEFINITION

Chlorpropamide contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 1-[(4-chlorophenyl)sulphonyl]-

3-propylurea, calculated with reference to the dried substance.

CHARACTERS

A white, crystalline powder, practically insoluble in water, freely soluble in acetone and in methylene chloride, soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides.

It shows polymorphism.

IDENTIFICATION

First identification C, D. Second identification A, B, D.  A. Melting point (2.2.14): 126 °C to 130 °C.

 B. UV-spectroscopy. Dissolve 0.10 g in methanol R and dilute to 50.0 ml with the same

solvent. Dilute 5.0 ml of the solution to 100.0 ml with 0.01 M hydrochloric acid. Dilute 10.0 ml of the solution to 100.0 ml with 0.01 M hydrochloric acid. Examined between 220 nm and 350 nm

(2.2.25), the solution shows an absorption maximum at 232 nm. The specific absorption at the maximum is 570 to 630.

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

Examine the substances prepared as discs. If the spectra obtained show differences, dissolve the substance to be examined and the reference

substance in methylene chloride R, evaporate to dryness and record the new spectra using the residues.

 D. Mineralization of chlorpropamide and revealing Sulphur and

Chloride.Heat 0.1 g with 2 g of anhydrous sodium carbonate R until a dull red

colour appears for 10 min. Allow to cool, extract the residue with about 5 ml of water R, dilute to 10 ml with water R and filter. The solution gives

the reaction (a) of chloride (2.3.1) and Sulphur:

a) Revealing in filtrate of chloride-ions:CL - + Ag + → AgCl ↓

white curdled precipitateAgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2O

[Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3(This reaction use for difference chlorpropamide from tolbutamide,

which does not contain some Chlorine in molecule).b) Revealing in a filtrate of sulphate-ions:

To 5 ml of filtrate add 5 ml of diluted HCl R and 1 ml solution of barium chloride R1; the white precipitate is formed:

SO42– + Ba2+ BaSO4 white precipitate

The precipitate is insoluble in mineral acids, alkalis

Other reactions of identification:Other reactions of identification: 1. Alkaline hydrolysis of chlorpropamide and identification of 1. Alkaline hydrolysis of chlorpropamide and identification of

hydrolysis products. hydrolysis products. 0,1g of chlorpropamide heat up with 3 drops of solution 0,1g of chlorpropamide heat up with 3 drops of solution

NaOH; allocated steams (NH3NaOH; allocated steams (NH3) paint ) paint the red litmus paper,the red litmus paper, moistened with water (bring near test tube aperture) in moistened with water (bring near test tube aperture) in dark blue dark blue colourcolour..

SO2Cl NH C

O

NH C3H7 + NaOH SO2Cl ONa + C3H7NH2 + NH3 + Na2CO3

2. Acid hydrolysis of chlorpropamide and identification of hydrolysis products.

To 0,5 g of chlorpropamide add 40 ml 50 % solution of sulphatic acid H2SO4 and heat up with a return refrigerator within 30 minutes. Cool in cooler with ice, crystals filter, wash out water before neutral reaction on methyl orange and dry at 100–105 C within 2 hours. Melting point of syntesed p-chlorobenzenesulphamide 143–144 C.

SO2Cl NH C

O

NH C3H7 SO2Cl NH2 + C3H7NH2

HOH

H2SO4t0

+ CO2

TESTSTESTS Related substancesRelated substances Examine by thin-layer chromatography Examine by thin-layer chromatography (2.2.27)(2.2.27), using a suitable silica , using a suitable silica

gel as the coating substance. gel as the coating substance.

Heavy metals (2.4.8)

Loss on drying (2.2.32)

Not more than 0.5 per cent, determined on 1.000 g by drying in an oven at 100 °C to 105 °C.

Sulphated ash (2.4.14)

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

ASSAYASSAY Alkalimetry, direct titration of alcoholic solutionAlkalimetry, direct titration of alcoholic solution Dissolve 0.250 g in 50 ml of Dissolve 0.250 g in 50 ml of alcohol Ralcohol R previously neutralised using previously neutralised using

phenolphthalein solution R1phenolphthalein solution R1 as indicator and add 25 ml of as indicator and add 25 ml of water Rwater R. . Titrate with Titrate with 0.1 M sodium hydroxide0.1 M sodium hydroxide until a pink colour is obtained. until a pink colour is obtained.

