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.
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.



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-paminophenol (acetaminophenol), a producr that retained a good measure
of the desired activities. Another approach to the detoxication of paminophenol 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.
Paracetamol

O
General Notices

OH







СН3СОNHC6H4OH
C8H9NO2
М m. = 151,2 g/mol
The chemical name: N - (4hydroxiphenyl)
p-acetaminophenol.
Content


C
Paracetamolum


NH
99.0 per cent to 101.0 per
cent (dried substance).
CH3
Obtaining
1. Nitrosation of phenol with the next
reduction and aceetylation:
O
N
H
Na-O-N=O
OH
- CH3COOH
NH3
OH
OH
C
CH3
(CH3CO)2O
H2S
H2SO4
HN
NH2
O
OH

CHARACTERS


Appearance


White, crystalline powder.


Solubility


Sparingly soluble in water, freely soluble in alcohol, very slightly
soluble in methylene chloride.


IDENTIFICATION


First identification A, C.




Second identification A, B, D, E.

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).


Preparation Discs.



Comparison paracetamol CRS.

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).





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
Other reactions of identification
1. SPU. Formation azo dye (identification of a primary aromatic
amino group after acid hydrolysis). The examinee a solution
acidify HCl 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.
NaO
+
NHCOCH3
N
NH2
N
N
HO
N
H
+H2O
H-O-N=O
HCl
(NaNO2 + HCl)
Cl
NaOH
- CH3COOH
OH
OH
OH
ONa
orange or red
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:
N
OH
N
ONa
H
Cl
+
NHCOCH3
2NaOH
N
N
- HCl
R
R
+ NaCl + 2H2O
NHCOCH3
azo dye of red colour


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 ml of sulphatic acid diluted 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.
ASSAY
Ceriumetry, 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.
OH
O
+3
+4
+ Ce2(SO4)2
+ 2 Ce(SO4)2
O
O
HN
N
C
C
CH3
CH3
Еm (C8H9NO2) = M. m./2
1 ml of 0.1 M cerium sulphate is equivalent to 7.56 mg of C8H9NO2.
+
H2SO4

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

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
Vitamin K
Quinone derivatives
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.

Numerous compounds have been tested for their antihemorrhagic
activity, and significant biologic activity is manifested in compounds
with the following structure when:
R
R'
A
B
R"
R"'
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.

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.
O
O
CH3
CH3
NaHSO3
SO3Na
O
O
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.

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.
OPO3Na2
CH3
OPO3Na2
It is available in ampules for use subcutaneusly, intramuscularly,
intravenously and in tablets for oral administration.



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.
O
O
CH3
2
CH3
SO3Na
+
+
2
H2SO4
O
Na2SO4 + 2 SO2
+
H2O
O
C. Destruction of Menadione Sodium Bisulfite in base medium to sodium sulphite and 2methyl-1,4- naphthoquinone. 2-Methyl-1,4- naphthoquinone may be identified by its
melting point (104-107*C).
O
O
CH3
CH3
SO3Na
O
+
NaOH
+
Na2SO3
+
H2O
O
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.


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.


Phenolphthalein
(Ph Eur monograph 1584)



C20H14O4
318.3
77-09-8



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(4hydroxyphenyl)isobenzofuran-1(3H)-one, calculated with reference
to the dried substance.


Phenol
(Ph Eur monograph 0631)



C6H6O
M.m. 4.1
108-95-2








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 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:
H
SO3H
+
HOSO3H
+
H2O
b) eutralization of a product by means of Са (OH) 2 with formation
calcium salts of benzolsulphoacid:
SO3
SO3H
2
+
Ca
Ca(OH)2
+2H2O
2
Surplus Ca(OH)2 eliminate by 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:
SO3Na
SO3
Ca2CO3 +
Ca + Na2CO3
2
2
d) The received solution evaporate and alloy with alkali NaOH; sodium
phenolate is formed:
ONa
SO3Na
+
2NaOH
t
+
Na2SO3 + H2O
e) At processing of phenolate by sulphatic acid Н2SO4 obtain
phenol:
OH
ONa
2
+
H2SO4
Na2SO4
+
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 (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.
O
OH
O
O
H
OH
O
H
NaClO
O
H
N
-H2O
-H2
NH
OH
N
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.
H
..
H5C6-O
6C6H5OH +
FeCl3
O-C6H5
..
O C6H5
Fe
H
+ 3HCl
O-C6H5
O-C6H5
..
O-C6H5
H
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 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.
OH
OH
Br
Br
+
+ 3Br2




3H2O
Br
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

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:
ONa
OH
NaOH
+N
+
-H2O
H
ONa
N
Cl
-HCl
SO3H
N
N
SO3H
dark red or orange-red colour



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:
OH
OH
OH
NO2
H
+ 2H2O
+
+ 2HONO2
NO2
H
o-nitrophenol
b) with HNO3 concentrated:
OH
p-nitrophenol
OH
O2N
+
NO2
3HONO2
+
NO2
3H2O
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.
OH
H
C
H
H +
O
+ H
OH
H2SO4
-H2O
H
HO
O
C
OH
-H2O
H
HO

CH
aurin dye of red colour
O







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:
OH
OH
Br
Br
+
+ 3Br2
Br
3H2O



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–
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.



