Theme: Pharmaceutical analysis of amino aromatic carboxylic acids
and their derivatives, derivatives of acetanilide as drug substances:
synthesis, properties, analysis, storage, action and use.
p-Aminobenzoic acid derivatives
Like amino acids of
a fatty series, aminoaromatic acids have amphoteric
character, but presence of an aromatic ring leads to prevalence of acid properties.
The most simple representative aminoaromatic
acids – p-aminobenzoic acid
(PABA)
In 1940 it has been enlisted to vitamins
(vitamin Í1). It is not only
the vital factor for many microorganisms, but also a necessary element for
biosynthesis of some vitamins of group of
folic acid.
Esters of PABA shows local anesthetic effect and became synthetic substitutes of the
first anesthetic cocaine (alkaloid, which is obtained from plant Erythroxylon Coca, that grows in
containing the rest of
benzoic acid, which esterified by organic base, containing nitrogen. Such
grouping is available in molecules of procaine hydrochloride, tetracaine
hydrochloride, etc.
Local
anesthesia may be defined as the loss of sensation or the loss of motor
function in a circumscribed area of the body. Local anesthetics are drugs that
produce this conditions by applied locally to the nerve tissue in appropriate
concentrations. To be useful clinically, the action should always be
reversible. The local anesthetic agents are useful chemical tools for the
temporary relief of localized pain in dentistry and minor surgical procedures,
as well as for producing a state of nonresistance (e.g., spinal anesthesia)
without general anesthesia.
The origin of
the modern local anesthetic agents can be traced to the independent discoveries
of two distinctly different alkaloids, cocaine and isogramine. Cocaine is an
aminoalkyl ester of benzoic acid; isogramine is a 2-(aminialkyl)indole. Insufficient data are available to make definitive
statements about the relationship of the common structural features of the two
molecules to local anesthetic activity.
Lidocaine
derivatives are essentially anilide progenies of isogramine with the following
general structural characteristics:
The benzoic
acid derivatives are synthetic compounds derived from the structure of cocaine
and may be represented as follows:
The
clinically useful members of this series possess as aryl radical attached
directly to the carbonyl group or attached through a vinyl group. Although alicyclic and aryl aliphatic
carboxylic acid esters are active, conjugation of the aromatic group with the
carbonyl enhances local anesthetic activity. Substitution
of the aryl group with the substituents that increase the electron density of
the carbonyl oxygen enhance activity. The brige X may be carbon, oxygen,
nitrogen, or sulfur. In a isomeric procaine series,
conduction-anesthetic potency decreased in the following order: sulfur, oxygen,
carbon, nitrogen. The aminoalkyl group is not necessary for local anesthetic
activity, but it is used to form water-soluble salts.
Esters
of p-aminobenzoic acid
General Notices
(Ph Eur monograph 0011) Benzocaine
Aethylis àminobenzoas*
Benzocaine
Åthyl àminobenzoate
C9H11NO2
Ì m. = 165,19 g/mol
The chemical name: ethyl ester of p-aminobenzoic acid;
ethyl-p-aminobenzoate.
DEFINITION
Benzocaine contains not less than 99.0 per cent and not more than the
equivalent of 101.0 per cent of ethyl
4-aminobenzoate, calculated with reference to the dried substance.
The first time it
is synthesised in 1830, and in
medicine as drug apply since 1902.
Obtaining
Initial raw
materials is toluene Ñ6H5ÑH3 , which nitrations by means of mix nitric HNO3 and sulphatic H2SO4
acids, then to oxidize methyl group –ÑÍ3 to carboxylic –ÑÎÎÍ by means of chromic mix (solution K2Cr2O7
in H2SO4), to
esterify by ethanol Ñ2Í5ÎÍ and reduce
nitrogroup–NO2 to an amino group–NH2 by means of iron at
presence of acetic acid ÑÍ3ÑÎÎÍ:
Toluene p-nitrotoluene p-nitrobenzoic acid
benzocaine
The received
product clear recrystallization from the diluted alcohol with the activated coal
and sodium hydrogensulphite NaHSO3, to
decolour the soluble painted impurity by reduction.
CHARACTERS
A white, crystalline powder or colourless
crystals, very slightly soluble in water, freely soluble in alcohol.
IDENTIFICATION
First identification A, B.
Second identification A, C, D.
A. Melting point (2.2.14):
B. Examine by infrared absorption spectrophotometry (2.2.24),
comparing with the spectrum obtained with benzocaine CRS.
C. To about 50 mg in a test-tube add 0.2 ml of a 500 g/l
solution of chromium trioxide R.
Cover the mouth of the tube with a piece of filter paper moistened with a
freshly prepared mixture of equal volumes of a 50 g/l solution of sodium nitroprusside R
and a 200 g/l solution of piperazine
hydrate R. Boil gently for at least 30 s. A blue colour develops on the
filter paper.
D. Dissolve about 50 mg in alcohol R and dilute
to 100 ml with the same solvent. 2 ml of the solution gives the reaction of primary aromatic amines (2.3.1).
1. Reaction of primary
aromatic amino group (SPU) (diazotization
with the next azocoupling).
Some
crystals of test substance dissolve in 2 ml of water R, acidify of HCl R, add 0,2 ml of sodium
nitrite solution R NaNO2 and through 1–2 mines
add 1 ml of alkaline solutionb-naphthol; there is an intensive orange or red colouring and, as a rule, the precipitate
of the same colour is formed.
salt diazonium azo dye of
red colour
2. Lignin test (of aromatic amino group, spend
reaction to a newsprint!). On a newsprint slice to put some crystals of
substance and to moisten with solution HCl; there is a yellow stain, which becomes in due course orange.
The
newsprint contains lignin, in which there are aromatic aldehydes. At interaction with aromatic amines are formed azomethine dye (Schiff base)
orange
colour:
orange
Other reactions
(SPU):
1. Alkaline hydrolysis with
the next revealing of ethanol Ñ2H5OH with the help iodoform test (of ester
group).
Drug
heat up with solution of sodium hydroxide NaOH and add solution of
iodine ²2 before not
disappearing yellow colouring; there is iodoform
smell ÑͲ3.
C2H5OH +
4I2 + 6NaOH → CHI3 ↓ + 5NaI + HCOONa + 5H2O
iodoform smell
2.
Hydroxamic reaction (of ester group).
At alkaline
hydrolysis of esters at presence hydroxylamine
NH2OH are formed hydroxamic
acids, which with salts of heavy metals (it is the most often Iron (²²²)) form the salts painted in red colour – hydroxamates:
red
4. Oxidation of drug by means of chloramine at
presence of chloride acid HCl leads to formation of reaction product, which
at churning (shake up) with ether
paints ether layer in orange colour.
