Transcript Анализ на фенотиазинови производни

Анализ на фенотиазинови
производни
•С диметиламинопропилова верига при N10
•С пиперазинов хетероцикъл при N10
•С пиперидинов хетероцикъл при N10
CH3
3
N
N
2
CH3
Cl
10
S
Chlorpromazine
H3C
H3C
N
N
N
N
S
Trifluoperazine
CF3
N
SCH3
S
Thioridazine
•Antipsychotic — Chlorpromazine; Fluphenazine; Mesoridazine;
Methotrimeprazine; Perphenazine; Pipotiazine; Prochlorperazine;
Promazine;
Thioproperazine;
Thioridazine;
Trifluoperazine;
Triflupromazine;
•Antipsychotic adjunct — Pericyazine;
•Anesthetic adjunct — Chlorpromazine; Methotrimeprazine,
intravenous;
•Antidyskinetic, Huntington's chorea — Chlorpromazine;
Thioridazine;
•Antiemetic — Chlorpromazine; Methotrimeprazine; Perphenazine;
Prochlorperazine; Trifluoperazine; Triflupromazine;
•Antineuralgia adjunct — Fluphenazine;
•Sedative — Chlorpromazine; Methotrimeprazine; Thioridazine;
•Analgesic — Methotrimeprazine;
Фенотиазинови производни
СВОЙСТВА:
Фенотиазините са разтворими в липиди, бързо се
разпределят в биомембраните. Съдържат един или два
базични N атома, които дават възможност за
образуване на водноразтворими соли. Представляват
бели кристални вещества. Базите са оцветени от светло
до тъмнокафяво и са гъсти масла, неразтворими във
вода. рКа стойностите им са между 8.0 и 9.5. Всички
фенотиазинови производни, използвани в терапията са
много чувствителни на светлина (УВ), нагряване и
окисление.
H
N+
Мезомерни
резонансни
структури
1a
S
Висока електронна
плътност при S атом,
което обуславя лесно
окисление
H
N
1b
S
Липса на базичност при
N атом (малка ел.
плътност)
H+
N
1c
S
Фенотиазинови производни
Спрежение с p-системата
от ароматното ядро
H
S
S
N H
145 0
H intra Form
N
H extra Form
Тетрагонална сгъната конфигурация,
доказана с квантово-химични изследвания
Chlorpromazine
CH3
Стабилност при
влияние на светлина
(УВ) и окисление
N
N
Cl
1
S
e
+e
CH3
Елиминиране на електрон
CH3
N
N
+
CH3
Cl
2a
S
CH3
CH3
N
N
CH3
Cl
N
2b
S
N+
CH3
Cl
2c
S
+
Мезомерно стабилизиран цветен радикал
– 2а, 2b и 2c
феназатиониев йон
1
2b +
2c
N
+
CH3
CH3
N
N
CH3
N
Cl
+
CH3
Cl
+H2O
S
S
+
O+
3
H
H
Реакцията е обратима.
Радикалите (непропорцинално)
образуват феназатиониев йон,
който във водна среда реагира
като електрофилен реагент и
образува моносулфоксид.
Непропорционалността на
радикалите се потиска в кисела
среда – стабилизиране.
2H
+
CH3
N
CH3
Cl
N
S
O
4
моносулфоксид
N
CH3
CH3
N
N
CH3
Cl
ox.
N+
CH3
Cl
3
S
OH
red.
S
O
В силно кисела среда радикалите образуват Chlorpromazinе и 3хидрокси производно, от което при окисление се формира цветен
продукт.
Chlorpromazine Hydrochloride
3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine hydrochloride
IDENTIFICATION OF PHENOTHIAZINES
(Ph. Eur. method 2.3.3)
Carry out the method for thin-layer chromatography protected from light using
kieselguhr G as the coating substance. Impregnate the dry plate by placing it in a tank
containing a shallow layer of a solution containing 10% v/v of 2-phenoxyethanol and
5.0% w/v of polyethylene glycol 300 in acetone so that the plate dips about 5 mm
beneath the surface of the liquid and allowing the impregnating solvent to ascend at
least 17 cm above the line of application. Remove the plate from the tank and use it
immediately. Carry out the chromatography in the same direction as the impregnation.
