Lecture №24
Alkaloids derivatives of tropane,
ecgonine and isoquinoline. Social
significance of the research which help
to find the morphine-type analgesics
As. Kozachok S.S.
Тropane – bicyclic condensed system,
which contains the piperidine and
pirrolidine cycles.
7
N
H
ÏPyrrolidine
³ðî ë ³äè í
N
H
Ï Piperidine
³ï åðè äè í
6
1
2
N
CH3 3
5
Òðî
ï àí
Tropane
4
Тropane is a base of the alkaloids row and
their structural analogs. According to the
chemical structure these compounds are
divided into two groups: derivatives of
tropane alcohol (1) and derivatives of
tropane-2- carboxylic–ecgonine (2):
COOH
N
1
CH3
OH
N
2
CH3
OH
Tropane’s alkaloids are in the plants of
Solanaceae family (belladonna, datura,
hioscyamus niger).
The maine representatives of topane’s alkaloids are racemic
atropine, its left rotation isomer – hyoscyamine and the analogue of
hyoscyamine - scopolamine.
Atropine was first isolated from belladonna in 1833. In the plants
it is contained in very small quantities with hyoscyamine and
scopolamine together.
Obtaining the atropine and hyoscyamine from plant materials in
the form of bases (after treatment with ammonia), organic solvents
(dichloromethane, benzene). Atropine is formed from hyoscyamine by
racemization at 114-116 ° C, at a higher temperature is formed
apoatropin having no pharmacological activity of atropine. After
hyoscyamine separation from solution, scopolamine is released.
Synthetically extracted from amber aldehyde,
methylamine, acetone and d, l-tropic acid.
Atropine sulphate (Atropini sulfas) (SPhU)
CH2OH
N
CH3
O
C
CH
C6H5
* H2SO4 * H2O
O
2
bis(1R,ЗR,5S)-3-[(RS)-(3-hydroxy-2-phenylpropanoate)
oxy]-8-methyl-8-azabicyclo[3.2.1] octane sulfate
monohydrate
Bis[(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2RS)-3hydroxy-2-phenylpropano] sulphate monohydrate.
Tropine ester d,l-tropic acid sulfate monohydrate
Scopolamine hydrobromide
(Scopolamini hydrobromidum)
CH2OH
O
N
CH3
O
C
CH
C6H5 * HBr * 3 H2O
O
Scopolamine ester (-)-tropic acid hydrobromide, trihydrate
IUPAC
(–)-(S)-3-hydroxy-2-phenylpropionic
acid(1R,2R,4S,7S,9S)-9-methyl-3-oxa-9azatricyclo[3.3.1.02,4]non-7-yl ester
Physical properties
Atropine sulphate
White or almost white,
crystalline powder or
colourless crystals. Very
soluble in water, freely
soluble in ethanol (96 per
cent).
Melting at 190°С and
decomposing.
Scopolamine
hydrobromide
White or almost white,
crystalline powder or
colourless crystals.
Freely soluble in water
soluble in ethanol, very
slightly soluble in
chloroform.
Identification
Atropine sulphate
1. According to the physicalchemical constants: infrared
spectroscopy and optical rotation
(-0,5о-+0,05о).
2. Melting point of atropine picrate.
3. Vitali's-Morena reaction ( on
tropic acid).
4. It gives the reactions of sulphates.
5. It gives the reaction of alkaloids
Non pharmacopoeia reaction:
а) Melting point of atropine base
(115-117 °С) after settled down
by ammonia solutiobn;
b) formation of benzaldehyde (small
of bitter almond) at the heating
atropine with sulfuric
concentrated acid and crystalline
potassium dichromate:
1.
2.
3.
4.
Scopolamine hydrobromide
It gives the reactions of
bromides (three reaction
according to SPhU).
Vitali's-Morena reaction ( on
tropic acid).
Melting point (192-196 °С) and
optical rotation : -22° till -26°
(5 %-water solution).
It gives the reaction of alkaloids
Formation of benzaldehyde
Vitali's-Morena reaction
To about 1 mg add 0.2 ml of fuming nitric acid R and evaporate to
dryness in a waterbath, formation a polynitrocompound of a
yellow colour. Dissolve the residue in 2 ml of acetone R and add
0.1 ml of a 30 g/l solution of potassium hydroxide R in methanol
R. A violet colour develops.
Purity test
Atropine sulphate
1.
