LECTURE № 14
Theme: Derivatives of barbituric acid:
properties, analysis, storage, action and
use. Primidone as structural analog of
barbiturates
Associate prof. Mosula L.M.
The plan
1. Medical preparations from group of derivatives
of barbituric acid: barbital, barbital sodium,
phenobarbital, phenobarbital sodium, benzonal,
hexenal, thiopental sodium.
2. Primidone as structural analog of barbiturates.
 Derivatives of pyrimidine

In structure of many natural and synthetic drugs is
pyrimidine – hexatomic heterocycle with two atoms of
Nitrogene, which are in the position 1,3:
3
3
N
N
2
N
Completely
hydrogenated
3
hexahydropyrimidine:
N
1
cycle
1
of
4
HN
2
5
1
HN
6
2
pyrimidine
names
In medical practice the synthetic preparations, which contains
hexahydropyrimidine cycle with three hydroxy-groups
-С=О in the position 2,4,6 – derivatives of barbituric acid are
widely applied:
3
HN
O
O
4
2
5
HN
6
1
O
Barbituric acid – is hexahydropyrimidine-2,4,6-trione.
Barbituric acid is cyclic ureide – product of condensation
of carbamide (urea) and dibasic malonic acid (propane
diacid):
O
NH2
O
C
HO
C
NH2
HO
HN
H
C
+
C
O
3
H
2
O
-2H2O
4
5
H
6
HN
H
1
O
O
Derivatives of barbituric acid are products of condensation of
carbamide (urea) and derivatives of malonic acid:
O
NH2
O
C
HO
C
HO
HN
R1
C
+
NH2
3
C
-2H2O
R2
O
O
O
4
R1
2
5
HN
6
1
O
R2
Barbiturates are cyclic imides used as hypnotics and (in
the case of phenobarbital) as anticonvulsants. They are
derivatives of barbituric acid (which is not
pharmacologically active) and differ only in their
substituents on the 5-position of the ring.
The hypnagogue action of barbiturates was revealed in
the early ХХ-th century by Fisher and Mering. In the 1904
Fisher was synthesized barbital, after that were synthesized
many barbiturates and was fixed relationship between
structure and action.
1. The hypnagogue action is characteristic for derivatives of
barbituric acid, which have in the position 5,5 alkyl, aryl or
other radicals.
2. The impact surface and valid time of barbiturates are
increased at increase of lenght of hydrocarbonic chain in the
alkyl substitute in the position 5,5 until 5-6 atoms of Carbon.
Then lenght of hydrocarbonic chain in the barbiturates is
more? Such drugs have stimulant action.
3. The pharmacological effect at hydrocarbonic chain
branching, presence of unsaturated bonds, alkoholic
4. Then action of barbiturates is more intensified the
hypnagogue effect is shot.
5. With one phenyl radical (C6H5) on the 5-position of the ring
to intensify action, not change duration of action, but then
second phenyl radical on the 5-position is presents the
hypnagogue action is decreased.
6. Then alkyl radical is on the 1- or 3-position (nearly imide
group) valid time of drugs is abbreviated.
7. The change of hydrogen on the 1-position on the rest of
aromatic acid (for example, benzoic acid) add to drug
antiepileptic action (benzonal).
8. Then atoms of hydrogen of imide groups (1- and 3-positions
of the ring) are substituted such drug can make
convulsions.
9. Derivatives of thiobarbituric acid (atom of sulphur on the 2position of the ring ) have more intensive and short-time
action unlike oxygen analogue of barbiturates.
Chemical properties of barbituric acid and barbiturates
Barbiturates contain nitrogen atoms, but the lone pair on the
nitrogen is not available for reaction with protons, so barbiturates
are not basic.
Barbituric acid and derivatives have the acid nature. Thus
barbituric acid in 5–6 times is stronger then acetic acid. 5Monosubstituted of barbituric acid (for example, 5-ethylbarbituric
acid) – enough strong acids, and 5,5-disubstituted of barbituric acid
(for example, 5,5-diethylbarbituric acid) – very weak acid.
Acid properties of these compounds are caused keto-enol
tautomerism of barbituric acid – at the expense of Hydrogene atoms of
methylene groups –СН2–.