TESTS
Appearance of solution
Dissolve
Acidity or alkalinity
Dissolve
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on
ASSAY
Nitritometry, direct titration
Dissolve
Determine the end-point electrometrically or by the use of the prescribed indicator:
internal indicators: tropeolin 00 – before yellow colouring, a mix
tropeolin 00 and methylen dark blue – transition of red-violet colouring to blue, neutral red – before dark blue
colouring or
external indicators:
potassium iodide test paper – before dark blue colouring.
In
parallel spend control experience.
Carry out the
determination of primary aromatic
amino-nitrogen (2.5.8):
1) Diazotization of free aromatic amino group:
T
2NaNO2 + 2KI + 4HCl à I2 + 2NO + 2KCl + 2NaCl + 2H2O
excess drop
Åm (C9H11NO2) = Ì. ì.
1 ml of
STORAGE
Store protected from light.
Action and use
Local anaesthetic.
Ph Eur
Procaine hydrochloride (Novocaine)
(Ph Eur monograph
0050)
Procaini hydrochloridum
Novocainum (N)
Aethocain
Allocaine
C13H20N2O2,HCl
or C13H21ClN2O2
Ì m. = 272,8 g/mol
The chemical name: 2-(diethylamino)ethyl 4-aminobenzoate hydrochloride or b-2-diethylaminoethylester
of p-aminobenzoic acid hydrochloride.
DEFINITION
Procaine hydrochloride contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 2-(diethylamino)ethyl
4-aminobenzoate hydrochloride,
calculated with reference to the dried substance.
It is synthesised in 1904.
Reception
1. From benzocaine by means
of alcoholysis reaction with b-diethylaminoethanol in the presence of sodium
alcoholate: at interaction esters
with alcohols occurs retherification
(interesterification) – an exchange alcoholic rests).
novocaine-basis
Formed ethanol Ñ2Í5ÎÍ is easily driven
away, as its temperature of boiling is considerable below boiling temperature diethylaminiethanol.
The obtained basis of
novocaine transfer in salt action of the calculated quantity alcoholic solution of HCl:
2. From p-nitrotoluene reaction of oxidation to p-nitrobenzoic acid with the next condensation its acid chloride (SOCl2
– thionyl chloride) with b-diethylaminoethanol and nitrogroup reduction.
Diethylaminoethanol obtained by condensation ethylene oxide with diethylamine in alcoholic
solution (see tetracaine hydrochloride). For this purpose gas ethylene
oxide pass throught solution diethylamine
in methanol.
CHARACTERS
A white, crystalline powder or colourless
crystals, very soluble in water, soluble in alcohol.
IDENTIFICATION
First identification A, B, E.
Second identification A, C, D, E, F.
A. Melting point (2.2.14):
B. Examine by infrared
absorption spectrophotometry (2.2.24), comparing with the spectrum
obtained with procaine hydrochloride CRS.
C. To about 5 mg add
0.5 ml of fuming nitric acid R.
Evaporate to dryness on a water-bath, allow to cool and dissolve the residue in
5 ml of acetone R. Add 1 ml
of
D. To 0.2 ml of solution S (see Tests) add 2 ml of water
R and 0.5 ml of dilute sulphuric
acid R and shake. Add 1 ml of a 1 g/l solution of potassium permanganate R.
The colour is immediately discharged.
E. It gives reaction
(a) of chlorides (2.3.1)
AgNO3 + Procaine×HCl = AgCl↓ +
Procaine×HNO3
AgCl + 2NH4OH = [Ag(NH3)2]Cl
+ 2H2O
F. Dilute 1 ml of solution S to 100 ml with water R.
2 ml of this solution gives the reaction
of primary aromatic amines (2.3.1):
Reaction of primary
aromatic amino group (diazotization with the next azocoupling).
Some
crystals of test substance dissolve in 2 ml of water R, acidify of HCl R, add 0,2 ml of sodium
nitrite solution R NaNO2 and through 1–2 mines
add 1 ml of alkaline solutionb-naphthol; there is an intensive orange or red colouring and, as a rule, the precipitate
of the same colour is formed.
salt
diazonium azo dye
of red colour
Other reactions of identification:
1. Hydroxamic reaction (see benzocaine, reaction 3).
2. Reaction with perhydrol. To solution of
novocaine add perhydrol (30 % solution hydrogen
peroxide Í2Î2) and concentrated sulphatic acid H2SO4; gradually there is a lilac colouring.
3. Precipitation of procaine-base. To solution of
procaine hydrochloride add solution NaOH; the oily liquid (prokain-basis) is
formed:
Procaine×HCl + NaOH =
Prokain-base¯ + NaCl + H2O
4. Reaction with bromic water (for aromatic ring). To solution of
procaine hydrochloride add bromic water Br2; the precipitate of dibromderivative is
formed:
precipitate of
dibromderivative
TESTS
Solution S
Dissolve
Appearance of solution
Solution S is clear (2.2.1) and
colourless (2.2.2, Method II).
pH (2.2.3)
Dilute 4 ml of solution S to 10 ml with carbon
dioxide-free water R. The pH of the solution is 5.0 to 6.5.
Related substances
Examine by thin-layer chromatography (2.2.27),
using silica gel GF254 R as the coating substance.
Test solution Dissolve
Reference solution Dissolve 50 mg of 4-aminobenzoic acid R in water
R and dilute to
100 ml with the same solvent. Dilute 1 ml of the solution to 10 ml with water
R.
Apply separately to the plate 5 µl of each
solution. Develop over a path of
Heavy metals (2.4.8)
Dissolve
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on
ASSAY
Nitritometry, direct titration
Dissolve
Carry out the
determination of primary aromatic
amino-nitrogen (2.5.8):
1) Diazotization of free aromatic amino group:
T
2NaNO2 + 2KI + 4HCl à I2 + 2NO + 2KCl + 2NaCl + 2H2O
excess drop
Åm(C13H21ClN2O2)
= Ì. ì.
1 ml of
STORAGE
Store protected from light.
Action and use
Local anaesthetic.
Ph Eur
Tetracaine hydroñhloride
(Ph Eur monograph
0057)
NOTE: The name Amethocaine Hydrochloride
was formerly used in the
Dicainum
Tetracaini hydroñhloridum
C15H24N2O2,HCl
Ì m. = 300,83 g/mol
The chemical name: β-Dimethylaminoethylester
of p-butylaminobenzoic acid
hydrochloride.
DEFINITION
Tetracaine hydrochloride contains not less
than 99.0 per cent and not more than
the equivalent
of 101.0 per cent of
2-(dimethylamino)ethyl 4-(butylamino)benzoate
hydrochloride, calculated with reference to the dried substance.