Apoatropine(<0,5%)визначають
spectrophotometrically
Scopolamine
hydrobromide
1.
2.
Outsiders (foring) alkaloids
Thin layer chromatography (TLC)
Apoatropine, aposcopolamine
and other reducing substances
according to the reaction with
0,1 М of potassium
permanganate – the pink
colour doesn’t develop during
5 minutes.
Outsiders (foring) alkaloids
are determined by the addition
of ammonia solution, after that
must be any turbidity
observation.
Quantitative determination
Atropine sulphate
Acid-base titration in
nonaqueous medium, a
direct titration with
potentiometric fixing of the
equivalent point. (Е=М.м).
2) Alkalimetry in ethanolchloroform medium
(Е=М.м/2).
3) Photocolorimetry by the
reaction with picric acid.
1)
Scopolamine
hydrobromide
1) Acidimetry in
nonaqueous medium, a
direct titration at the
present of mercury (II)
acetate, the indicator crystal violet (Е=М.м).
2) Argentometry by the
Faience method in the
acetate medium, the
indicator - bromophenol
blue (Е=М.м).
CH2OH
CH3COOH
N
O
CH3
CH
C
C6H5 * H2SO4 + HClO4
O
2
CH2OH
H
N+ CH
3
ClO4-
O
CH
C
CH2OH
+
C6H5
O
H
N+ CH
3
HSO4-
O
C
CH
C6H5
O
CH2OH
CH3COOH
2O
N
CH3
O
C
CH
C6H5 * HBr + Hg(CH3COO)2 + 2 HClO4
O
CH2OH
2 O
H
+
N
CH3
O
C
O
CH
C6H5 ClO4- + HgBr2 + 2 CH3COOH
Storager, applcation
Atropine sulphate
Protected from light.
Anticholinergic (spasmolytic,
under the influence of atropine is a
strong dilation of the pupils midriatic effect ) medicine. Used to
study the eye fundus, at the
spasms of smooth muscles,
antidote to acetylcholine.
Intravenous injection , inner muscular
injectio, eye drops. Producing powder, ampoule 0,1% - 1,0.
Poisoning substance. H.d..-0,001 g,
H.d.d.- 0,003 g.
Preparations:
Atropine Eye Drops
Atropine Eye Ointment
Atropine Injection
Atropine Tablets
Morphine and Atropine Injection
Scopolamine
hydrobromide
Protected from light.
Anticholinergic . Midriatic effect is
not continue. Exhibits a calming
effect on the CNS. Treatment of
parkinsonism .
hypodermic injection, eye drop.
Producing - powder, ampoule 0,05%
- 1,0. Poisoning substance. H.d.0,0005 g, h.d.d.- 0,0015 g.
Scopolamine butylbromide
(Spazmobryu, Buscopan,
Buskotsin-M)
Synthetic analogues of atropine
Atropine and scopolamine - valuable medicinal compounds, but
they often give side effects. In the search for new biologically
active compounds of the tropane’s rows there were synthesized
esters of tropine with almond and diphenylacetate acids homatropine and tropacyn
Homatropine hydrobromide
(Homatropini
hydrobromidum)
OH
N
CH3
O
C
CH
Tropacyn, Diphenyltropane
hydrochloride (Tropacinum)
C6H5
N
C6H5 * HBr
CH3
O
C
CH
C6H5 * HCl
O
O
Tropine ester of almond acid
hydrobromide
(N-methyl-8-azoniabicyclo[3.2.1]oct-3-yl)
2-hydroxy-2-phenylacetate bromide
Tropine ester of diphenylacetate acids
hydrochloride
Tropaphenine
(Tropaphenum). Expressed
α-adrenaline receptors
agonist, weak
anticholinergic.
Producing:lyophilized powder
for injection.
Troventoline
(Troventolum).
Bronchodilatory drug.
Aerosol.
Atrovent
((Ipratropiumbromide
). Bronchodilatory drug.
Aerosol.
Obtaiing of synthetic
analogs of atropine
According to the interaction between
tropine and according acid or its
chlorhydride:
R1
O
C
N
CH3
OH
Cl
CH
R2
R1
N
CH3
O
C
CH
R2
O
Physical properties
Homatropine
hydrobromide
White or almost white,
crystalline powder. Freely
soluble in water, slightly
soluble in alcohol, very
slightly soluble in
chloroform, practically
insoluble in ether.