O
HN
O
HN
H
O
H
OH
O
кето-форма
HN
H
O
O
HN
енольная форма
HN
H
O
HN
OH
O
H
HN
O
O
кето-форма
H
HN
енольная форма
Besides, at the expense of Hydrogene atoms of imide groups-NH
- it is possible imido-imidolnic tautomerism:
OH
O
HN
N
R1
R2
HN
HN
R1
O
O
O
O
R1
R2
R2
N
O
O
R1
HN
R2
HO
O
HN
N
O
OH
OH
For barbiturates, which
Hydrogene atoms of
methylene groups are
substituted on radicals, is
possible only imidoimidolnic tautomerism
(lactam-lactim
N
O
HN
O
O
HN
HN
HN
HO
O
O
N
tautomerism).
O
O
N
HN
O
O
OH
Thus it is necessary to notice, that unlike barbituric acids derivatives of
barbituric acid in water solutions almost not dissociates; at presence of
ions ОН–– they are dissociated as acids also are capable to give salts
with metals:
O
O
N
H+ O
R1
_
N
NaOH
-H2O
R2
HN
pH ~10
O
Na+ O
ONa
R1
_
NaOH
pH~13
R2
HN
O
N
R1
N
R2
O
ONa
Barbituric acid and its salts do not have medical properties and
consequently are not drugs.
General formula of barbiturates (imide form):
H
O
4
3N
O
R1
5
2
R2
6
N1
R
O
General formula of Na-salts (imidol-form):
O
3N
NaO
(NaS)
4
R1
5
2
N1
R
6
O
R2


Synthesis of barbiturates
Derivatives of barbituric acid are synthezed by condensation of urea
and corresponding esters of malonic acid. Therefore synthesis
consists of two stages.
1. Synthesis corresponding esters of malonic acid:
O
R1
C
OC2H5
C
OC2H5
C
R2
O
2. Condensation of ester and urea in the presence of Na-alcoholate in
the solution of absolute alcohol.
For example,Osynthesis of barbital:
H
C
OC2H5
C
H
C
OC2H5
2C 2H5Br
C2H5ONa
-2HBr
C2H5
C
C2H5
C
O
O
HN
C2H5
HN
C2H5
O
O
O
OC2H5
C
O
HCl
O
OC2H5
H2N
C
H2N
C2H5ONa
-C 2H5OH
O
HN
C2H5
N
C2H5
NaO
O
Chemical structure and properties of
derivatives of barbituric acid
Barbital
3
HN
O
O
4
C2H5
5
2
N1
General Notices (Ph Eur monograph 0170)
H
6
C2H5
O
Barbitalum
C8H12N2O3
184.2
DEFINITION
57-44-3
Barbital contains not less than 99.0 per cent and not more than the equivalent of
101.0 per cent of 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated
with reference to the dried substance.
CHARACTERS
A white, crystalline powder or colourless crystals, slightly soluble in water, soluble in
boiling water and in alcohol. It forms water-soluble compounds with alkali hydroxides
and carbonates and with ammonia.
Phenobarbital
3
General Notices (Ph Eur monograph 0201)
Phenobarbitalum
HN
O
O
4
C2H5
5
2
HN1
6
C6H5
O
C12H12N2O3
DEFINITION
Phenobarbital contains not less than 99.0 per cent and not more
than the equivalent of 101.0 per cent of 5-ethyl-5phenylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated with
reference to the dried substance.
CHARACTERS
A white, crystalline powder or colourless crystals, very slightly
soluble in water, freely soluble in alcohol. It forms water-soluble
compounds with alkali hydroxides and carbonates and with
O
Benzonal
Benzonalum
HN
C2H5
N
C6H5
O
O
C
O
C6H5
1-benzoyl-5-ethyl-5-phenyl-barbituric acid
CHARACTERS
A white, crystalline powder, melting point 134-137 С; very
slightly soluble in water, partly soluble in alcohol, freely soluble in
chloroform, soluble in ether.