Obtaining
Initial
substances for synthesis tetracaine hydrochloride is p-aminobenzoic acid (its synthesis from toluene – see benzocaine) and dimethylaminoethanol, which obtained by
condensation ethylene oxide with dimethylamine in the medium of alcohol:
Tetracaine
hydrochloride obtained under such scheme:
p-aminobenzoic acid heat up in the
alkaline medium with p-butylbromide
and obtained p-butylaminobenzoic acid
by interaction with thionyl chloride
SOCl2 transform in acid
chloride, which condense with β-dimehylaminoethanol.
CHARACTERS
A white, crystalline powder, slightly
hygroscopic, freely soluble in water, soluble in alcohol.
It melts at about
IDENTIFICATION
First identification A, B, D.
Second identification B, C, D.
A. Examine by infrared
absorption spectrophotometry (2.2.24), comparing with the spectrum
obtained with tetracaine hydrochloride CRS.
B. To 10 ml of solution S (see Tests) add 1 ml of ammonium thiocyanate solution R. A white, crystalline precipitate is formed which, after
recrystallisation from water R and drying at
C. Nitration of tetracaine
hydrochloride with the next formation aci-nitroform of potassium salt salts
with ortho-quinoid structure. To about 5 mg add 0.5 ml of fuming nitric
acid R. Evaporate to dryness on a water-bath, allow to
cool and dissolve the residue in 5 ml of acetone R. Add 1 ml of
D. Solution S gives reaction
(a) of chlorides (2.3.1).
AgNO3
+ Tetracaine×HCl = AgCl↓ + Tetracaine×HNO3
*For
salts of the organic bases test of solubility of formed precipitate AgCl spend
after filtration and washings of precipitate by water. AgCl +
2NH4OH = [Ag(NH3)2]Cl
+ 2H2O
Other peactions:
1. Reaction of secondary amino
group after alkaline hydrolysis.
a) at boiling solution
of test substance with solution NaOH is formed sodium salt p-butylaminobenzoic acid:
b) At acidifying
hydrolysis product by chloride acid HCl the
white precipitate p-butylaminobenzoic acid, which is
dissolved in excess of
HCl:
white precipitate
c) At action of sodium nitrite NaNO2 in
the medium of chloride acid diluted HCl precipitate of N-nitroso compound of this acid is
formed:
2. Hydroxamic reaction (see benzocaine, reaction 3).
3. Unlike benzocaine and novocaine, tetracaine hydrochloride not diazotized (does not contain a free
amino group–NH2).
TESTS
Solution S
Dissolve
Appearance of solution
Dilute 2 ml of solution S to 10 ml with water
R. The solution is clear (2.2.1) and colourless (2.2.2, Method II).
pH (2.2.3)
Dilute 1 ml of solution S to 10 ml with carbon
dioxide-free water R. The pH of the solution is 4.5 to 6.5.
Related substances
Examine by thin-layer chromatography (2.2.27),
using a TLC silica gel GF254plate R. Carry out a preliminary development over a
path of
Test solution Dissolve
Reference solution Dissolve 50 mg of 4-aminobenzoic acid R in water
R and dilute to
100 ml with the same solvent. Dilute 1 ml of the solution to 10 ml with water
R.
Apply to the plate 5 µl of each solution.
Develop over a path of
Heavy metals (2.4.8)
12 ml of solution S complies with limit test A
for heavy metals (10 ppm). Prepare the standard using lead standard
solution (1 ppm Pb) R.
Loss on drying (2.2.32)
Not more than 1.0 per cent, determined on
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on
ASSAY
Dissolve
1 ml of
SPU. Alkalimetry (of bounded
HCl). Exact volume of test solution of
tetracaine hydrochloride titrate
with standard solution of NaOH in the presence of chloroform (to extract
the tetracaine-base) and the indicator
– phenolphthalein before occurrence light-pink
colou.
Tetracaine
×HCl + NaOH Ä Tetracaine ×base¯ + NaCl + H2O
Åm (C15H24N2O2
×HCl) = Ì m.
Other method of
assay:
1. Nitritometry, direct
titration (nitrosation of secondary amino group)
Nearby
As the indicator it is possible to
use:
Internal
indicators (tropeolin 00 – titrate
from red before yellow colouring; a mix tropeilin 00 and methyl dark blue –
from red-violet before blue colouring; neutral red – from crimson before dark
blue colouring);
The external
indicator – potassium iodide test paper (titrate before occurrence of dark
blue colouring).
2NaNO2 + 2KI
+ 4HCl ® I2 +
2NO + 2KCl
+ 2NaCl + 2H2O
STORAGE
Store protected from light.
Action and use
Local anaesthetic.
Preparation
Tetracaine Eye Drops
PROCAINAMIDE
HYDROCHLORIDE
(Ph Eur monograph
0567)
Procainamidi hydrochloridum
Novocainamidum (N)
Procainamidum
Amidoprocain
C13H21N3O,HCl or C13H22ClN3O
Ì m. = 271,78 g/mol
The chemical name:4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride or β-diethylaminoethylamide
of p-aminobenzoic acid hydrochloride
(SPU).
DEFINITION
Procainamide
hydrochloride contains not less than 98.0
per cent and not more than
the equivalent of 101.0
per cent of 4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride, calculated with reference
to the dried substance.
Obtaining (like obtaining of novocaine
and benzocaine)
Initial raw
materials is toluene C6H5CH3
which nitration, oxidize to p-nitrobenzoic
acid; acid chloride to condense with diethylaminoethylamine
with the next reduction of nitrogroup
and acidifying by means of chloride
acid:
Procainamide
hydrochloride
CHARACTERS
A white or very slightly yellow, crystalline
powder, hygroscopic, very soluble in water, freely soluble in alcohol, slightly
soluble in acetone.
IDENTIFICATION
First identification C, D.
Second identification A, B, D, E.
A. Melting point (2.2.14):
B. UV-spectroscopy
of an alkaline solution. Dissolve 10.0 mg in
C. Examine by infrared
absorption spectrophotometry (2.2.24), comparing with the spectrum
obtained with procainamide hydrochloride CRS.
D. Dilute 1 ml of solution S to 5 ml with water R.
The solution gives reaction (a) of
chlorides (2.3.1):
AgNO3 + Procainamide ×HCl = AgCl↓ + Procainamide ×HNO3
*For
salts of the organic bases test of solubility of formed precipitate AgCl spend
after filtration and washings of precipitate by water. AgCl +
2NH4OH = [Ag(NH3)2]Cl
+ 2H2O
At
addition of HNO3 white precipitate AgCl again is formed:
[Ag
(NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3
E. Dilute 1 ml of solution S (see Tests) to 2 ml with water
R. 1 ml of this solution gives the reaction of primary aromatic amines (2.3.1).
Reaction of solution S on
primary aromatic amines (SPU) (diazotization
with the next azocoupling).