Tropacyn
White or almost creamy
white crystalline
powder. Freely soluble
in water, alcohol and
chloroform, practically
insoluble in ether and
benzole.
Identification
1.
2.
3.
4.
5.
6.
7.
Homatropine hydrobromide
It gives the reactions of bromides
(three reaction according to SPhU).
It gives the reaction of alkaloids
With iodine solution settled down
the brown sediment of substance
periodide.
With КОН solution –white
sediment, it’s dissolved in the
excess of the reagent.
Homatropine base at the heating
with mercury (II) chloride alcohol
gives yellow colour which transfers
into red-orange (unlike from the
most of alkaloids, except atropine
and hyoscyamine).
Hydroxamic reaction .
Doesn’t
give
Vitali's-Morena
reaction.
Tropacyn
1. Give Vitali's-Morena reaction
2.
3.
4.
5.
(on diphenylacetate acid).
Melting point.
It gives the reaction of
alkaloids
It gives the reactions of
chlorides (two reaction
according to SPhU).
Hydroxamic reaction.
Vitali's-Morena reaction on tropacyn:
Quantitative determination
Homatropine
hydrobromide
Tropacyn
1) Acidimetry in nonaqueous
Acidimetry in nonaqueous
medium, a direct titration at
the present of mercury (II)
acetate, the indicator - crystal
violet (Е=М.м).
2) Alkalimetry in water-alcohol
medium at the present in
chloroform (Е=М.м).
1)
medium, a direct titration at
the present of mercury (II)
acetate, the indicator crystal violet (Е=М.м).
2) Tropacyn in tablets is
determined argentometric
by Folgard’ method
(Е=М.м).
Storage, application
Homatropine
hydrobromide
Protected from light.
Anticholinergic (midriatic)
medicine. Using eye drops 0,250,5-1% solutions. Doesn’t use at
the treatment of glaucoma.
Producing - powder, ampoules
0,1% - 1,0. Poisoning
substance. H.d.-0,001g, H.d.d.0,003 g.
Tropacyn
Protected from light.
Anticholinergic. Midriatic effect
is not continue,
actively influence on the central
holynoreactive system.
Treatment of Parkinson's
disease, spasms of smooth
muscles of the abdominal
cavity, stomach ulcers.
Intravenous. Producing - powder,
tablets 1, 3, 5, 10, 15 mg.
Poisoning substance. H.d.-0,03
H.d.d.- 0,1 g.
Tropane’s alkaloids ecgonine
types
Cocaine hydrochloride (Cocaini
hydrochloridum)
COOCH3
N
CH3
O
C
C6H5 * HCl
O
Hydrochloride of methyl ester benzoylecgonine
• Cocaine is methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8methyl-8-azabicyclo[ 3.2.1]octane-2-carboxylate
hydrochloride
(Erythroxylon Coca)
• May be obtained from the
leaves of Erythroxylum
coca Lam. and other
• species of Erythroxylum or
by synthesis.
Physical properties
Colourless crystals or a white,
crystalline powder. Slightly volatile.
Very soluble in water; freely soluble in ethanol
(96%), soluble in chloroform and glycerinein,
practically insoluble in ether.
Identification
1. It gives the reactions of chlorides.
2. Melting point (not lell 195 °С); optical rotation
- from -71 ° till -73° (2,5 %-water solution);
specific absorption rate .
3. Hydroxamic reaction (on the ester group).
4. It gives the reaction of alkaloids
5. With potassium permanganate solution forming the violet
crystalline sediment- cocaine permanganate (difference
from novocain):
6. If, in an aqueous solution of cocaine to add drop by drops a
5% solution of chromic acid H2CrO4, then from each drop
not stable turbidity appears. With further addition of HCl
conc. formed an amorphous orange-yellow precipitate.
7. At the heating of cocaine hydrochloride with sulfuric
concentrated acid appearance the acidic hydrolysis its
products are methyl alcohol, benzoic acid. These products
interact with each other to form methyl benzoate, which
has a characteristic odor:
At long staing from the reaction mixture crystals of benzoic
acid settle down
•
l
•
Purity test
Unacceptable impurity cinnamoylcocaine and other reducing
substances – with КМnО4 solution it doesn’t colourlessed during 30
minutes.