For the mobile phase shake a mixture of 100 volumes of petroleum spirit (boiling
range, 50° to 70°) and 2 volumes of diethylamine with 6 to 8 volumes of 2phenoxyethanol until a persistent cloudiness is obtained, decant and use the
supernatant layer even if cloudy. Apply separately to the plate 2 µl of each of two
solutions in chloroform containing (1) 0.2% w/v of the substance being examined and
(2) 0.2% w/v of the corresponding European Pharmacopoeia Chemical Reference
Substance. After removal of the plate, examine under ultraviolet light (365 nm) and
observe the fluorescence produced after a few minutes. The spot in the chromatogram
obtained with solution (1) is similar in position, colour, fluorescence and size to that in
the chromatogram obtained with solution (2). Spray the plate with ethanolic sulphuric
acid ( 10%) and observe the colour produced. The colour of the spot in the
chromatogram obtained with solution (1) is the same as that in the chromatogram
obtained with solution (2) and has a similar stability over a period of at least 20 minutes
after spraying.
Chlorpromazine Hydrochloride
Abstract: An automated on-line method for simultaneous analysis of five
phenothiazine drugs by high-performance liquid chromatography
(HPLC)/sonic spray ionization mass spectrometry (SSI-MS) has been
established, using backflush column switching. A 400-μl portion of serum
sample diluted 81-fold with distilled water was subjected to the on-line
system. In the system, an Oasis HLB cartridge was used as the precolumn
for extraction; large molecules such as proteins in serum were discarded
by use of distilled water containing 0.1% formic acid as a mobile phase.
After switching a valve, the analytes trapped in the precolumn were eluted
in the backflush mode and separated by a Chromolith Performance RP18e column, which is composed of C18-bonded monolithic silica. The
column effluents were then introduced into the SSI-MS. The present
method provided successful separation and determination of six
phenothiazines including an internal standard. Satisfactory linearities,
reproducibility, and sensitivity were obtained at concentration levels that
matched the toxic levels of phenothiazines. All drug peaks appeared within
18 min, and the system could be reequilibrated in only about 8 min for the
next run. Because of the simplicity and rapidness of the method, it is likely
to be useful in the fields of emergency medicine and forensic toxicology.
Metabolites of Chlorpromazine
Chromatogram of the separation of chlorpromazine and five metabolite standards
Promethazine
H 3C
H
C
N
CH3
O
CH3
N
N+
H
N
S
S
S
O
O
H
C
O
N
N
S
S
O
Promazine
CH3
N
CH3
N
S
Fluphenazine
N
N
N
S
CF3
OH
Levomepromazine
CH3
CH3
N
N
(Methotrimeprazine)
CH3
OCH3
S
(R)-10-[ 3-(dimethylamino)2-methylpropyl]-2methoxyphenothiazine
levomepromazine
Acidity or alkalinity To 10 ml of solution S
add 0.1 ml of bromocresol green solution
R. Not more than 0.5 ml of 0.01M sodium
hydroxide or 1.0 ml of 0.01M hydrochloric
acid is required to change the colour of the
indicator.
Specific optical rotation (2.2.7). +9.5° to
+11.5°, determined on solution S and
calculated with reference to the dried
substance.
Related substances Carry out the test
protected from bright light. Examine by
thin-layer chromatography (2.2.27), using
silica gel GF254 R as the coating
substance.
Loss on drying (2.2.32). Not
more than 1.0 per cent,
determined
on 1.000 g by
drying in an oven at 100°C to
105°C for 3 h.
Sulphated ash (2.4.14). Not
more than 0.1 per cent,
determined on 1.0 g.