Some
crystals of test substance dissolve
in 2 ml of water R, acidify of HCl R, add 0,2 ml
of sodium
nitrite solution R NaNO2
and through 1–2 mines add 1 ml of an alkaline solutionb-naphthol, there is an intensive orange or red colouring and, as a rule, the precipitate
of the same colour is formed.
salt
diazonium azo dye
of red colour
Other reactions:
1. Hydroxamic reaction of ester
group, see benzocaine, reaction 3).
2. Reaction with ammonium vanadate.
To test solution add solution of ammonium
vanadate NH4VO3, sulphatic
acid concentrated H2SO4 and heat up; dark
red colouring (difference from novocaine)
is formed.
3. Lignin test (of
aromatic amino group, see benzocaine, reaction 5).
4. Reaction with bromic water (of aromatic ring). To test solution
add bromic water Br2; the precipitate
of dibromoderivative
is formed:
TESTS
Solution S
Dissolve
Appearance of solution
Solution S is clear (2.2.1) and not
more intensely coloured than reference solution B6 (2.2.2, Method II).
pH (2.2.3)
The pH of solution S is 5.6 to 6.3.
Related substances
Examine by thin-layer chromatography (2.2.27),
using silica gel GF254 R as the coating substance.
Test solution Dissolve
Reference solution Dilute 1 ml of the test
solution to 200 ml with alcohol R.
Apply to the plate 5 µl of each solution.
Develop over a path of
Heavy metals (2.4.8)
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on
ASSAY
Nitritometry, direct titration
Dissolve
Carry out the
determination of primary aromatic
amino-nitrogen (2.5.8):
1) Diazotization of free aromatic amino group:
R=NH-CH2CH2 N(C2H5)2
T
2NaNO2 + 2KI + 4HCl à I2 + 2NO + 2KCl + 2NaCl + 2H2O
excess
drop
Åm (C13H22ClN3O)
= Ì. ì.
1 ml of
STORAGE
Store in an airtight container
, protected from light.
Action and use
Anti-arrhythmic.
Preparations
Procainamide Injection
Procainamide Tablets
Ph Eur
Articaine hydrochloride
Articaini hydrochloridum
Ultracainå
Õèìè÷åñêîå íàçâàíèå: methyl ester of 4-methyl-3[2-propylaminopropionamide]-2-thiophene
carboxylic acid hydrochloride.
(Ph Eur monograph 1688)
C13H20N2O3S,HCl M.m. = 320.8 g/mol
DEFINITION
Methyl 4-methyl-3-[[(2RS)-2-(propylamino)propanoyl]amino]thiophene-2-carboxylate hydrochloride.
Content
98.5
per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white,
crystalline powder.
Solubility
Freely soluble in water and
in alcohol.
IDENTIFICATION
First identification B, D.
Second identification A, C, D.
A. Dissolve 50.0 mg
in a 1 g/l solution of hydrochloric acid R and dilute to 100.0 ml with
the same acid. Dilute 5.0 ml of the solution to 100.0 ml with a 1 g/l solution
of hydrochloric acid R. Examined between 200 nm and 350 nm (2.2.25),
the solution shows an absorption maximum
at 272 nm. The specific absorbance
at the maximum is 290 to 320.
B. Infrared absorption spectrophotometry (2.2.24).
Preparation Place dropwise 20 µl of the
test solution on 300 mg discs.
Test solution Dissolve
Comparison articaine hydrochloride
CRS.
C. Thin-layer chromatography (2.2.27).
Test solution Dissolve 20 mg of the substance to be examined in 5 ml
of alcohol R.
Reference solution Dissolve 20 mg of articaine hydrochloride CRS
in 5 ml of alcohol
R.
Plate TLC silica gel F254plate R.
Mobile phase triethylamine R, ethyl
acetate R, heptane R (10:35:65 V/V/V).
Application 5 µl.
Development Over a path of
Drying In air.
Detection Examine in ultraviolet light at 254 nm.
Results 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.
D. It gives reaction
(a) of chlorides (2.3.1):
AgNO3 + Articaine ×HCl = AgCl↓ + Articaine ×HNO3
*For
salts of the organic bases test of solubility of formed precipitate AgCl spend
after filtration and washings of precipitate by water. AgCl +
2NH4OH = [Ag(NH3)2]Cl
+ 2H2O
At
addition of HNO3 white precipitate AgCl again is formed:
[Ag
(NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3
SPU. Other reactions of identification:
1. Drug pyrolysis (dry or
damp) with the next definition ionogenic bounded of Sulfur.
a) Dry pyrolysis (substance burning) leads to
formation of hydrogen sulphide H2S,
which reveal by means of darkening lead-acetic paper Pb (CH3COO)
2:
Pb2+ + S2– ® PbS↓
dark brown or black
b) Damp pyrolysis: mineralizes of
drug by action strong HNO3, that does not contain Sulfur; thus Sulfur
passes in structure of sulphate-ions
SO42 - , which reveal behind formation of a white precipitate at interaction
with BaCl2 or Ba (NO3) 2:
Ba2 + + SO42 - → BaSO4
↓
white
The precipitate is insoluble
neither in acids, nor in alkalis.
2. Hydrolysis of articaine
with the next identification of methanol (for ester group –COO–):
Methanol identifies after
its oxidation to formaldehyde HCÍÎ by solution of KMnÎ4 in the medium of phosphatic
acid H3PO4:
5CH3OH + 2KMnÎ4 + 3H3PO4 ® 5HCÍÎ + 2MnHPO4 + K2HPO4
+ 8H2O
Formaldehyde identifies by
means of interaction
with disodium salt chromotrope acid in the presence of concentrated sulphatic acid H2SO4;
it is formed aurin dye of violet colour:
aurin dye of violet colour
3. Hydrolysis of articaine with
the next identification of primary amino group R–NH2 (of amide bound–CO–NH–)
TESTS
Solution S
Dissolve
Appearance of solution
Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY6 (2.2.2, Method I).
pH (2.2.3)
4.2 to 5.2.
Dissolve
Related substances
Liquid chromatography (2.2.29).
Test solution Dissolve 10.0 mg of the substance to be examined in
the mobile phase
and dilute to 10.0 ml with the mobile phase.
Reference solution (a) Dilute 1.0 ml of the test
solution to 100.0 ml with the mobile
phase. Dilute 1.0 ml of this solution to 10.0 ml with the mobile phase.
Reference solution (b) Dissolve 10.0 mg of articaine
impurity A CRS and 5.0 mg of articaine
impurity
Reference solution (c) Add 1.0 ml of reference solution
(b) to 50.0 mg of articaine
hydrochloride CRS and dilute to 50 ml with the mobile phase.
Reference solution (d) Dilute 1.0 ml of reference
solution (b) to 50.0 ml with the mobile
phase.
Column:
—size: l
=
—stationary
phase: spherical end-capped octadecylsilyl silica gel for chromatography
R (5 µm) with a specific surface area of 335 m2/g and a carbon
loading of 19 per cent,
—temperature:
Flow rate 1 ml/min.