The method is based on The method is based on acid propertiesacid properties of a substance at the of a substance at the expense of presence in molecule expense of presence in molecule sulphamide groupsulphamide group –SO2–NH––SO2–NH–::

SO2Cl NH C

O

NH C3H7 + NaOH SO2Cl N C

O

NH C3H7

Na

+ H2O

Em (C10H13ClN2O3S) = М m. 1 ml of 0.1 M sodium hydroxide is equivalent to 27.67 mg of C10H13ClN2O3S.

Other method of assay:Gravimetry

After mineralization of chlorpropamide and reconducting (transistorizing) of Sulphur in sulphate-anions (chande S on SO42-), receive

precipitate BaSO4 (weight or gravimetric form), which dry, calcinate to constant weight and weighing. By means of weight BaSO4 calculates

maintenance of chlorpropamide in drug.

STORAGESTORAGE Store protected from light. Store protected from light. Action and use Action and use Hypoglycaemic. Hypoglycaemic. Preparation Preparation Chlorpropamide Tablets Chlorpropamide Tablets Ph EurPh Eur

(Ph Eur monograph 0718)(Ph Eur monograph 0718) GlibenclamideGlibenclamide GlibenclamidumGlibenclamidum Maninil*Maninil* Daonil*Daonil*

OCH3

Cl

CHN

O

H2C

H2C S

HN

O

O

CHN

O

C23H28ClN3O5S М m. = 494,0 g/molDEFINITION

1-[[4-[2-[(5-Chloro-2-methoxybenzoyl)amino]ethyl]phenyl]sulphonyl]-3-cyclohexylurea.

Content 99.0 per cent to 101.0 per cent (dried substance).

CHARACTERS Appearance

White or almost white, crystalline powder.

Solubility Practically insoluble in water, sparingly soluble in methylene chloride, slightly soluble in

alcohol and in methanol.

IDENTIFICATIONIDENTIFICATION First identificationFirst identification  A, C.A, C. Second identificationSecond identification  A, B, D, E.A, B, D, E.   A. Melting pointA. Melting point (2.2.14)(2.2.14): : 169 °C to 174 °C.169 °C to 174 °C.   B.B. UV-spectroscopy.UV-spectroscopy. Dissolve 50.0 mg in Dissolve 50.0 mg in methanol Rmethanol R, with the aid of ultrasound if , with the aid of ultrasound if

necessary, and dilute to 50.0 ml with the same solvent. To 10.0 ml of the solution add 1.0 necessary, and dilute to 50.0 ml with the same solvent. To 10.0 ml of the solution add 1.0 ml of a 103 g/l solution of ml of a 103 g/l solution of hydrochloric acid Rhydrochloric acid R and dilute to 100.0 ml with and dilute to 100.0 ml with methanol Rmethanol R. . Examined between 230 nm and 350 nm Examined between 230 nm and 350 nm (2.2.25)(2.2.25), the solution shows an absorption , the solution shows an absorption maximummaximum at at 300 nm300 nm and a less intense maximum at and a less intense maximum at 275 nm275 nm. The . The specific absorbances specific absorbances at the maxima are 61 to 65 and 27 to 32, respectively. at the maxima are 61 to 65 and 27 to 32, respectively.

  C. Infrared absorption spectrophotometryC. Infrared absorption spectrophotometry (2.2.24)(2.2.24). . PreparationPreparation  Discs of Discs of potassium bromide Rpotassium bromide R. . ComparisonComparison  glibenclamide CRSglibenclamide CRS. . If the spectra obtained show differences, moisten separately the substance to be If the spectra obtained show differences, moisten separately the substance to be

examined and the reference substance with examined and the reference substance with methanol Rmethanol R, triturate, dry at 100-105 °C and , triturate, dry at 100-105 °C and record the spectra again. record the spectra again.

