Download 06 Salts of carboxylic acids,saturated amino acids of aliphatic series

LECTURE № 6
Salts of carboxylic acids and saturated
aminoacids aliphatic series as drugs
Associate prof. Mosula L. M.
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The plan
1. Salts of carboxylic acids as drugs:
potassium acetate, calcium lactate, sodium
hydroxybutyrate, sodium citrate, calcium
gluconate.
2. The saturated aminoacids of aliphattic
series: glutamic acid, cysteine hydrochloride,
acetylcysteine, methionine, aminalonum.
Salts of carboxylic acids as drugs
 Potassium acetate
 CH3COOK
Description. Potassium acetate is a white
crystalline powder; it is a slightly
hydroscopic with characteristic odor of
acetic acid and salty test.
Solubility. It is soluble in water and
alcohol.
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Identification.
A. Yields the reaction characteristic of
potassium salts:
K+ + HOOC-(CHOH)2-COOH
wine acid
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3 FeCl3
H+
B. Yields the reactions characteristic of
carboxylic acids: reacts with ethyl alcohol to
form ether:
2CH3COOK
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HOOC-(CHOH)2-COOK
+
+
H2SO4
+
2 C2H5OH
2 CH3COOC2H5
+
K2SO4
+ 2 H2O
C. Acetate-ion reacts with iron (III) chloride
solution to form a red complex:
+
9 CH3COOK + 2 H2O
[(CH3COO)6Fe3(OH)2]+CH3COO- + 2CH3COOH + 9 KCl
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Assay. Carry out a water-free titration. Dissolve the exact
amount of potassium acetate in ice acetic acid and titrate with 0.2N
hydrochloric acid use a crystalline-violet as an indicator.
+
-
(CH3COOKH) * CH3COO
CH3COOK CH3COOH
+
+
CH3COOH HClO4
(CH3COOH2) * ClO4
+
+
KClO4 3CH3COOH
(CH3COOKH) * CH3COO + (CH3COOH2) * ClO4
+
CH3COOK
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+
HClO4
KClO4 + CH3COOH
Potassium acetate is indicated for the treatment and prevention of
potassium deficiency. It also finds usefulness as a diuretic substance.
Sodium γ -oxibutyrate
 HOCH2CH2CH2COONa
It occurs as white or slightly yellow crystalline
powder with characteristic odor.
Identification.
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A. Yields a reaction characteristic of sodium salts.
B. Sodium oxibutyrate reacts with hydrochloric acid to form γbutyrolactone. Extract synthesized γ-butyrolactone with ether and
identify by refractive index (1.4280-1.4360).
HOCH2CH2CH2COONa
+
HCl
+
O

NaCl
+
H2O
O
Assay. Cary out a water-free titration as for assay
of potassium acetate.
Sodium citrate
(Sodium hydrocitrate for injection)
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It is a white crystalline powder or colorless crystals, odorless with
salty test.
Identification.
A. Yields the reaction characteristic of sodium salts:
Na+ + Zn[(UO2)3(CH3COO)8] + CH3COOH + 9 H2O
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B. Sodium citrate reacts with calcium chloride to form calcium salt
that is insoluble in boiling water:
-
CH2 COONa
2 HO C
COONa
CH2 COONa
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+
NaZn[(UO2)3(CH3COO)9] * 9 H2O + H
CH2 COO
+
3 CaCl2
HO C
COO-
3-
Ca2
3
-
CH2 COO
+
2
Calcium citrate that is obtained is soluble in hydrochloric acid.
+
6 NaCl
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Assay. Carry out a neutralization titration
after ion exchange chromatography.
CH2 COONa
HO C COONa
CH2 COONa
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CH2 COOH
+
3 [Kat]-H+
3 [Kat]-Na+ + HO C COOH
CH2 COOH
Titrate obtained citrate acid with 0.05M
potassium or sodium hydroxide.
4% solution of calcium citrate is used for
protection of blood coagulation.
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Calcium gluconate
Obtaining
The gluconic acid used in the preparation of calcium gluconate can be
prepared by electrolytic oxidation of glucose as follows:
H
O
COO-
C
H
C
OH
HO
C
H
H
C
OH
H
C
OH
NaBr
CaCO3
Carbon electrodes
CH2OH
D
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-
Glucose
H
C
OH
HO
C
H
H
C
OH
H
C
OH
CH2OH
Ca2 +
2
Calcium gluconate
Gluconic acid is produced on a commercial scale by the action of a
number of fungi bacteria, and molds upon 25% to 40% solutions of
glucose. The fermentation is best carried out in the presence of
calcium carbonate and oxygen to give almost quantitative yields of
gluconic acid. The fermentation is complete in 8 to 18 days.