Detection Spectrophotometer at 276 nm.
Injection 10 µl; inject the test solution and reference
solutions (a), (c) and (d).
Run time 5 times the retention time of articaine.
Relative retentions with reference to
articaine (retention time = about 9.3 min):
impurity B = about 0.6; impurity D = about 0.7; impurity A = about 0.8;
impurity E = about
0.86; impurity F = about 0.9; impurity G = about 1.7; impurity H = about
2.1; impurity I = about 2.6; impurity C
= about 3.6; impurity J = about 4.0.
System suitability Reference solution (c):
—resolution:
minimum 1.2 between the peaks due to impurity A and impurity E.
Limits:
—impurity A:
not more than the area of the corresponding peak in the chromatogram obtained
with reference solution (d) (0.2 per cent),
—any other
impurity: not more than the area of the principal peak in the chromatogram
obtained with reference solution (a) (0.1 per cent),
—total of other
impurities: not more than 5 times the area of the principal peak in the
chromatogram obtained with reference solution (a) (0.5 per cent),
—disregard limit:
half the area of the principal peak in the chromatogram obtained with reference
solution (a) (0.05 per cent).
Heavy metals (2.4.8)
Maximum 5 ppm.
Dissolve
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on
Sulphated ash (2.4.14)
Maximum 0.1 per cent,
determined on
IMPURITIES
Specified impurities A, B, C.
Other detectable
impurities D, E,
F, G, H, I, J.
A. R = CH3,
R = H: methyl
3-[[2-(propylamino)acetyl]amino]-4-methylthiophene-2-carboxylate
(acetamidoarticaine),
B. R = H, R = CH3:
4-methyl-3-[[(2RS)-2-(propylamino)propanoyl]amino]thiophene-2-carboxylic
acid (articaine acid),
C. R = CH(CH3)2, R = CH3: 1-methylethyl 4-methyl-3-[[(2RS)-2-(propylamino)propanoyl]amino]thiophene-2-carboxylate
(articaine isopropyl ester),
D. R1 = CH2-CH3,
R2 = H, R3 = OCH3: methyl 3-[[(2RS)-2-(ethylamino)propanoyl]amino]-4-methylthiophene-2-carboxylate
(ethylarticaine),
E. R1 = CH(CH3)2, R2 = H, R3 = OCH3:
methyl 4-methyl-3-[[(2RS)-2-[(1-methylethyl)amino]propanoyl]amino]thiophene-2-carboxylate
(isopropylarticaine),
F. R1 = CH2-CH2-CH3,
R2 = H, R3 = NH-CH2-CH2-CH3: 4-methyl-N-propyl-3-[[(2RS)-2-(propylamino)propanoyl]amino]thiophene-2-carboxamide (articaine acid
propionamide),
G. R1 = (CH2)3-CH3,
R2 = H, R3 = OCH3: methyl 3-[[(2RS)-2-(butylamino)propanoyl]amino]-4-methylthiophene-2-carboxylate
(butylarticaine),
H. R1 = R2 = CH2-CH2-CH3,
R3 = OCH3: methyl 3-[[(2RS)-2-(dipropylamino)propanoyl]amino]-4-methylthiophene-2-carboxylate
(dipropylarticaine),
J. methyl 3-[[(2RS)-2-bromopropanoyl]amino]-4-methylthiophene-2-carboxylate (bromo compound).
Ph Eur
ASSAY
Dissolve
1 ml of
Other metods of assay (SPU):
1. Argentometry (for bounded
HCl)
Volhard
method, back titration. To investigated solution add double excess of standard solution of AgNO3. Excess of AgNO3 titrate with standard
solution of NH4SCN in the
presence of ammonium iron alum (NH4)
Fe (SO4) 2 as indicator before red-pink colouring.
R×HCl + AgNO3 ®R×HNO3 +
AgCl ↓
AgNO3 +
NH4SCN = AgSCN¯ + NH4NO3
3NH4SCN
+ (NH4) Fe (SO4) 2 = Fe (SCN) 3 + 2
(NH4) 2SO4
red-pink
Åm = Ì m.
2. Àlkalimetry (for bounded HCl) in the medium of organic
solvent.
Exact
volume of articaine test solution titrate with standard solution of NaOH in the presence of organic solvent (e.g. chloroform) (for
infusion of articaine-base) and the indicator – phenolphthalein before occurrence light-pink colouring.
Articaine×HCl + NaOH =
Articaine ×base¯ + NaCl + H2O
Åm = Ì m.
STORAGE
Protected from light.
Action and use
Local anaesthetic.
Ph Eur
Derivatives arylaliphatic
acids as drugs
To this
group of druds concerns ibuprofen –
2-phenylpropionic acid derivative.
Ibuprofen
General Notices
(Ph Eur monograph 0721)
C13H18O2 M.m. = 206.3
DEFINITION
(2RS)-2-[4-(2-Methylpropyl)phenyl]propanoic acid.
Content
98.5 per cent to 101.0 per cent (dried
substance).
CHARACTERS
Appearance
White, crystalline powder or
colourless crystals.
Solubility
Practically insoluble in water, freely soluble
in acetone, in methanol and in methylene chloride. It dissolves in
dilute solutions of alkali hydroxides and carbonates.
IDENTIFICATION
First identification A, C.
Second identification A, B, D.
A. Melting point (2.2.14):
B. UV-spectroscopy.
Dissolve 50.0 mg in a 4 g/l solution of sodium hydroxide R and
dilute to 100.0 ml with the same alkaline solution. Examined between 240 nm and 300 nm (2.2.25), using a
spectrophotometer with a band width of 1.0 nm and a scan speed of not more than
50 nm/min, the solution shows a shoulder at 258 nm and 2 absorption maxima, at 264 nm and 272 nm. The ratio of the
absorbance measured at the maximum at 264 nm to that measured at the shoulder
at 258 nm is 1.20 to 1.30. The ratio of the absorbance measured at the maximum
at 272 nm to that measured at the shoulder at 258 nm is 1.00 to 1.10.
C. Infrared absorption spectrophotometry (2.2.24).
Preparation Discs.
Comparison ibuprofen CRS.
D. Thin-layer chromatography (2.2.27).
Test solution Dissolve 50 mg of the substance to be examined in methylene chloride
R and dilute to 10 ml with the same solvent.
Reference solution Dissolve 50 mg of ibuprofen CRS in methylene
chloride R and
dilute to 10 ml with the same solvent.
Plate TLC silica gel plate R.
Mobile phase anhydrous acetic acid R,
ethyl acetate R, hexane R (5:24:71 V/V/V).
Application 5 µl.