Impurity of truxilline and other coca alkaloids are determined
by the addition of ammonia solution: if the impurities are not
present the cocaine base settles down, if they are present
any sediment formation.
Quantitative determination
•
•
•
Acidimetry in nonaqueous medium, a direct titration at the
present of mercury (II) acetate, the indicator - crystal violet
(Е=М.м).
Alkalimetry in ethanol-chloroform medium (Е=М.м).
Iodometry, back titration after precipitation of polyiodide
cocaine C17H21NO4•HJ•J2 (Е=М.м./2).
Storage
Protected from light.
Action and use
Local anaesthetic.
Used as a surface anesthetic for anesthesia of the cornea (1-3%
solution) and the mucous membranes of the nose, throat,
urinary tract (2-5% solution). Has a marked effect on the
CNS, can cause euphoria, excitement, and then CNS
depression (addictive - cocainism). Because the drug is
toxic and quite deficient, synthesized series of its
substitutes (benzocaine, procaine, trimekain, lidocaine),
with account relationship between structure and action
local anaesthetic drugs.
Producing – powder, ampoules 2%-1,0. Poisoning substance.
H.d.- 0,03 g, h.d.d.- 0,03 g.
Alkaloid – isoqinoline derivatives
From the many alkaloids, isoquinoline derivatives in medicine is
mainly used as two groups of drugs: derivatives of 1benzylisoquinoline and morphinan (phenantrenisoquinoline).
The source of the 1-benzylisoquinoline and morphinan of the alkaloids
derivatives are opium - the milky juice of the immature fruits
soporific poppy (Papaver somniferum). The composition of opium
(20-25%) is more than 20 alkaloids (morphine, narcotine,
papaverine, codeine, thebaine, etc.). Alkaloids found in opium in the
form of salts of meconate ( -oxy-  -pyrone-  -dicarboxylic), lactic
and sulfuric acids. Narcotine and papaverine as a very weak basis
are in a free state.
The separation scheme of main opium alkaloids by the method of
Kanevska-Klyachkina
Opium
4-th tymes extraction by water at 50-55 0C
The remainders from the extraction
Water extract
contains ballast substances, a little papaverine,
(concentrated in vacuum at
and 2/3 half of all narcotine. Alkaloids are
0C add ammine and ethanol
60-70
extracted by the dichloroethane
Filtrate
Sediment
contains morphine, narcotine, meconate
acidified by an acetic acid at the
ammonium which are not soluble in alcohol
present of sodium acetate and
Dichloroethane extract
extracted by dichloroethane
Contains papaverine which is like a very weak
Water solution
base doesn’t form with acetatic acid at the
contains codeine, thebaine and
present of sodium acetate, salt. Remove the
solvent from the extract
other alkaloids which are formed
Papaverine
with acetic acid water solubility
is purified according to the formation of a
acetates at the present of sodium
hard soluble salt
acetate
The precipitate obtained by the mixing of an aqueous extract of opium
with an alcoholic solution of ammonia, processed according to the
scheme:
The precipitate is heated with the diluted alcohol at 70 0C and filtrated
The precipitate
The filtrate
is extracted by an acetic acid.
Narcotine as a very weak base
doesn’t form the salt. And it is in
sediment.
Filtrate
Narcotine
sediment
is purified by a
crystalisation from
an alcohol or
acetone
contains morphine
acetate to add
ammine and to
filtrate
Morphine
is purified by a
crystalisation from a
diluted hydrochloric
asid solution
contains meconate ammonium
meconate acid
Alkaloids of 1-benzylisoquinoline derivatives
Papaverine hydrochloride
(Papaverini hydrochloridum)
H3CO
H3CO
H3CO
5
C2H5O
4
6
N
2
8
21
1
1
3
11
4
4
5
6
3
3
7
1
Drotaverine hydrochloride
(Drotaverini hydrochloridum)
NО-Shpa (Nospanum)
C2H5O
C2H5O
CH2 * HCl
61
H3CO
51
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy
isoquinolinehydrochloride
NH
2
7
1
8
21
31
CH * HCl
11
C2H5O
4
61
1
51
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy1,2,3,4-tetrahydro- isoquinoline
hydrochloride
Physical properties
Papaverine hydrochloride (SPhU)
White or almost white crystalline powder or white
or almost white crystals. Sparingly soluble in water,
slightly soluble in alcohol. It can fuse with KOH (forming
dimethoxyisoquinoline and dimethoxytoluol) and oxidized
by КMnO4 (oxidation products are pyridine- threecarbonic
acid and 3,4-dimethoxybenzoate (veratic) acid).