O
Barbital sodium
Barbitalum-Natricum
HN
C2H5
N
C2H5
NaO
O
sodium 5,5-diethyl-barbiturate
CHARACTERS
A white, crystalline powder without smell, bitter taste. Water
solution has alkaline reaction;
freely soluble in water, slightly soluble in alcohol, practically
insoluble in ether.
Hexenal
Hexenalum
Hexobarbitalum
O
3
N
NaO
4
CH3
5
2
N
H3C
6
1
O
sodium 1,5-dimethyl-5-(cyclohex-1-enyl)-1Н,3Н,5Нpyrimidine-2,4,6-trion
CHARACTERS
A white foamy consistence, at action CO2 (on the air) decomposes.
Hygroscopic.
very soluble in water and alcohol, practically insoluble in ether
Barbamyl
Barbamylum
3
HN
NaO
O
4
C2H5
5
2
N1
6
H2 H2
C C CH
C5H11
CH3
CH3
O
sodium 5-ethyl-5-isoamyl-1Н,3Н,5Н-pyrimidine-2,4,6-trion
CHARACTERS
A white fine-crystalline powder without smell, hygroscopic;
freely soluble in water, practically insoluble in ether.
O
Thiopental sodium
HN
(Thiopental Sodium and Sodium Carbonate,
C 2H 5
NaS
Ph Eur monograph 0212)
Thiopentalum-Natriсum
C5H11
N
O
H
C
2
H2 H2
C C CH3
3
4
5
CH3
1
(mix with anhydrous Na2CO3)
DEFINITION
Thiopental sodium and sodium carbonate is a mixture of the sodium derivative
of 5-ethyl-5-[(1RS)-1-methylbutyl]-2-thioxo-2,3-dihydropyrimidine4,6(1H,5H)-dione (C11H17N2NaO2S; Mr 264.3) and anhydrous sodium
carbonate, containing the equivalent of not less than 84.0 per cent and not more
than 87.0 per cent of thiopental and not less than 10.2 per cent and not more than
11.2 per cent of Na, both calculated with reference to the dried substance.
CHARACTERS
A yellowish-white powder, hygroscopic, freely soluble in water,
partly soluble in ethanol.
 Identification
 1. Formation of the painted complexes (various colours for
different barbiturates) with salts of heavy metals (Co (NO3)
2 in the presence of CaCl2, CuSO4 in the presence of
КНСО3 and К2СО3, CuSO4 in neutral medium (that not are
formed precipitates Me(OH)n).
 This is group reaction.
O
O
N
C2H5
O
C6H5
NH
O
Cu
N
C2H5
HN
C6H5
O
O
O
N
R1
O
R2
N
O
Cu
2. Fusion with alkalis
Molecules of barbiturates are break up to ammonia NH3 and
sodium carbonate Na2CO3.
Then product of reaction dilute in water and add dilute hydrochloric
acid HCl, gas CO2 is allocated and is present characteristic smell of
conforming disubstituted acid (for example, diethylacetic acid – smell
of rancid butter, 2-phenylpentanoic acid – smell of acacia)
 3. Reactions of condensation with
aldehydes and the concentrated sulphatic
acid
 At heating with formaldehyde НСНО and
concentrated sulphatic acid H2SO4 (the Mark
reactant) the products painted in various
colour are formed: phenobarbital and
benzonal – pink colouring (for phenylacetic
acid); hexenal – dark red colouring with green
fluorescence.

From steam-dimethylaminobenzaldehyde
and concentrated H2SO4:
4. Interaction with solution of chloride acid (for sodium
salts of barbiturates – barbital-sodium, hexenal, barbamyl).
At interaction of test solution with HCl there is a reaction of
neutralisation with formation of precipitate (barbiturates). The precipitate
of barbiturate filter, wash out water, dry and identify on fusion
temperature, and in a filtrate find out Sodium ions. .
O
HN
O
HN
R1
NaO
+ HCl
R2
HN
R1
+ NaCl
O
R2
HN
O
H
C
O
O
C
OCH3
_
O
+ Na+
H
C
O
C
OCH3
ONa
Reactions for definition of functional group
(on position 1 and 5,5)
1. Reaction nitration (for phenyl radical C6H5)
(phenobarbital and benzonal)
At heating of test substance, which contain in a molecule benzoic
cycle, with concentrated sulphatic acid H2SO4 and solution of
sodium nitrate NaNO3 (or a mix conc. HNO3 and H2SO4) occurs
nitration in meta-position with formation of nitroderivative of
yellow colour.