Development Over a path of
Drying At
Detection Lightly spray with a 10 g/l solution of potassium
permanganate R in dilute sulphuric acid R and heat
at
Results The principal spot
in the chromatogram obtained with the test solution is similar in position, colour and size
to the principal spot in the chromatogram
obtained with the reference solution.
TESTS
Solution S
Dissolve
Appearance of solution
Solution S is clear (2.2.1) and
colourless (2.2.2, Method II).
Angle of optical rotation (2.2.7)
- 0.05° to + 0.05°.
Dissolve
Related substances
Liquid chromatography (2.2.29).
Test solution Dissolve 20 mg of the substance to be examined in 2 ml
of acetonitrile R
and dilute to 10.0 ml with mobile phase A.
Reference solution (a) Dilute 1.0 ml of the test
solution to 100.0 ml with mobile phase
A.
Reference solution (b) Dissolve 20 mg of ibuprofen
CRS in 2 ml of acetonitrile R,
add 1.0 ml of a 0.06 g/l solution of ibuprofen impurity B CRS in acetonitrile
R and dilute to 10.0 ml with mobile
phase A.
Column:
—size: l
=
—stationary
phase: octadecylsilyl silica gel for chromatography R (5 µm).
Mobile phase:
—mobile phase A:
mix 0.5 volumes of phosphoric acid R, 340 volumes of acetonitrile R
and 600 volumes of water R; allow to equilibrate and dilute to 1000
volumes with water R,
—mobile phase B: acetonitrile
R,
Flow rate 2 ml/min.
Detection Spectrophotometer at 214 nm.
Equilibration For about 45 min with mobile
phase A.
Injection 20 µl.
System suitability Reference solution (b):
—peak-to-valley
ratio: minimum of 1.5, where Hp = height above the
baseline of the peak due to impurity B, and Hv = height above
the baseline of the lowest point of the curve separating this peak from the
peak due to ibuprofen. If necessary, adjust the concentration of acetonitrile
in mobile phase A.
Limits:
—impurity B:
not more than the area of the corresponding peak in the chromatogram obtained
with reference solution (b) (0.3 per cent),
—any other
impurity: not more than 0.3 times the area of the principal peak in the
chromatogram obtained with reference solution (a) (0.3 per cent),
—total of all
impurities apart from impurity B: not more than 0.7 times the area of the
principal peak in the chromatogram obtained with reference solution (a) (0.7 per
cent),
—disregard limit:
0.05 times the area of the principal peak in the chromatogram obtained with
reference solution (a) (0.05 per cent).
Impurity F
Gas chromatography (2.2.28): use the
normalisation procedure.
Methylating solution Dilute 1 ml of N,N-dimethylformamide dimethyl acetal R and 1 ml of pyridine R to 10 ml with ethyl
acetate R.
Test solution Weigh about 50.0 mg of the substance to be examined
into a sealable vial,
dissolve in 1.0 ml of ethyl acetate R, add 1 ml of methylating solution,
seal and heat at
Reference solution (a) Dissolve 0.5 mg of ibuprofen
impurity F CRS in ethyl acetate R
and dilute to 10.0 ml with the same solvent.
Reference solution (b) Weigh about 50.0 mg of ibuprofen
CRS into a sealable vial, dissolve
in 1.0 ml of reference solution (a), add 1 ml of methylating solution, seal
and heat at
Column:
—material:
fused-silica,
—size: l
=
—stationary
phase: macrogol 20 000 R (film thickness 2 µm).
Carrier gas helium for chromatography
R.
Flow rate 5.0 ml/min.
Temperature:
—column:
—injection port:
—detector:
Detection Flame-ionisation.
Injection 1 µl; inject the test solution and reference solution
(b).
Run time Twice the retention time
of ibuprofen.
System suitability:
—relative
retention with reference to ibuprofen (retention time = about 17 min):
impurity F = about 1.5.
Limit:
—impurity F:
maximum 0.1 per cent.
Heavy metals (2.4.8)
Maximum 10 ppm.
12 ml of solution S complies with limit test
B. Prepare the standard using lead
standard solution (1 ppm Pb) prepared by diluting lead standard
solution (100 ppm Pb) R with methanol
R.
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on
Sulphated ash (2.4.14)
Maximum 0.1 per cent, determined
on
IMPURITIES
Specified impurities A, B, C, D, E.
Other detectable
impurities F, G,
H, I, J, K, L, M, N, O, P, Q, R.
A. R1 = OH, R2 = CH2-CH(CH3)2,
R3 = H: (2RS)-2-[3-(2-methylpropyl)phenyl]propanoic acid,
B. R1 = OH, R2 = H,
R3 = [CH2]3-CH3: (2RS)-2-(4-butylphenyl)propanoic
acid,
C. R1 = NH2,
R2 = H, R3 = CH2-CH(CH3)2: (2RS)-2-[4-(2-methylpropyl)phenyl]propanamide,
D. R1 = OH, R2 = H,
R3 = CH3: (2RS)-2-(4-methylphenyl)propanoic acid,
E.
1-[4-(2-methylpropyl)phenyl]ethanone,
F. 3-[4-(2-methylpropyl)phenyl]propanoic acid,
G. cis-7-(2-methylpropyl)-1-[4-(2-methylpropyl)phenyl]-1,2,3,4-tetrahydronaphthalene-1,4-dicarboxylic acid,
H. X = O: (3RS)-1,3-bis[4-(2-methylpropyl)phenyl]butan-1-one,
I. X = H2:
(3RS)-1,3-bis[4-(2-methylpropyl)phenyl]butane,
J. R = H, R4 =
CO-CH(CH3)2: (2RS)-2-[4-(2-methylpropanoyl)phenyl]propanoic
acid,
K. R = H, R4 = CHO:
(2RS)-2-(4-formylphenyl)propanoic acid,
L. R = H, R4 =
CHOH-CH(CH3)2:
2-[4-(1-hydroxy-2-methylpropyl)phenyl]propanoic acid,
M. R = OH, R4 = CH2-CH(CH3)2:
(2RS)-2-hydroxy-2-[4-(2-methylpropyl)phenyl]propanoic acid,
N. R = H, R4 = C2H5:
(2RS)-2-(4-ethylphenyl)propanoic acid,
O. R = H, R4 =
CH(CH3)-C2H5:
2-[4-(1-methylpropyl)phenyl]propanoic acid,
P. R = CH3:
(2RS)-2-[4-(2-methylpropyl)phenyl]propan-1-ol,
Q. R = H:
2-[4-(2-methylpropyl)phenyl]ethanol,
R. 1,1-bis[4-(2-methylpropyl)phenyl]ethane.
Ph
Eur
ASSAY
Alkalimetry of methanol solution, direct titration
Dissolve
Åm (C13H18O2)
= Ì m.
1 ml of
Storage
The list of strong substances. In
the air-tight container, in the place protected from light.