It has reducing property according to the two
aromatic fragments bounding by methylene group, as well
as a four methoxide groups.
Drotaverine hydrochloride
Yellow crystalline powder. Soluble in water and ethanol, not
soluble in an ether.
Identification of Papaverine hydrochloride
1. Determination of specific absorption by UV spectroscopy.
2. Melting point of a papaverine base after it is settled down by
ammonia. To 10 ml of solution S (see Tests) add 5 ml of
ammonia R dropwise and allow to stand for 10 min. The
precipitate, washed and dried, melts (at 146 °C to 149 °C.
3. Karolinov’s test : after the heating of the substance with acetic
anhydride and sulphuric acid solution is pained in an yellow
colour with a green fluorescence.
4. It gives reaction of chlorides.
5. Nonpharmacopoeia reactions:
а) with a concentrated sulphuric acid the substance at the heating is
coloured in violet;
b) at mixing ethanol’s solutions of papaverine and iodine a darkred crystals of the hydroiodide diiodopapaverine
C29H19O4NJ2•HJ settle down;
c) It gives the reaction of alkaloids ;
d) With nitric acid forming an yellow colour that
transfers into orange at the heating;
H3CO
H3CO
H3CO
N
HNO3
H3CO
N
N
HNO3
H3CO
0
CH2
t C
CH2
H3CO
O2N
NO2
NO2
H3CO
OCH3
H3CO
OCH3
жовте забарвлення
CH2
H3CO
OCH3
оранжеве забарвлення
e) With bromine water papaverine forms an yellow
sediment brompapaverine hydrobromide
f)
With Marki reagent at the first step forming a red colour
than yellow and bright-orange. Formed
methylendipapaverine with bromine water and ammine
gives a violet sediment, which is dissolved in an
alcohol and gives violet-red colour.
OCH3
C
H2
H3CO
H3CO
OCH3
OCH3
H3CO
C
H2
OCH3
+
N+
N
H
H
C
H2
2-
OCH3 SO4
Drotaverine hydrochloride
Drotaverine’s molecule is considered as the
condensation product of 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline
and
3,4Dimethoxybenzaldehide. The
drug
has a
characteristic absorption spectrum in the UV region
Drotaverine has more basic properties than
papaverine, therefore, for the extraction of the basics
from the medicine solution you need to add alkaline
solution.
As well as papaverine, drotaverine has a
reducing properties. When added to a sample of the
drug a conc. H2SO4 and added followed by drop a
diluted HNO3 appearance a dark brown colour.
Quantitative determination of papaverine
hydrochloride
•
•
•
Alkalimetry in a mixture medium of an alcohol and
0,01М chloric acid with potentiometric fixing of the
equivalent point. (Е=М.м).
Acidimetry in nonaqueous medium, a direct titration at the
present of mercury (II) acetate, the indicator - crystal
violet (Е=М.м).
Alkalimetry in a water-alcohol medium without
chloroform, cause papaverine is a very weak base
(Е=М.м).
•
•
•
Argentometric by Folgard’ method.
Spectrophotometry (in dosage forms) (Е=М.м).
Quantitative determination of a drotaverine hydrochloride
by the same methods as a papaverine hydrochloride.
Storage, application
• Papaverine
hydrochloride
Protected from light
Phosphodiesterase inhibitor;
smooth muscle relaxant.
Using per oral 40-80 mg 3-4 times
a day, parenteral 1-2 ml of 2%
solution.
Producing - powder, tablets 40
mg, ampoules 2% - 2,0,
suppositories 0,2 g.
Strong action stuff.
Included in the tablets of Papazol,
andypal, Nicoverine.
• Drotaverine
hydrochloride
Protected from light.
smooth muscle relaxant.
Using per oral 40-80 mg 2-3 times
a day, inject i/m 2-4 ml of 2%
solution.
Producing - tablets 40 mg,
ampoules 2% - 2,0. Strong
action stuff.