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

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.



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.



General Notices
Benzoic Acid
(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
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:
O
OH
CH3
+3Cl2
-3HCl
CCl3
+3HOH
-3HCl
C
OH
OH
-H2O
C
OH



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.
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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
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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
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TESTS
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Solution S
Dissolve 5.0 g in alcohol R and dilute to 100 ml with the same
solvent.
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Appearance of solution
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Solution S is clear (2.2.1) and colourless (2.2.2, Method II).
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Carbonisable substances
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Oxidisable substances
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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.
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Halogenated compounds and halides.
Heavy metals (2.4.8)
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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.
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Sulphated ash (2.4.14)
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Not more than 0.1 per cent, determined on 1.0 g.
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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.
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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
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Ph Eur
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General Notice
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Sodium benzoate
COONa
(Ph Eur monograph 0123)
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C7H5NaO2
M.m.=144.1
532-32-1
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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.
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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
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A white, crystalline or granular powder or flakes,
slightly hygroscopic, freely soluble in water,
sparingly soluble in alcohol (90 per cent V/V).
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IDENTIFICATION
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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
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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.
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C6H5COONa + HCl = C6H5COOH + NaCl
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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.
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ASSAY
Action and use
Expectorant.
It is used as a preservative in acidic liquid preparations in which
benzoic acid is released.
Preparations
Powder, mixture.
Esters of aromatic carboxylic
acids
 Methyl Salicylate
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General Notices
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(Ph Eur monograph 0230)
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C8H8O3
M.m. = 152.1
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Chemical name: methyl salicylate, methyl 2-hydroxybenzoate, methyl
ester of 2-oxybenzoic acid, methyl ester of salicylic acid.
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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 2hydroxybenzoate.
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CHARACTERS
A colourless or slightly yellow liquid, very slightly soluble in water, miscible with alcohol
and with fatty and essential oils.
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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.
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HOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2O
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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 .
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HO
H
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+
H
C
H
+
H
OH
O
HOOC
H2SO4
COOH
H
HO
C
[O]
OH
H
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HOOC
HO
HOOC
COOH
C
H
O
.
COOH
B. To 10 ml of a saturated solution add 0.05 ml of iron (III) chloride (ferric chloride) solution
R1. A violet colour develops.
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СН3ОСОС6Н4ОН + FeCl3 = СН3ОСОС6Н4ОFeCl2 + HCl
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violet colour
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ASSAY
Acidimetry after alkaline hydrolysis, back titration
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HOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2O
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excess
 NaOC6H4COONa + HCl = HOC6H4COONa + 2NaCl
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T
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2NaOH + 2HCl = 2NaCl + 2H2O
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rest
 Еm(C8H8O3) = М. м./2
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Store protected from light.
STORAGE
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Counter-irritant.
Action and use
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Preparations
Methyl Salicylate Liniment
Methyl Salicylate Ointment
Amides of aromatic acids and their
derivatives as drugs
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Salicylamide
O
Salicylamidum
C
Algamon
NH2
Salamide
Salіamide
НОС6Н4СОNH2
М m. = 137,14
OH
g/mol
Not less than 99,0 %
The chemical name: salicylamide, o-hydroxybenzamide, amide of salicylic
acid.
A white crystaline powder without a smell. At heating it is sublimated.
Melting point 140–142 C.
Very slightly soluble in water, soluble in 95 % ethanol, ether, slightly soluble
in chloroform.
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Identification
1. Interaction with iron (III)
chloride FeCl3 solution
(presence phenolic hydroxyl);
red-violet colour is formed:
O
C
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2. Reaction with bromic water
(for benzene ring). A substance
3. Alkaline hydrolysis with
ammonia allocation (for amide
group). At boiling of substance with 30 %
NaOH is felt a specific smell of ammonia
NH3 which can be identified by means of
blue discoloration wet litmus paper:
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NH2
C
+ FeCl3
OH
dissolve in alcohol, dilute with water and
add 1 ml of bromic water Br2; the white
precipitate dibromderivatives is formed:
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O
+ HCl
OFeCl2
O
C
NH2
O
Br
NH2
C
+ 2Br2
OH
NH2
OH
Br
O
O
C
NH2
OH
H O Na
+
t
0
C
ONa
OH
+ NH3
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Assay
Modified Keldal method, establishing the maintenance of
ammonia, which is formed at alkaline hydrolysis.
a) Hydrolysis of substance by alkali NaOH:
 НОС6Н4СОNH2 + NaOH = НОС6Н4СООNa + NH3
b) The allocated ammonia distil off in the container (receiver)
with hydrochloric acid:
 NH3 + HCl = NH4Cl
c) Ammonium chloride titrate with standard solution of sodium
hydroxide:
 NH4Cl + NaOH = NH4OH + NaCl
In parallel spend control experience.
 Еm (НОС6Н4СОNH2) = M.m.
Storage. In good corked container, in the place protected from
light.
Action and use. Anaesthetic, antipyretic and
antirheumatic.
Preparations: powder and tablets (0,25 g and 0,5 g).
 Thanks
for attention!