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Prorerties.Calcium gluconate occurs as a white crystalline or granular
powder, without odor or test. Its solutions are neutral to litmus paper.
Solubility . One gram of calcium gluconate dissolves slowly in about
30 ml of water and in 5 ml of boiling water. It is insoluble in alcohol
and in many organic solvents.
The mineral acids that are stronger than gluconic acid will decompose
calcium gluconate. It is incompatible with soluble sulphates,
carbonates, bicarbonates, citrates, tartrates, salicylates and benzoates.
Identification.
A. Calcium gluconate solution yields the reaction
characteristic for calcium salts.
B. Solution reacts with iron chloride in neutral medium to
form green complex.
9 (CH2OH-(CHOH)4-COO-)2Ca2++6 FeCl3 + H2O
+
4 CH2OH-(CHOH)4-COOH + 9 CaCl2
[(CH2OH-(CHOH)4-COO)6Fe3(OH)2]+CH2OH-(CHOH)4-COO-+
Assay.
Dissolve 0.4 g in 20 ml of water. Cool and add 10 ml of ammonium
buffer solution, and 0.1 g of chromium-blue as an indicator, and titrate with
0.05M EDTA antill blue-violet color is obtained.
H2O
OH
OH
(CH2OH-(CHOH) 4-COO- )2Ca
N
OH
N
+
SO3Na
NaO3S
blue
CH2OH-(CHOH)4-COONH4
CH2OH-(CHOH)4-COOH + NH4OH
CH2COONa
N
CH2COOH
CH2
CH2
CH2COOH
N
CH2COONa
+
O
+
CH2OH-(CHOH)4-COONH4
+
N
OH
O
+
N
NaO3S
SO3Na
H2O
CH2COONa
N
CH2COOH
CH2
CH2
CH2COOH
N
CH2COONa
pink
CH2COONa
N
CH2COO
CH2
Ca
CH2
CH2COO
N
CH2COONa
colorless
OH
OH
+
N
OH
N
NaO3S
blue -violet
N
OH
+
H2O
H2O
Ca
O
NaO3S
SO3Na
pink
+ 2 CH2OH-(CHOH)4-COOH
CH2COONa
N
CH2COO
CH2
Ca
CH2
CH2COO
N
CH2COONa
colorless
(CH2OH-(CHOH) 4-COO- )2Ca
CH2OH-(CHOH)4-COOH + NH4OH
H2O
Ca
O
N
H2O
SO3Na
+2
CH2OH-(CHOH)4-COOH
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Each ml of 0.05M EDTA is equivalence to 0.02242 g
of calcium gluconate.
Calcium gluconate fills the need for a soluble
nontoxic well-tolerated form of calcium that can be
employed orally, intramuscularly, or intravenously.
Calcium therapy is indicated in conditions such as
parathyroid deficiency (tetany), general calcium
deficiency, and when calcium is the limiting factor
in increased clotting time of the blood. It can be
used both orally and intravenously.
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Amino Acids as drugs
Proteins are essential components of all living matter. As
cellular components, proteins perform numerous
functions. The chemical reactions fundamental to the life
of the cell are catalyzed by proteins called enzymes. Other
proteins are structural constituents of protoplasm and cell
membranes. Some hormones are characterized as
proteins or proteinlike compounds because of their
polypeptide structural features.
Proteins are biosynthesized from α-amino acids, and when
proteins are hydrolyzed, amino acids are obtained. Some
very complex (conjugated) proteins yield other hydrolysis
products in addition to amino acids. α-Amino acids are
commonly characterized with the generalized structure:
H
R
C
COOH
NH2
The relative high melting point, solubility,
behavior, and acid-base properties
characteristic of amino acids can be
accounted for on the basis of the dipolar
ion structure (commonly called zwitterion).
Amino acids in the dry solid state are
dipolar ions (inner salts). Amino acids when
dissolved in water can exist as dipolar ions.
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(Ph Eur monograph 0750)
Glutamic acid
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C5H9NO4
147.1
56-86-0
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Action and use
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Amino acid.
Ph Eur
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DEFINITION
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Glutamic acid contains not less than 98.5 per cent and not more than the equivalent of 100.5 per
cent of (2S)-2-aminopentanedioic acid, calculated with reference to the dried substance.