Included in the tablets of Nishpan
(with nicotinic acid), Bishpan
(with isopropamide)
Alkaloid of morphinan derivatives
The main alkaloid of opium is morphine, it is the derivatives of
morphinan:
Morphinan
Morphine: 3,6-dioxy-N-methyl-
4,5-epoxymorphinen-7;
In the molecule of morphine are 5 asymmetric carbon atoms. High
reactivity of oxygroups, yields to obtain a large number of its
semisynthetic derivatives:
Morphine hydrochloride (Morphini
hydrochloridum)
HO
O
* HCl * 3 H2O
N
CH3
HO
Three hydrate hydrochloride 3,6-dioxy-4,5-epoxy-17
methylmorphinen-7
7,8-Didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol
hydrochloride trihydrate.
Physical and chemical properties of
Morphine
White needle-shaped crystals or white crystalline
powder, slightly yellow during storage. Slowly soluble in
water, difficult soluble in alcohol, very slightly soluble in
chloroform and ether.
Acid-base properties are explained by the presence of a
tertiary nitrogen atom (the center core) and phenolic
hydroxyl (center of acidity). The basic properties of
morphine are less expresed than in ammonia, and acidic is
somewhat stronger than in phenol .
Pronounced reducing properties are dued to the affiliation of
morphine to a partially hydrogenated phenanthrene system,
as well as the presence of phenolic hydroxyl and the
secondary alcohol group.
Identification of Morphine
hydrochloride
1.
2.
3.
4.
5.
6.
Optical rotation from -97° till -99° (2 % water solution).
Appearance of the 5 asymmetric carbon atoms (5, 6, 9, 13,
14) gives an optical activity for a substance.
It gives reaction of chlorides.
When to added an ammonia to a solution of a substance
releasing a white crystalline precipitate which is dissolved in
a solution of sodium hydroxide (according to the formation
of sodium’s salt due to the presence of phenolic hydroxyl).
It gives the reaction of alkaloids
With Phrede reagent morphine gives a violet color, passing
into blue, at a staying - in green.
With Marki reagent appearance a purple coloration, rapidly
transforms into a blue-violet (unlike from codeine).
7. Oxidation of morphine by Mandelina reagent (a solution
of ammonium vanadate in the conc. H2SO4) leads to the
formation of the purple product.
8. With Erdman reagent forming a red product.
9.
Pellagry reaction. At the action of a concentrated H2SO4 or a
concentrated HCl forming apomorphine, which from the addition
of a concentrated HNO3 becomes intense red color. If
apomorphine is dissolved in water, which is neutralized by
Na2CO3 and to add 1-3 drops of iodine solution, then appearance a
green color. If the green solution shake with ether, the ethereal
layer is painted in red and water remains green.
С17H19O3N → C17H17O2N + H2O
morphine
apomorphine
10. With a concentrated HNO3 formig an intramolecular chelate of
orange-red color.
11. The oxidizing by a potassium hexacyanoferrate (III)
in acidic medium with forming oxydimorphine. At the
further addition of iron (III) chloride to the prepared
solution it is formed "Prussian blue" (dark blue color):
12. With a solution of iron (III) chloride appearance a blue coloration
(reaction to the phenolic hydroxyl), which quickly disappears
according to the oxidation of morphine by the reagent.
13. Halogenation (reaction to a phenolic hydroxyl).
14. With diazonium’s salts it is formed an azo dye (due to the
presence of phenolic hydroxyl).
15. The Oxidation of the secondary alcoholic hydroxyl to a ketone with
a subsequent formation of an oximes, hydrazones, semicarbazone
16. Esterification goves either a phenolic or the secondary alcoholic
hydroxyl group.
17. Morphine, just like other phenols, easily is oxidized. Since the
interaction with HJO3 it releases a free iodine. Alkaline solutions
of morphine are very easy oxidized and form oxydimorphine
(dihydromorphine, psevdomorphine, oxyimorphine):
Quantitative determination of Morphine hydrochloride
Acidimetry in nonaqueous medium, a direct titration at the
present of mercury (II) acetate, the indicator - crystal violet
(Е=М.м).
Argentometric by Folgard’ method (Е = М.м.).
Alkalimetry in ethanol-chloroform medium (Е=М.м).
Storager, application of morphine
Protected from light.
Opioid receptor agonist; analgesic.
Strong analgesic action. It has an antishock action at traumas,
in bigger doses has a hypnotic effect. It is used in the
preparation and after surgery, at traumas, cancers.