Action and use
Anti-inflammatory;
analgesic.
Preparations
Ibuprofen Cream
Ibuprofen Gel
Ibuprofen Oral Suspension
Ibuprofen Tablets
Ph Eur
To
derivatives of acetanilide Ñ6Í5–NH–CO–CH3,
containing diethyl aminogen group –N (C2H5) 2,
which causes local anesthetic effect,
drugs – lidocaine and trimecaine hydrochloride concern.
Lidocaine (in
Lidocainum
Xycainum
Xylocainum
Ñ14Í22N2O×HCl
Ì m. = 270,79 g/mol
The chemical name: 2-diethylamino-2,6-dimethylacetanilide hydrochloride
(Ph Eur monograph 0727)
Lidocaine
NOTE: The name Lignocaine was formerly used in the
Preparation Lidocaine
Ointment
C14H22N2O
M.m. = 234.3 g/mol
DEFINITION
Lidocaine contains not less than 99.0 per cent
and not more than the equivalent of 101.0 per cent of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide,
calculated with reference to the
anhydrous substance.
CHARACTERS
A white or almost white, crystalline powder, practically insoluble in water, very soluble in
alcohol and in methylene chloride.
(Ph Eur monograph
0227)
Lidocaine
hydrochloride
NOTE: The name Lignocaine Hydrochloride was
formerly used in the
C14H22N2O,HCl,H2O
M.m. = 288.8 g/mol
DEFINITION
Lidocaine hydrochloride contains not less than
99.0 per cent and not more than the equivalent of 101.0 per cent of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide hydrochloride, calculated with reference
to the anhydrous substance.
CHARACTERS
A white, crystalline powder,
very soluble in water, freely
soluble in alcohol.
Obtaining
Initial substance
for lidocaine obtaining is 2,6-dimethylanilide, which acetylizes by means of acid chloride chloracetic acid Cl–CH2–CO–Cl,
and then condense with diethylamine in benzene at presence of chloride acid HCl:
IDENTIFICATION
First identification A, B, F.
Second identification A, C, D, E, F.
A. Melting point (2.2.14):
B. Examine by infrared
absorption spectrophotometry (2.2.24), comparing with the spectrum
obtained with lidocaine hydrochloride CRS.
C. Interaction with picric acid. Dissolve
D. To about 5 mg add
0.5 ml of fuming nitric acid R.
Evaporate to dryness on a water-bath, cool and dissolve the residue in 5 ml of acetone R. Add 0.2 ml of alcoholic potassium hydroxide solution
R. A green colour is produced.
E. Reaction with cobalt (²²) nitrate. To 5 ml of
solution S (see Tests) add 5 ml of water R and make alkaline with dilute
sodium hydroxide solution R. Collect the precipitate on a filter and wash
with water R. Dissolve half of the precipitate in 1 ml of alcohol R
and add 0.5 ml of a 100 g/l solution of cobalt nitrate R. A bluish-green precipitate is formed.
F. It gives reaction
(a) of chlorides (2.3.1).
AgNO3 + Lidocaine×HCl ® AgCl↓ + Lidocaine ×HNO3
white
AgCl + 2NH4OH ® [Ag(NH3)2]Cl + 2H2O
Other
reaction of identification:
1. Alkaline hydrolysis of drug
with the next identification of 2,6-dimethylaniline:
a) Formation azo dye of orange or red
colour (this is reaction diazotization
with the next azocoupling (presence of a primary aromatic amino group)):
azo dye of
orange or red colour
b) Formation azomethine dye (Schiff base) (at interaction with acetone ÑÍ3ÑÎÑÍ3 (presence of a primary aromatic amino group):
2. Alkaline hydrolysis of drug with the next
identification sodium 2-diethylaminoacetate. The second product of alkaline
hydrolysis – sodium 2- diethylaminoacetate concerns to tertiary amine, having characteristic smell.
characteristic smell
TESTS
Solution S
Dissolve
Appearance of solution
Solution S is clear (2.2.1) and
colourless (2.2.2, Method II).
pH (2.2.3)
Dilute 1 ml of solution S to 10 ml with carbon
dioxide-free water R. The pH of the solution is 4.0 to 5.5.
Impurity A
Solution (a) Dissolve
Solution (b) Dissolve 50 mg of 2,6-dimethylaniline
R in methanol R and dilute to 100
ml with the same solvent. Dilute 1 ml of the solution to 100 ml with methanol
R. This solution
is used to prepare the standard.
Using three flat-bottomed tubes, place in the
first 2 ml of solution (a), in the second 1 ml of solution (b) and 1 ml of methanol
R and in the third 2 ml of methanol R (used to prepare a blank). To each tube add 1 ml of a
freshly prepared 10 g/l solution of dimethylaminobenzaldehyde R
in methanol R and 2 ml of glacial acetic acid R and allow to stand at room temperature for 10
min. The intensity of the yellow colour of the test solution is between that of
the blank and that of the standard (100 ppm).
Heavy metals (2.4.8)
Dissolve
Water (2.5.12)
5.5 per cent to 7.0 per cent, determined on
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on
IMPURITIES
A. 2,6-dimethylaniline.
ASSAY (Ph Eur) of
Lidocaine (Ointment) (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide)
Acidimetry, non-agueous titration
To
1 ml of
SPU : direct titration of solution test substance in anhydrous
acetic acid R ÑÍ3ÑÎÎÍ with standard solution perchloric acid
HClO4 at presence merccury (²²) acetate Hg (CH3COO) 2 (for bound
of chlorides-ions in the form of slightly soluble salt) and uses crystal violet as indicator.
Åm (Ñ14Í22N2O×HCl) = Ì m.
ASSAY (Ph
Eur) of Lidocaine hydrochloride (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide hydrochloride)
Dissolve
1 ml of
Ph
Eur
Other methods of assay:
Argentometry (for fixed(boud,
combined) HCl)
a) Faience Method. Direct titration of an investigated solution with standard solution
of AgNO3 in acetic-acid medium ÑÍ3ÑÎÎÍ, using bromthymol dark blue as indicator.
AgNO3 + Lidocaine×HCl ® AgCl↓ + Lidocaine ×HNO3
Åm (Ñ14Í22N2O×HCl) = Ì m.
b) Volhard method, back titration. To
investigated solution add double excess of standard solution of AgNO3. Excess of AgNO3 titrate with standard solution of NH4SCN in the
presence of ammonium iron alum (NH4)
Fe (SO4) 2 as indicator before red-pink colouring.
Lidocaine ×HCl + AgNO3 ® Lidocaine ×HNO3 + AgCl↓
AgNO3
+ NH4SCN ® AgSCN¯ + NH4NO3
3NH4SCN + (NH4)Fe(SO4)2 ® Fe(SCN)3 + 2(NH4)2SO4
red-pink colouring
Åm (Ñ14Í22N2O×HCl) = Ì m.