Ph Eur
Thioridazine
H3C
(RS)-10-[2-(1- methyl-2piperidyl)ethyl]-2(methylthio)phenothiazine
N
N
SCH3
S
Trifluoperazine
H3C
N
N
10-[3-(4- methyl-1piperazinyl)propyl]-2trifluoromethylphenothiazine
N
S
CF3
Тиоксантени
Chlorprothixene
(Z)-3-(2-Chloro-9H
thioxanthen-9-ylidene)N,N-dimethylpropan-1amine hydrochloride.
Тиоксантени
Стабилни в киселинна и алкална
среда, както и при нагряване
Промени под действие на UV-светлина:
Chlorprothixene
UV
UV
O
O
Cl
Cl
S
S
IMPURITIES
(E)-3-(2-chloro-9H-thioxanthen-9-ylidene)-N,Ndimethylpropan-1-amine (E-isomer).
Flupentixol
DEFINITION
2-[4-[3-[(EZ)-2-(trifluoromethyl)-9Hthioxanthen-9-ylidene]propyl]piperazin
-1-yl]ethanol dihydrochloride.
Content
- flupentixol dihydrochloride: 98.0 per
cent to 101.5 per cent (dried
substance),
- Z-isomer: 42.0 per cent to 52.0 per
cent.
2-(trifluoromethyl)-9H-thioxanthen-9-one.
The structure of flupentixol is based on the
thioxanthene ring to which the side chain is linked by a
C=C double bond. Because of the double bond linking
of the side chain to the thioxanthene ring structure,
flupentixol exists as two geometric isomers, namely cis
(Z) and trans (E) isomers. It is interesting to note that,
in pharmacological studies, the neuroleptic activity is
associated with the cis (Z) isomer, while the trans (E)
isomer is practically inactive. The oral form of
flupentixol, administered as tablets or drops, is an
equimolar mixture of the active cis (Z) and the inactive
trans (E) isomers, while the parenteral preparation for
intramuscular injection is the decanoic acid ester of the
isolated cis (Z) isomer.
Fluoroorganic compounds
D. Mix about 5 mg with 45 mg of heavy
magnesium oxide R and ignite in a
crucible until an almost white residue is
obtained ( usually less than 5 min). Allow
to cool, add 1 ml of water R, 0.05 ml of
phenolphthalein solution R1 and about 1
ml of dilute hydrochloric acid R to render
the solution colourless. Filter. Add 1.0 ml
of the filtrate to a freshly prepared
mixture of 0.1 ml of alizarin S solution R
and 0.1 ml of zirconyl nitrate solution R.
Mix,
allow to stand for 5 min and
compare the colour of the solution with
that of a blank prepared in the same
manner. The test solution is yellow and
the blank is red.
Ph Eur
Alizarine
Title:
METHOD AND APPARATUS FOR DETERMINATION OF
CARBON-HALOGEN COMPOUNDS AND APPLICATIONS
THEREOF
Abstract:
A method and apparatus for determination of fluoroorganic compounds
in liquid gaseous, or crystalline or amorphous solids is based on the
detection of carbon-halogen bonds by laser Raman spectroscopy.
The method and apparatus provide a general method for detecting and
determination of haloorganic compounds. The method and apparatus
are applicable in the pharmaceutical industry, in the fluorinated drug
research and manufacturing in the medical and clinical studies of the
effects of fluoroorganic compounds, in the environmental and
agricultural studies and screening, in the analysis of water, soils and air
contaminated with fluoroorganic compounds.
As a basis for quantitative determination of
fluorinate species, flourine-19 nuclear magnetic
resonance (19F NMR) offers several potential
advantages compared to chromatography. 19F
NMR spectroscopy has a large spectral window
associated with it. Typically organofluorine nuclei
lie within a window of 300 ppm, resulting in a
small probability of peak overlap between
molecules. Moreover, the spin 1/2 19F isotope is
100% abundant and possesses a sensitivity
which is 81% of a 1H nucleus. The technique can
be used for spectral identification of an analyte
and for quantification, when an internal standard
of known concentration is included
19F
NMR spectra of cis(Z)- (A), trans(E)-flupentixol (B), and
their mixture (C) in acetonitrile/methanol (2:1 v/v) solvent