Take per oral 10-20 mg in powder form, or in hypodermic
injection - 1% -1.0.
Morphinomania is a passion to morphine using. Morphilongis a 0, 5% solution of morphine hydrochloride in 30%
aqueous solution of polivinylpyrrolidone. Omnopon is a
mixture of hydrochlorides of opium alkaloids (up to 50%
morphine, etc.).
Naltrexone hydrochloridel, nalorfin and Naloxone (SPhU) are
the antidotes to morphine, opiate receptor antagonists.
Codeine medicines
• Codeine (Codeinum)
(SPhU)
H3CO
O
• Codeine phosphate (Codeini
phosphas)
H3CO
* H 2O
O
N
CH3
HO
4,5α-epoxy-3-methoxy-17-methyl-7,8Didehydro-morphinan-6α-оl;
7,8-Didehydro-4,5a-epoxy-3-methoxy17-methylmorphinan-6a-ol.
* H3PO4 * 1,5 H2O
N
CH3
HO
Phosphate 3-methoxy-6α-oxy-4,5αepoxyepoxy-17-methylmorphinan-7;
7,8-Didehydro-4,5a-epoxy-3-methoxy-17methylmorphinan-6a-ol phosphate
hemihydrate.
Physical properties
Codeine
Codeine phosphate
White or almost white,
crystalline powder or
colourless crystals.
Solubility
Soluble in boiling water,
freely soluble in ethanol
(96 per cent). It has the
strongest basic properties
among all alkaloids (рН
codeine water solution 9,0).
White or almost white,
crystalline powder or
small, colourless
crystals.
Solubility
Freely soluble in water,
slightly soluble or very
slightly soluble in ethanol
(96 per cent).
Identification of Codeine medicines
1-3. Melting point, compare The IR spectra of the
pharmacopoeia sample and determine the maximal
absorption peaks by UV spectroscopy.
4. It gives the reaction of alkaloids
5. At the heated with concentrated sulfuric acid and a solution of
iron (III) chloride appearance a blue color (due to the
formation of apomorphine containing phenolic hydroxide).
According to the apomorphine formation codeine gives
positive Pellagry reaction (look morphine).
6.
Non pharmacopoeia reaction:
а) With Marki reagent appearance blue-violet color
b) with a concentrated nitric acid appearance an orange color,
which transfers to yellow.
c) With Phrede reagent – violet color;
d) With Erdman reagent – red.
е) The esterification of the secondary alcoholic hydroxy.
Identification of Codeine phosphate:
а) By the reaction of the detection of phosphate ion with a solution
of Silver nitrate on the formation of yellow precipitate.
PO43- + 3Ag+  Ag 3 PO4 
b) on phosphate ion with molybdenvanadium reagent
appearance yellow color;
PO43- + HVO3 + 11H2MoO4 + 4NH4+ 
(NH4)4[PO4(MoO3)11VO3] + 11H2O + H+
c) Melting point of codeine base, precipitated by sodium
hydroxide (154-157 °С).
Quantitative determination
Codeine medicines
Codeine
Acidimetry in nonaqueous
medium, a direct titration at
the present of mercury (II)
acetate, the indicator crystal violet (Е=М.м).
Codeine as a strong base is
determined by alkalimetry in
water-alcohol medium, the
indicator – methyl red (Е =
М.м.).
Codeine phosphate
Acidimetry in nonaqueous
medium(Е = М.м.).
Alkalimetry in chloroformalcohol medium, idicator phenolphthalein (Е =
М.м./2).
Storager, applcation of Codeine
Protected from light.
Opioid receptor agonist; analgesic.
Antitussive, mild analgesic effect. It is included in the
tablets of Kodterpine (terpinehydrate, sodium
bicarbonate), Tablets from cough, Pentalgin, sedalgin
Solpadein, Behterrov tincture (sodium bromide,
tincture adonis).
Release form – powder, tablets. H.d.-0, 05 g;
H.d.d.-0, 2 g.
Codeine phosphate as a less toxic (80% codeine base)
can be taken in higher doses for children. Produsing powder. H.d - 0, 1 g; H.d.d.-0, 3 g.
Ethylmorphine hydrochloride
(Aethylmorphini hydrochloridum)
Dionine (Dioninum)
C2H5O
O
*
Properties
Crystalline powder of
white or nearly white.