O
HN
O
HN
C2H5
NaNO 3
H2SO4(conc)
-H 2O
O
HN
O
H
C 2H 5
O
HN
O
NO2
 2. Reaction for benzoate-ion after alkaline
hydrolysis of preparation (benzonal)

SPU. To 1 ml of test solution add 0,5 ml solution of
iron(ІІІ) chloride R1; the pale yellow precipitate, soluble in
ether R is formed:
O
O
6
C
+ 2FeCl3 + 10 H2O
C
O
ONa
.
.
Fe Fe(OH)3 7H2O
3
+ 3C6H5COOH + 6NaCl
3. Reaction for double bound (hexenal) – decolouration
solution of potassium permanganate KMnO4 or bromic water
O
O
Br2.
N
N
CH3
NaO
+ Br2
NaO
N
H3C
N
O
CH3
H3C
Br
O
Br
 4. Reactions for revealing of Sulphur (thiopental sodium)

a) At heating of test substance in the presence of
sodium hydroxide NaOH and lead acetate (CH3COO) 2Pb a
black precipitate is formed (lead sulphide PbS).
O
N
C2H5
6NaOH
NaS
HN
CH
H 2 H2
C C CH3
C2H5
H
HC C
COONa
H2 H2
C C CH3
CH3
+ Na2S + NH3 + 2Na2CO3
O CH3
Na2S + Pb(CH3COO)2
PbS + 2CH3COONa
black precipitate
b) At mineralization of preparation with mix for sintering (mix
Na2CO3 and NaNO3) Sulphur passes in anions SO42 - which
reveals by means of solution BaCl2:
SO42– + Ba2+ → BaSO4↓
white precipitate
 5. Reaction with silver nitrate AgNO3 in the
medium of soda Na2CO3

At interaction with ions Ag + are formed onesubstituted (soluble in water) and two- substituted
(insoluble in water) silver salts. In the presence of Na2CO3
at first Na-salt, and then Ag-salt in positions 4 and 6 are
formed
N
R1
O
N
Na 2CO 3
R1
O
N
Na 2CO 3
R2
OH
N
R2
OH
OAg
R1
N
R1
OH
OAg
O
N
O
R2
N
OH
N
AgNO 3
-NaNO 3
R2
N
OAg
ONa
OH
R1
O
N
R2
ONa
OAg
AgNO 3
N
R1
N
R2
O
OAg
 Tests

Specific impurities – products of
semisynthesis
 1. Barbital – ethylbarbituric acid
 2. Phenobarbital – phenylbarbituric
acid
 3. Barbamyl, thyopental sodium,
hexenal – methanol








 Assay of barbiturates
For quantitative definition of barbiturates
various methods are used:
1. Titrimetric:
a) acid- base titration in water,
aqueous-alcoholic and non-aqueous
mediums;
b) argentometry;
c) bromatometry;
d) iodo-chlorometry (for barbiturates
with nonsaturated bonds, for example,
hexenal).
2. Gravimetry.
3. Photocolorimetry.
1. Alkalimetry, non-aqueous titration
This method is applied to quantitative definition of barbital, phenobarbital,
benzonal.
Medium – mixture of DMF and benzene (1:3), preliminarily neutralized by
thymol blue in the DMF (protophilic solvent, which can intensify acid properties of
barbiturates).
Standard solution – solution of sodium methylate CH3ONa or sodium
hydroxide NaOH in the mixture of methanol CH3OH and benzene C6H6 to blue colour.
This method is based on ability of barbiturates to tautomeric
transformations and formation imidolic or the acid-form, which have
acid character:
O
HN
O
R1
O
O
+
R2
N
R
O
H
N
_
R1
O
C
N
+
CH3
CH3
O
C
R2
N
R
H
O
+
N
H
CH3
CH3
а) Titrant – solution of sodium methylate CH3ONa: Em = М. m.