D. Thin-layer chromatography(D. Thin-layer chromatography(2.2.272.2.27). ). Test solutionTest solution  Dissolve 10 mg of the substance to be examined in a mixture of equal volumes of Dissolve 10 mg of the substance to be examined in a mixture of equal volumes of methanol Rmethanol R and and methylene chloride Rmethylene chloride R and dilute to 10 ml with the same mixture of solvents. and dilute to 10 ml with the same mixture of solvents. Reference solutionReference solution  Dissolve 10 mg of Dissolve 10 mg of glibenclamide CRSglibenclamide CRS in a mixture of equal volumes of in a mixture of equal volumes of methanol Rmethanol R and and methylene chloride Rmethylene chloride R and dilute to 10 ml with the same mixture of solvents. and dilute to 10 ml with the same mixture of solvents. PlatePlate  TLC silica gel GF254plateTLC silica gel GF254plate R R. . Mobile phaseMobile phase  alcohol Ralcohol R, , glacial acetic acid Rglacial acetic acid R, , cyclohexane Rcyclohexane R, , methylene chloride Rmethylene chloride R (5:5:45:45 (5:5:45:45 V/V/V/V V/V/V/V). ). ApplicationApplication  10 µl. 10 µl. DevelopmentDevelopment  Over a path of 10 cm. Over a path of 10 cm. DryingDrying  In air. In air. DetectionDetection  Examine in ultraviolet light at 254 nm. Examine in ultraviolet light at 254 nm. ResultsResults  The principal spot in the chromatogram obtained with the test solution is similar in position and size to the principal spot in the chromatogram obtained with the reference solution. The principal spot in the chromatogram obtained with the test solution is similar in position and size to the principal spot in the chromatogram obtained with the reference solution.   E. Fluorescence of test substance solution in sulphatic acid. Dissolve 20 mg in 2 ml of E. Fluorescence of test substance solution in sulphatic acid. Dissolve 20 mg in 2 ml of sulphuric acid Rsulphuric acid R. The solution is colourless and shows blue fluorescence in ultraviolet light at 365 nm. Dissolve 0.1 g of . The solution is colourless and shows blue fluorescence in ultraviolet light at 365 nm. Dissolve 0.1 g of chloral hydrate Rchloral hydrate R in the solution. Within about 5 min, the in the solution. Within about 5 min, the

colour changes to deep yellow and, after about 20 min, develops a brownish tinge.colour changes to deep yellow and, after about 20 min, develops a brownish tinge.

Heavy metals Heavy metals (2.4.8)(2.4.8) Maximum 20 ppm. Maximum 20 ppm. 1.0 g complies with limit test D. Prepare the standard using 2 ml of 1.0 g complies with limit test D. Prepare the standard using 2 ml of lead lead

standard solution (10 ppm Pb) Rstandard solution (10 ppm Pb) R. . Loss on drying Loss on drying (2.2.32)(2.2.32) Maximum 1.0 per cent, determined on 1.000 g by drying in an oven at 100-Maximum 1.0 per cent, determined on 1.000 g by drying in an oven at 100-

105 °C. 105 °C. Sulphated ash Sulphated ash (2.4.14)(2.4.14) Maximum 0.1 per cent, determined on 1.0 g. Maximum 0.1 per cent, determined on 1.0 g.

TESTS

Related substances

ASSAYASSAY Alkalimetry, direct titration alcoholic solutionAlkalimetry, direct titration alcoholic solution Dissolve 0.400 g with heating in 100 ml of Dissolve 0.400 g with heating in 100 ml of alcohol Ralcohol R. Titrate with . Titrate with 0.1 M sodium hydroxide0.1 M sodium hydroxide, using 1.0 , using 1.0

ml of ml of phenolphthalein solution Rphenolphthalein solution R as indicator, until a pink colour is obtained. as indicator, until a pink colour is obtained.

NaOH

OCH3

Cl

CHN

O

H2C

H2C S N

O

O

CHN

O

H2O

OCH3

Cl

CHN

O

H2C

H2C S N

O

O

CHN

O

+

+

H

Na

Еm (C23H28ClN3O5S) = М m. 1 ml of 0.1 M sodium hydroxide is equivalent to 49.40 mg of C23H28ClN3O5S

STORAGE Store protected from light.

Action and use

Hypoglycaemic.

Preparation

Glibenclamide Tablets

Ph Eur

DichlothiazidumDichlothiazidum

The chemical name: 6-The chemical name: 6-хлорхлор-7-sulfamoyl-3,4-dihydro-2-7-sulfamoyl-3,4-dihydro-2НН-1,2,4-benzothiazine--1,2,4-benzothiazine-1,1-dioxide.1,1-dioxide.

CHARACTERSCHARACTERS A white or white with yellowish shade, crystalline powder, very slightly A white or white with yellowish shade, crystalline powder, very slightly

soluble in water, slightly soluble in alcohol, very soluble in solutions of soluble in water, slightly soluble in alcohol, very soluble in solutions of alkalis. alkalis.

STORAGESTORAGE Store protected from light. Store protected from light. Action and use Action and use Diuretic.Diuretic. PreparationsPreparations

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