HCl * 2 H2O
Soluble in water and
N
CH3
96% alcohol,
practically insoluble in
ether.
HO
(5R, 6S) 4,5α-epoxy-3ethoxy-N-methylmorphine7-еn-6-ol hydrochloride
Identification of Ethylmorphine
hydrochloride
IR spectra.
Melting point of ethyl morphine base, precipitated
by sodium hydroxide.
At the heating a substance with a concentrated
H2SO4 and a solution of FeCl3 appearance a blue
color (formation of apomorphine), goes into the
red after the addition of a concentrated nitric acid
(Pellagry reaction).
It gives the reaction of chlorides.
Non pharmacopoeia reaction:
а) Iodoformic test. At the heating of a mixtuer of substance,
crystalline iodine and sodium hydroxide till boiling point,
appearance characteristic odor of iodoform:
b) 3 With a concentrated nitric acid appearance an orange
color.
c) UV spectroscopy .
Quantitative determination
1)
Acidimetry in nonaqueous medium, a direct titration
at the present of mercury (II) acetate, the indicator crystal violet (Е=М.м).
Alkalimetry in water-alcohol medium with addition of
chloroform (Е = М.м.).
Storager
Protection from light
Application
Analgesic (narcotic), and antitussive medicine. For
the treatment of the eye as anti-inflammatory agent
(1-2% drops or ointment). Powder, tab. at 0.01 and
0.015 g, the H.d. - 0,03 g; H.d.d. - 0,1 g.
Synthetic
analogue
of
morphine
on
the
pharmacological action. One of the first in this series
have been synthesized promedol, and more recently
- tramadol.
Other narcotic analgesics
Pentasocyn (Fortran) - Tables, amp, a strong analgesic, less
respiratory depression, rarely observed phenomenon of
addiction and withdrawal.
Buprenorphine h/chl (SPhU) - Tables. to 0.2 mg.
Butorphanol hydrotartratis (Beforal, moradol) – containes
in a car kits.
Promedol - table, amp, syringe-tube, a strong analgesic for
labor analgesia.
Fentanyl - amp, for sedation.
Tramadol (Tramal) - Capps, amp, suppositories.
Ketorolac (Ketanov, Ketorol, Ketolonga-Darnitsa, etc.) analgesic effect equated to morphine is not addictive,
Table, amp.
Ketoprofen (ketonal, F-gel, gel Fastum) - Tables,
tabl.retard, capsules, suppositories, amp, gel, cream)
Alkaloids of apomorphine
derivateves
4
5
(Apomorphini
hydrochloridum)
3
6
HO
2
1
N
7
CH3
HO
* HCl * 3/4 H2O
8
9
10
N
CH3
Àï î ðô ³í
5,6 dioxyapomorphine
Glaucine hydrochloride (Glaucini
hydrochloridum) Glauvent
Alkaloid from the herba of Glaucii Flavi
OCH3
H3CO
* HCl
H3CO
N
CH3
4,5,7,8tetramethoxyapomorphine
hydrochloride
H3CO
1.
2.
3.
4.
5.
6.
7.
Identification of apomorphine hydrochloride
It gives the reaction of chlorides.
With HNO3 conc.– blood-red color.
Alkali solution extract from the substance solution a free
apomorphine as a white precipitate which is dissolved in
excess of alkali (due to the formation of sodium salt due
to the presence of phenolic hydroxyl).
Oxidation reaction (Pellagry ): with iodine solution in the
presence of NaHCO3 and ether - the ether layer is painted
in red-violet color, and water becomes green.
Optical rotation from -46° till -52° (in HCl solution).
With Marki reagent – violet color which transfers in
green.
Vitali's-Morena reaction.
Quantitative determination
1) Acidimetry in nonaqueous medium, a direct titration at the
present of mercury (II) acetate, the indicator - crystal violet
(Е=М.м).
Storager
Protected from light
Applcation
Apomorphine hydrochloride – emetic, expectorant. At
poisoning it is used of 0,2-0,5 ml solution of 1%
hypodermic injection. Expectorant action - 5.1 mg orally.
Glaucine hydrochloride– antitussive medicine, unlike as
codeine does not suppress breathing, non-addictive, shows
a moderate hypotensive effect. Table. By 0,05 g.
Thanks for
attention