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CHARACTERS
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A white, crystalline powder or colourless crystals, freely soluble in boiling water, slightly soluble in
cold water, practically insoluble in acetic acid, in acetone and in alcohol.
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IDENTIFICATION
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First identification A, B.
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Second identification A, C, D.
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A. It complies with the test for specific optical rotation (see Tests).
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B. Examine by infrared absorption spectrophotometry (2.2.24),
comparing with the spectrum obtained with glutamic acid CRS.
Examine the substances prepared as discs. If the spectra obtained
show differences, dissolve the substance to be examined and the
reference substance separately in the minimum quantity of water R,
evaporate to dryness at 60 °C and record new spectra using the
residues.
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C. Examine the chromatograms obtained in the test for
ninhydrin-positive substances. The principal spot in the
chromatogram obtained with test solution (b) is similar in
position, colour and size to the principal spot in the
chromatogram obtained with reference solution (a).
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D. To 2.0 ml of solution S (see Tests) add 0.1 ml of
phenolphthalein solution R and 3.0 ml to 3.5 ml of 1 M
sodium hydroxide to change the colour of the indicator to
red. Add a mixture of 3 ml of formaldehyde solution R, 3
ml of carbon dioxide-free water R and 0.1 ml of
phenolphthalein solution R, to which sufficient 1 M sodium
hydroxide has been added to produce a pink colour. The
solution is decolourised. Add 1 M sodium hydroxide until a
red colour is produced. The total volume of 1 M sodium
hydroxide used is 4.0 ml to 4.7 ml.
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TESTS
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Solution S
Dissolve 5.00 g in 1 M hydrochloric acid with gentle heating, and
dilute to 50.0 ml with the same acid.
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Appearance of solution
Solution S is clear (2.2.1) and colourless (Method II, 2.2.2).
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Specific optical rotation (2.2.7)
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+ 30.5 to + 32.5, determined on solution S and calculated with
reference to the dried substance.
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Ninhydrin-positive substances
Examine by thin-layer chromatography (2.2.27), using a TLC silica gel
plate R.
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Chlorides (2.4.4)
Dissolve 0.25 g in 3 ml of dilute nitric acid R and dilute to 15 ml with water R. The solution, to
which 1 ml of water R is added instead of dilute nitric acid R, complies with the limit test for
chlorides (200 ppm).
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Sulphates (2.4.13)
Dilute 5 ml of solution S to 15 ml with distilled water R. The solution complies with the limit test
for sulphates (300 ppm).
Ammonium (2.4.1)
50 mg complies with limit test B for ammonium (200 ppm). Prepare the standard using 0.1 ml of
ammonium standard solution (100 ppm NH4) R.
Iron (2.4.9)
In a separating funnel, dissolve 1.0 g in 10 ml of dilute hydrochloric acid R. Shake with 3
quantities, each of 10 ml, of methyl isobutyl ketone R1, shaking for 3 min each time. To the
combined organic layers add 10 ml of water R and shake for 3 min. The aqueous layer complies
with the limit test for iron (10 ppm).
Heavy metals (2.4.8)
2.0 g complies with limit test D for heavy metals (10 ppm). Prepare the standard using 2 ml of
lead standard solution (10 ppm Pb) R.
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 °C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
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ASSAY
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Dissolve 0.130 g in 50 ml of carbon dioxide-free water R
with gentle heating. Cool. Using 0.1 ml of bromothymol
blue solution R1 as indicator, titrate with 0.1 M sodium
hydroxide until the colour changes from yellow to blue.
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1 ml of 0.1 M sodium hydroxide is equivalent to 14.71 mg
of C5H9NO4.
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STORAGE
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Protected from light.
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Ph Eur
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Glutamic acid hydrochloride (Acidulin)
It is essentially a pure compound that occurs as a white crystalline powder
soluble 1:3 in water and insoluble in alcohol. It has been used in place of
glycine in the treatment of muscular dystrophies, with rather unpromising
results. It also is combined with anticonvulsants for the petit small attacks of
epilepsy, a use that appears to depend on change in pH of the urine.