O
N
_
O
N
R1
O
+
CH3ONa
NaO
R
R
O
H
C
+
N
O
O
CH3
H
_
+
H
CH3O
R2
N
O
_
+
R2
N
R1
CH3OH
CH3O
C
CH3
+
N
CH3
CH3
b) Titrant – solution of sodium hydroxide NaOH: Em = М. m.
O
H
C
+
N
H
O
H
CH3
C
+ NaOH
N
CH3
CH3 + H2O + Na+
CH3
O
N
_
O
R1
+
+ Na
O
R
O
R1
N
R2
NaO
R2
N
N
R
O
2. Alkalimetry, non-aqueous substitute titration
(phenobarbital, etc.)
0,100 g substance dissolve in 5 ml pyridine R, add 0,5 ml of
thymolphthaleine solution R, 10 ml 87 g/l silver nitrate AgNO3 in
pyridine R and titrate with 0,1 M sodium hydroxide NaOH in the
ethanol before not disappearing blue colour.
Em = М. m.
O
HN
O
O
N
R1
O
+ NaOH
HO
R2
N
R
O
N
R1
O
R1
+ H2O
NaO
R2
N
R
C2H5OH
R2
N
R
O


3. Alkalimetry in the aqueous-alcoholic medium
This method can be used for quantitative definition of
all barbitrate, which have acid character.
 Titrant - solution sodium hydroxide NaOH.
 Indicator – thymolphthaleine.

Shot of preparation dissolve in neutralised on thymolphthaleine
alcohol С2Н5ОН (for solubility improvement of barbiturates and
preventions of hydrolysis formed sodium salt).
 Em = М. m.
O
HN
O
O
N
R1
O
+ NaOH
HO
R2
N
R
O
N
R1
O
R1
+ H2O
NaO
R2
N
R
C2H5OH
R2
N
R
O
4. Acidimetry in the water medium
This method can be used for quantitative definition of sodium salts of
barbiturates, which have basic character (barbital-sodium, barbamyl, hexenal).
Titrant - hydrochloric acid HCl.
Indicator – methyl orange or methyl red.
Na-salts of barbiturates are hydrolyzed in water solutions
with formation alkaline medium (рН 77) and therefore their can titrate
with acids, for example, with hydrochloric acid HCl in the presence of
methyl orange or methyl red as indicator (to pink colour).
Em = М. м.
O
O
N
HN
R1
+ HCl
NaO
+ NaCl
O
R2
N
R
R1
R2
N
O
R
O
The free alkaly (NaOH), which is formed at hydrolysis of sodium salts of barbiturates,
titrate with acid too:
O
O
N
N
R1
+ HOH
NaO
R
+ NaOH
HO
R2
N
O
R1
R2
N
R
O
Therefore the maintenance of Na-salt of barbitutates (Х, %)
calculate by means of formula:
,
Х 
VHCl  Kp  T 100 100
 % NaOH  K
mshot  (100  %.moisture)
Where:
% NaOH – the maintenance of free alkali in substance, in %;
K – coefficient (factor), which calculate as a parity between molar
weights of salt and sodium hydroxide NaOH.
At quantitative definition of thiopental sodium by means of acidimetry define
the total maintenance of Sodium (titrate with sulphatic acid H2SO4 in the presence of
methyl red as indicator).
5. Argentometry
1. Method of Fialkov and employees (benzonal)
Shot of test substance (the acid or salt form) dissolve in 5 %
anhydrous solution of sodium carbonate Na2CO3 and titrate with
nitrate AgNO3 without the indicator to occurrences of not
disappearing dregs (the two-substituted Ag-salt).
Proceeding processes it is possible explanes so.
At first barbiturate it is dissolved in sodium carbonate Na2CO3 with formation
one- substituted Na-salt, which reacts with silver nitrate AgNO3 with formation
soluble one- substituted Ag-salt. Then soluble Na-Ag-salt is formed.
In equivalence point excess of titrant AgNO3 destroys Na-Ag-salt and the
insoluble two- substituted Ag-salt is formed, that specifies in the titration end.