STORAGE
Store protected from light.
Action and use
Local anaesthetic;
anti-arrhythmic.
Preparations
Lidocaine Gel
Lidocaine and Chlorhexidine Gel
Lidocaine Injection
Lidocaine and Adrenaline Injection/Lidocaine
and Epinephrine Injection
Sterile Lidocaine Solution
Ph Eur
Trimecaine hydrochloride
Trimecainum
Ñ15Í24N2O×HCl
Ì m. = 283,93 g/mol
The chemical name:a-diethylamino-2,4,6-trimethylacetanilide hydrochloride
Differs
from lidocaine only presence of one more methyl group –ÑÍ3 (in position 4 phenylic ring).
Obtaining (it is similar to lidocaine).
Interaction acid chloride chloroacetic acid Cl–CH2–C
(O)–Cl with 2,4,6-trimethylaniline (mesidine), and then condensation with diethylamine (Ñ2Í5) 2NH at
presence of chloride acid HCl:
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The description. White or slightly yellowish crystal powder. Melting point of 136–137 °C.
Solubility. Very soluble in
water, freely soluble in alcohol and chloroform, it is practically insoluble in
ether. ðÍ water solution 4,5–5,2.
Solutions prepare on an isotonic solution of sodium chloride, sterilise at +100 °C within 30 minutes.
Identification
1. Acid or alkaline hydrolysis
of drug with the next identification 2,4,6-trimethylaniline
(presence of primary aromatic amino group):
a) Formation azo dye (orange or red colour) at reaction diazotization (with solution of
sodium nitrite NaNO2 and chloride
acid HCl) with the next azocoupling
(with alkaline solutionb-naphthol):
mesidine
azo dye of red colour
b) Formation azomethine dye (Schiff base)
at interaction with acetone ÑÍ3ÑÎÑÍ3:
2. Alkaline hydrolysis of test
substance with the next identification of sodium 2-diethylaminoacetate. The second product
of alkaline hydrolysis – sodium 2-diethylaminoacetate concerns to tertiary amines, having a characteristic smell.
characteristic smell
AgNO3 + Trimecaine×HCl ® AgCl↓ + Trimecaine
×HNO3
white
AgCl + 2NH4OH ® [Ag(NH3)2]Cl + 2H2O
4. Reaction with formaldehyde and alkali with formation of isonitrile.
5.
Oxidation alkyl radicals to carboxylic
group –ÑÎÎÍ.
6.
Nitrogene definition by means of Keldal method (for qualitative and
quantitative definition).
For difference Trimecaine from lidocaine use such reactions:
1. Oxidation of Trimecaine by
mix of copper(²²) sulphate CuSO4 and concentrated sulphatic acid H2SO4
at heating. After mix cooling, add
the concentrated solution of ammonia
NH4OH; there is a dark blue
colouring, and in UV-light red-pink fluorescence is observed.
2. Microcrystalloscopic
reaction. Oxidation of Trimecaine by chromic mix. At interaction of
Trimecaine with solution of K2Cr2O7
and sulphatic acid H2SO4
crystals in the form of the needles collected in bunches are formed.
Assay (it is similar to lidocaine)
1. Nitritometry, after acid
hydrolysis, direct titration with standard solution of sodium nitrite NaNO2 in chloride-acid medium HCl and presence of KBr as catalyst
with use external (potassium iodide
test paper) or internal (tropeolin 00, mix tropeolin 00
with methylene dark blue, etc.) indicators.
Åm (Ñ15Í24N2O×HCl) = Ì m.
2. Acidimetry, non-aqueous titration: direct titration of
solution Trimecaine in anhydrous ÑÍ3ÑÎÎÍ with standard solution of HClO4
at presence mercury(²²) acetate Hg (CH3COO) 2 (for bond
of chlorides-ions in the form of slightly soluble salt) and the indicator – crystal violet.
Åm (Ñ15Í24N2O×HCl) = Ì m.
In parallel spend control
experience.
3.
Argentometry (for fixed(boud, combined) HCl)
a) Faience Method. Direct titration of an investigated solution with standard solution
of AgNO3 in acetic-acid medium ÑÍ3ÑÎÎÍ, using bromthymol dark blue as indicator.
AgNO3 + Trimecaine ×HCl ® AgCl↓ + Trimecaine ×HNO3
white
Åm (Ñ15Í24N2O×HCl) = Ì m.
b)
Volhard method, back titration. To
investigated solution add double excess of standard solution of AgNO3. Excess of AgNO3 titrate with standard solution of NH4SCN in the
presence of ammonium iron alum (NH4)
Fe (SO4) 2 as indicator before red-pink colouring.
Trimecaine ×HCl + AgNO3 ® Trimecaine ×HNO3 + AgCl↓
AgNO3
+ NH4SCN ® AgSCN¯ + NH4NO3
3NH4SCN + (NH4)Fe(SO4)2 ® Fe(SCN)3 + 2(NH4)2SO4
red-pink colouring
Åm (Ñ15Í24N2O×HCl) = Ì m.
4.Mercurymetry: direct titration
with standard solution of mercury(²²) nitrate Hg (NO3) 2 at presence of HNO3 and the indicator diphenylcarbazone:
2R×HCl + Hg(NO3)2 ® HgCl2 + 2R×HNO3
The excess drop of
titrant Hg (NO3) 2 reacts with diphenylcarbazone with formation chelate of Mercury of
pink-violet colouring:
Åm (Ñ15Í24N2O×HCl) = Ì m.
5. Alkalimetry water solution of Trimecaine in the
presence of chloroform (for bounded HCl): direct titration with solution
of NaOH in the presence of organic solvent (chloroform or a mix of
chloroform with alcohol, for infusion the insoluble trimekaine-base in water)
and the indicator phenolphthalein to light-pink
colourings.
Trimecaine ×HCl + NaOH ® Trimecaine ¯ + NaCl + H2O
Åm (Ñ15Í24N2O×HCl) = Ì m.
Storage. In densely corked
container, in the place protected from light. The list of strong substances.
Application. Active local anesthetic.
On a chemical
structure and pharmacological action similarly to lidocaine. To
similarly lidocaine, is not the competitor sulphanylamide drugs. In force and
duration of action surpasses procaine hydrochloride. Causes
fast, deep and long anaesthesia, and at higher concentration (2–5 %) – and superficial anaesthesia.
It is a little toxic, does not show irritating action.
Shows also antiarrhytmic action, but less expressed in
comparison with lidocaine.
Release forms: powder, 0,25 % solution in ampoules on 10 ml; 0,5 % and 1 % solutions in ampoules on 2,5 and 10 ml; 2 % solution – on 1; 2; 5 and 10 ml; 5 % asolution – on 1 and 2 ml, is a part of an aerosol.