Identification. A. As all amino acids glutamic acid reacts with ningidrin:
O
O
COOH
O * H2O
+
CH
NH2
CH OH
CHO
+
NH3
R
R
O
O
O
O
O
N
+ HO
H H H
+
O
O
N
O
O
blue-violet
HO
N
H2O
O
ONH4
O
NH3
+
O
O
+
CO2
B. Amino acids react with copper salts to form blue-violet complexes:
2 HOOC CH2 CH2 CH COOH
+
CuSO4
+
2NaOH
NH2
O
CH
CH2
HOOC CH2
C
H2N
O
CH CH2 CH2 COOH
Cu
C
O
+
O
NH2
Na2SO4
C. Glutamic acid reacts with resorcin in presence of H2SO4k.
COOH
t*
H2O
HOOC CH2 CH2 CH COOH
+
NH
NH2
O
2
HO
COOH
NH
H2SO4
2H2O
HO
OH
COONH4
NH2
H2O
HO
O
red-violet
COONH4
NH4OH
O
O
OH
HO
NH2
OH
O
red
OH
+ 2 H2O
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Assay
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Alkalimetry, direct titration.
(neutralization titration) (using NaOH as
titrant; bromthymole blue as indicator).
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Еm(C5H9NO4) = М.m.
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Acetylcysteine (Mucomyst)
Is the N-acetyl derivative of L-cysteine. It is used
primarily to reduce the viscosity of the abnormally viscid
pulmonary secretions in patients with cystic fibrosis of the
pancreas or various tracheobronchial and
bronchopulmonary diseases.
Acetylcysteine is more active than cysteine.
Acetylcysteine is most effective in 10% to 20% solutions.
It is used by direct instillation or by aerosol nebulization.
It is available as a 20% solution of the sodium salt in 10and 30ml containers. An opened vial of acetylcysteine
must be covered, stored in a refrigerator, and used within
48 houts.
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Methioninum
Methionine (Amurex)
МETHIONINE
M. m. = 149,2 g/mol
С5H11NO2S
The chemical name:-amino - -метилтиомасляная acid; 2-2-4
(метилтио) бутановая acid.
DL-2-amino-4-(methylthio)-butyric acid
(CH3SCH2CH2CH(NH2)COOH) occurs as white crystalline platelets or
powder with a slight, characteristic odor; it is soluble in water
(1:30), and a 1% solution has a pH of 5.6 to 6.1. It is insoluble in
alcohol.
In therapy, methionine has been employed in the treatment of liver
injuries caused by poisons such as carbon tetrachloride, chloroform,
arsenic and trinitrotoluene. Methionin also has a function in the
syntethis of choline, cystine, lecytin and probably creatine.
Deficiency not only limits growth in rats, but also inhibits progression
of tumors.
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Aminalonum
Acidum gamma-aminobutyricum
Gamma bosoms
H2N-CH2–CH2–CH2–COOH
Gammalonum
M. m. = 103,12 g/mol
C4H9NO2
The chemical name: 4-aminobutyric acid, -aminobytyric acid.
Obtaining
Alkaline hydrolysis pirolidone-2 with the subsequent
neutralisation of salt of -aminobytyric acid by means of acetic acid
СН3СООН.
Properties
Description. A white crystal powder with specific smell of amino
acids. Hygroscopic.
Solubility. Freely soluble in water, very slightly soluble in alcohol,
it is practically insoluble in chloroform, acetone. рН a water
solution 6,5 – 7,5.
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Identification
1. Ninhydrin reaction; there is a blue-violet
colouring.
2. Reaction with alkaline solution CuSO4; it
is formed chelate compound of intensively dark
blue colour.
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3. Fusion with KSCN; allocation of
hydrogen sulphide H2S which revealing by means
of lead-acetic paper:
S2 - + Pb2 +  PbS
black
4. Heating with alloxan (mesoxalyl urea)
in the medium of dimethylformamide; there
is a bright-crimson colouring.
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Assay
1. Acidimetry, non-aqueous titration.
Тitrant – perchlorate acid HClO4, medium –
anhydrous acetic acid СН3СООН, the
indicator – crystal violet (from violet before
blue-green colouring).
HOOC–(CH2)3–NH2 + HClO4

HOOC–(CH2)3–NH3+ClO4–
In parallel spend control experience.
Еm (C4H9NO2) = M. m.
2. Alkalimetry, direct titration of an investigated
solution of a substance
by a standard solution NaOH in the presence of
the solution indicator bromthymol dark blue
before transition of yellow colouring in the bluegreen.
H2N - (CH2)3COOH + NaOH = H2N - (CH2)3COONa
+ H2O
Еm (C4H9NO2) = M. m.
Storage
In densely corked containers, in the dry cool place
protected from light.
Application. Neuromediator
The release form: tablets on 0,25 g.
Aminocaproic acid (Amicar)
6-Aminohexanoic acid occurs as fine, white
crystalline powder that is freealy soluble in water,
slightly soluble in alcohol, and practically insoluble
in chloroform.