N
R1
O
N
Na2CO3
R1
O
N
R2
OH
OAg
N
R1
Na2CO3
O
R2
OH
R1
OH
OAg
N
N
O
R2
N
OH
N
AgNO3
-NaNO3
R2
N
OAg
ONa
OH
R1
O
N
R2
ONa
OAg
AgNO3
N
R1
N
R2
O
OAg
6. Bromatometry, back titration, with iodometric
finishing
The method is used for quantitative definition of barbiturates
with nonsaturated bound, for example, hexenal.
This method is based on bromination substance in a place of
double bound.
KBrOO3 + 5KBr + 6HCl = 3Br2 + 6KCl
+ 3H2O
O
N
N
CH3
NaO
+ Br2
NaO
N
H 3C
N
O
CH3
H3C
Br
O
Br
Br2 + 2KI = I2 + 2KBr
I2 + 2Na2S2O3 = 2NaI + Na2S4O6
Carry out the control test.
Еm(hexenal) = М. m./2
7. Iodo-chlorometry, back titration
This method is used for quantitative definition of barbiturate with
nonsaturated bound (for example, hexenal).
(Iodochloride ICl reacts with hexenal in a place of double bound in cyclohexenyl
group):
O
N
O
N
CH3
NaO
+ ICl
NaO
N
H 3C
CH3
I
N
O
H3C
O
Cl
ICl + KI = I2 + KCl
I2 + Na2S2O3 = 2NaI + Na2S4O6
Carry out the control test.
Еm(hexenal) = М. m./2
8. Gravimetry
Gravimetric method usually is used for quantitative definitions of
Na-salts of barbiturates (for example, thiopental sodium), and also at
the analysis of medicinal mixtures.
To water solution of preparation add diluted chloride acid HCl.
O
HN
O
HN
R1
+ HCl
NaO
R2
HN
O
R1
+ NaCl
O
R2
HN
O
The received acid form (thiopental-acid) extract by means of
chloroform (5 times in the small portions). All chloroformic extraction
connect, chloroform distillates, and the rest dry at 70C to constant mass
Storage
Group of strong preparations.
In the dense corked container.
Hygroscopic preparations – in the dry, cool place, protected
from light.
Phenobarbital and benzonal – in the banks of dark glass, in the
place protected from light.
Hexenal and thiopental sodium – in glass bottles on 0,5–1,0 g,
which are hermetically closed by rubber stoppers, are fitted by
aluminium caps; in the dry, cool place protected from light. As the
stabilizer to hexenal add 0,05–0,25 % sodium hydroxide NaOH, to
thiopental sodium –
5–6 % of sodium carbonate Na2CO3.
Water solutions of barbiturates Na-salts easily hydrolyze,
therefore them prepare on a physiological solution in aseptic
conditions directly ahead of the use (ex tempore).
Action and use
Sedative and hypnagogue:
a) Long action – barbital, phenobarbital, barbital sodium;
b) Average duration – barbamyl;
c) Shot-term action – hexenal, thiopental sodium.
Protiepileptic (anticonvulsant) means: phenobarbital and
benzonal (hypnagogue action has not).
For intravenous narcosis: hexenal and thiopental sodium.
At long application and high doses of barbiturates can be a
poisoning, therefore their application should be supervised by the
doctor.
In case of barbiturates poisoning applied stimulators of the
central nervous system – strychnine, corasole, etc.
Subsequently it has been established, that the antagonist of
barbiturates is bemegride.
Primidone
Hexamidinum
Primidonum
O
HN
3
C2H5
4
2
5
1
C6H6
6
HN
O
C12H14N2O2
218.3
DEFINITION
5-Ethyl-5-phenyldihydropyrimidine-4,6(1H,5H)-dione.
The chemical structure of primidine is analogue of barbiturates, but unlike
phenobarbital, primidone do not have hydroxy-group =С= О on the 2-position in
the ring.
Content. 98.0 per cent to 102.0 per cent (dried substance).