Aminocaproic acid has been used in the control of
hemorrhage in certain surgical procedures. It is of
no value in controlling hemorrhage caused by
thrombocytopenia or other coagulation defects or
vascular disruption. Aminocaproic acid is well
absorbed orally. Plasma peaks occur in about two
hours. It is rapidly, largely unchanged.
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CYSTEINE
Cysteinum
M. m. = 121,2 g/mol
C3H7NO2S
Cysteine contains not less than 98,0 % and no more
than 101,0 % (R)-2-amino-3-mercaptopropanoic acid,
in recalculation on a solid.
The chemical name: (R)-2-amino-3-mercaptopropanoic
acid.
Properties
Description. A crystal powder of white colour or
colourless crystals with a characteristic smell.
Solubility. Freely soluble in water R and 96 % alcohol R,
it is practically insoluble in ether R.
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Identification
The first identification: A, B.
The second identification: A, B, C, D.
A. Measuring of specific optical rotation by means
method of polarimetry. From + 8,0to to + 9,5 in
recalculation on a solid. Definition make, using a
substance solution in a solution 220 g/l chloride acid R.
B. IR-spectroscopy.
C. Reaction with ninhydrin.
Technique. About 10 mg of a substance dissolve in 2 ml of
water R, add 0,1 M solution HCl to рН nearby 4,0, 0,5 ml
of a solution 2,5 g/l ninhydrin R, heat up on a water
heater during 10 mines; there is a yellow or yellowybrown colouring. The received solution cool to a room
temperature, add drops from 1 ml to 2 ml of 0,1 M
solution NAOH; there is a red-violet colouring.
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D. Identification mercapto-group with the help
sodium nitroprusside after heating with alkali
solution.
Technique. About 5 mg of a substance dissolve in 5 ml
water R, add 2 ml solution NaOH diluted R and 0,2 ml 25
g/l solution sodium nitroprusside Na2 [Fe (CN) 5NO], Р;
there is a yellow colouring which during 2 mines
passes in the red.
2HS–CH2–CH2–CH(NH2)–COOH + 4NaOH  Na2S +
2NH3 +
2HO–CH2–CH2–CH(OH)–COONa
Na2S + Na2[Fe(CN)5NO]  Na4[Fe(CN)5NOS]
E. Reaction with H2O2 and solution FeCl3 and the
next revealing SO42- by means of reagent barium of
chloride R1 in the medium of chloride acid diluted R.
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SO42 - + Ba2 +  BaSO4white precipitate or
opalescense
Reaction with salts of Copper (ІІ); the black
precipitate is formed.
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Tests
1. рН solution. From 4,5 to 6,0.
2. Specific optical rotation. From +8,0 to
+9,5, in recalculation on a solid. Measure
optical rotation of solution substance in 220g/l
solution chloride acid.
3. The general impurity of chlorides,
sulphates, ammonium of salts, Iron, heavy
metals – within corresponding standards.
4. Weight loss at drying. At drying 1,000 g
substance at temperature from 100 C to 105
C weight loss should be no more than 0,5 %.
9. Sulphatic ashes. No more than 0,1 %.
Definition spend with 1,0 g substance.
10. Pyrogens or bacterial endotoxins.
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ASSAY
1. SPU. Iodometry, back titration. Shot of substance dissolve in
НСl diluted R, cool in an ice cooler, add crystal КІ and excess of a
standard solution І2. After keeping of a solution during 15 mines in
the place protected from light not reacted І2 titrate by standard
solution Na2S2O3, using in the end of titration the indicator starch
(before disappearance of dark blue colouring).
NH 2
2 HS
H2
C
H
C
COOH
+ I2
S
H2
C
CH
S
H2
C
H
C
COOH
+ 2HI
COOH
NH 2
NH 2
cysteine
T
homocystin
I2 + 2Na2S2O3 = 2NaI + Na2S4O6
not reacted
In parallel spend control experience.
Еm (C3H7NO2S) = M. m.
Em=M.M
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2. Iodometry, direct titration. Shot of substance dissolve in
solution HCl, add KI and titrate by standard solution I2 in the presence
of starch before occurrence of dark blue colouring.
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2 HS
NH2
H2
C
H
C
COOH
+ I2
S
S
H2
C CH
H2
C
H
C
COOH
+ 2HI
Em=M.M
COOH
NH2
NH2
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Storage
In densely corked containers, in banks from dark glass, in the place
protected from light.
Application. For treatment of initial forms of a cataract.
Apply 5 % water solution at initial forms of a cataract. Is a part of eye
drops.
Thanks for attention!