Synthesys
Primidone is synthezed from phenylethylmalonic ester:
CO OC2H5
C2H5
C
C2H5
CO OC2H5
KOH
-HCl
-C2H5OK
CONH2
C2H5
CONH2
PCl5
C2H5
C2H5
O
HC
C2H5
COOH
COCl
C
C
NH2
C
C2H5
COOH
C2H5
COCl
2NH4OH
-2HCl
O
HN3
C2 H 5
4
2
5
1
HN
C6H6
6
O
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Very slightly soluble in water, slightly soluble in ethanol (96 per
IDENTIFICATION
A. (BrPh). Measure of ratio of the absorbance.
B. (BrPh). Infrared absorption spectrophotometry.
D. (BrPh, SP X). Melting with anhydrous sodium carbonate (BrPh) or
alkalis (SP X). Mix 0.2 g and 0.2 g of anhydrous sodium carbonate R. Heat until the mixture
melts. Ammonia is evolved which is detectable by its alkaline reaction
O
HN3
C2H5
4
2
O
5
1
HN
6
0
+NaOH
C2H5
tC
C6H6
2NH3
+ Na2CO3 + HC
+
H
CHCOONa
C2H5
(molecules ofO primidine are destroys).
Then alloy dilute with water and acidified by H2SO4, -phenylpentanoic acid with
characteristic smell is formed:
C2H5
C2H5
CHCOONa
CHCOOH +NaHSO
+H2SO4
C2H5
C2H5
The gas CO2 is allocated too:
Na2CO3 + H2SO4 = Na2SO4 + H2O + CO2
The formaldehyde can be identified by reaction C.
C. (BrPh, SP Х). Reaction with sodium salt of chromotropic
acid and concentrated sulphuric acid at heating (for
formaldehyde)
Dissolve 0.1 g in 5 ml of a 5 g/l solution of chromotropic acid,
sodium salt R in a mixture of 4 volumes of water R and 9 volumes of
sulphuric acid R. A pinkish-blue colour develops on heating.
SO3H HO3S
SO3Na
HO
+
2
HC
O
H2SO4
H
HO
SO3Na
HO
HO
C
H2
HO
OH
SO3H HO3S
SO3H HO3S
C
H
HO
O
OH
SO3H HO3S
OH
[O]
H2O
TESTS
IMPURITIES
Specified impurities A, B, C, D, E, F.
A. R1 = NH2, R2 = CO-NH2: 2-ethyl-2-phenylpropanediamide (ethylphenylmalonamide),
C. R1 = NH2, R2 = H: (2RS)-2-phenylbutanamide,
D. R1 = NH2, R2 = CN: (2RS)-2-cyano-2-phenylbutanamide,
E. R1 = OH, R2 = H: (2RS)-2-phenylbutanoic acid,
B. phenobarbital,
F. 5-ethyl-5-phenyl-2-[(1RS)-1-phenylpropyl]dihydropyrimidine-4,6(1H,5H)dione.
Ph Eur
ASSAY
(BpPh). Dissolve 60.0 mg with heating in 70 ml of ethanol (96 per cent) R,
cool and dilute to 100.0 ml with the same solvent. Prepare a reference solution in
the same manner using 60.0 mg of primidone CRS. Measure the absorbance
(2.2.25) of the 2 solutions at the absorption maximum at 257 nm.
Calculate the content of C12H14N2O2 from the absorbances measured and
the concentrations of the solutions.
Other method – Keldal method (defenition of total Nitrogen after
mineralization. The test substance mineralize by boiling with K2SO4, CuSO4
and concentrated H2SO4. Nitrogen is passed to ammonium hydrosulphate
NH4HSO4, which react with 30 % solution of NaOH and ammonia gas NH3 is
formed :
NH4HSO4 + 2NaOH  NH3 + Na2SO4 + 2H2O
Obtaned ammonia distil off to flask with HCl:
NH3 + HCl  NH4Cl
Ammonia chloride titrate with 0,1 М solution of NaOH:
NH4Cl + NaOH  NH4OH + NaCl
Em = М. m./2
Storage
List of strong preparations.
In the dense corked container.
Action and use
Anticonvulsant.
Preparations
Primidone Oral Suspension
Primidone Tablets
Ph Eur
Thanks for attention!