瑞格列奈(EP7.0)

EUROPEAN PHARMACOPOEIA 7.0
Repaglinide
B.R =S-CH 2-CH 2-NH 2:2-[[[5-[(dimethylamino)methyl]furan-2-
yl]methyl]sulfanyl]ethanamine,D.R =S-CH 2-CH 2-NH-CO-CH 2-NO 2:N -[2-[[[5-[(dimethyl-amino)methyl]furan-2-yl]methyl]sulfanyl]ethyl]-2-nitroace-tamide,F.R =OH:
[5-[(dimethylamino)methyl]furan-2-yl]methanol,C.N -[2-[[[5-[(dimethylamino)methyl]furan-2-yl]methyl]sulfin-yl]ethyl]-N ′
-methyl-2-nitroethene-1,1-diamine,E.N -[2-[[[5-[(dimethyloxidoamino)methyl]furan-2-yl]methyl]sulfanyl]ethyl]-N ′
-methyl-2-nitroethene-1,1-diamine,G.3-(methylamino)-5,6-dihydro-2H
-1,4-thiazin-2-one-oxime,H.N
-methyl-2-nitroacetamide,I.2,2′-methylenebis[N -[2-[[[5-[(dimethylamino)methyl]furan-2-yl]methyl]sulfanyl]ethyl]-N ′-methyl-2-nitroethene-1,1-
diamine],J.1,1′-N -[methylenebis(sulfanediylethylene)]bis(N ′-methyl-2-
nitroethene-1,1-diamine),K.N -methyl-1-methylthio-2-nitroethenamine.01/2010:1369
RAPESEED OIL,REFINED
Rapae oleum raffinatum
DEFINITION
Fatty oil obtained from the seeds of Brassica napus L.and Brassica
campestris
L.by mechanical expression or by extraction.It is then refined.A suitable antioxidant may be
added.CHARACTERS
Appearance :clear,light yellow liquid.
Solubility :practically insoluble in water and in ethanol (96per
cent),miscible with light petroleum (bp:40-60°C).Relative density :about 0.917.
Refractive index :about 1.473.
IDENTIFICATION
Identification of fatty oils by thin-layer chromatography (2.3.2).
Results :the chromatogram obtained is similar to the
corresponding chromatogram shown in Figure 2.3.2.-1.TESTS
Acid value (2.5.1):maximum 0.5,determined on 10.0g.
Peroxide value (2.5.5,Method A ):maximum 10.0.
Unsaponifiable matter (2.5.7):maximum 1.5per cent,determined on 5.0g.
Alkaline impurities (2.4.19).It complies with the test.
Composition of fatty acids (2.4.22,Method A ).Use the mixture
of calibrating substances in Table position of the fatty-acid fraction of the oil :
—palmitic acid :2.5per cent to 6.0per cent,
—stearic acid :maximum 3.0per cent,
—oleic acid :50.0per cent to 67.0per cent,
—linoleic acid :16.0per cent to 30.0per cent,
—linolenic acid :6.0per cent to 14.0per cent,
—eicosenoic acid :maximum 5.0per cent,
—erucic acid :maximum 2.0per cent.
Water (2.5.32):maximum 0.1per cent,determined on 1.00g.
STORAGE
In an airtight,well-filled container,protected from light.
LABELLING
The label states whether the oil is obtained by mechanical expression or by extraction.
01/2008:2135corrected 6.0
REPAGLINIDE
Repaglinidum
C 27H 36N 2O 4M r 452.6[135062-02-1]General Notices (1)apply to all monographs and other texts 2847
Repaglinide EUROPEAN PHARMACOPOEIA
7.0
DEFINITION
2-Ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]bu-tyl]amino]-2-oxoethyl]benzoic acid.
Content:99.0per cent to101.0per cent(dried substance). CHARACTERS
Appearance:white or almost white powder.
Solubility:practically insoluble in water,freely soluble in methanol and in methylene chloride.
It shows polymorphism(5.9).
IDENTIFICATION
A.Specific optical rotation(2.2.7):+6.3to+7.7.
Dissolve1.00g in methanol R and dilute to20.0mL with the same solvent.
B.Infrared absorption spectrophotometry(2.2.24).
Comparison:repaglinide CRS.
If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference
substance separately in anhydrous ethanol R,evaporate to dryness and record new spectra using the residues. TESTS
Enantiomeric purity.Liquid chromatography(2.2.29).Prepare the solutions in amber flasks and vials.
Test solution.Dissolve10.0mg of the substance to be examined in methanol R and dilute to10.0mL with the same solvent. Reference solution(a).Dissolve5.0mg of repaglinide impurity E CRS in methanol R and dilute to50.0mL with the same of solvent.
Reference solution(b).Dilute2.0mL of reference solution(a) to100.0mL with methanol R.
Reference solution(c).Mix1.0mL of the test solution and
10mL of reference solution(a)and dilute to50.0mL with methanol R.
Column:
—size:l=0.1m,Ø=4.0mm,
—stationary phase:silica gel AGP for chiral chromatography R (5μm).
Mobile phase:
—mobile phase A:1.0g/L solution of potassium dihydrogen phosphate R adjusted to pH4.7with dilute sodium
hydroxide solution R;
—mobile phase B:acetonitrile R;
Time (min)Mobile phase A
(per cent V/V)
Mobile phase B
(per cent V/V)
0-480→6020→40
4-66040 Equilibration after installation of the column for use:using water R,slowly increase the flow rate from0.2mL/min to 0.5mL/min.Maintain the flow rate at0.5mL/min for5min. The column must be washed for1h at a flow rate of1mL/min with water R and for1h with the mobile phase at the initial composition prior to the1st analysis.
Flow rate:1.0mL/min.
Detection:spectrophotometer at240nm.
Injection:10μL of the test solution and reference solutions(b) and(c).
Retention time:repaglinide=about3.3min;
impurity E=about5.0min.
System suitability:reference solution(c):
—resolution:minimum1.5between the peaks due to repaglinide and impurity E.Limit:
—impurity E:not more than the area of the principal peak in the chromatogram obtained with reference solution(b)
(0.2per cent).
Related substances.Liquid chromatography(2.2.29).
Test solution.Dissolve30.0mg of the substance to be examined in acetonitrile R and dilute to10.0mL with the same solvent. Reference solution(a).Dilute5.0mL of the test solution to 100.0mL with acetonitrile R.Dilute2.0mL of this solution to 100.0mL with acetonitrile R.
Reference solution(b).With the aid of an ultrasonic bath, dissolve the contents of1vial of repaglinide for system suitability CRS in2.0mL of acetonitrile R.
Column:
—size:l=0.15m,Ø=4.6mm,
—stationary phase:silica gel for chromatography, alkyl-bonded for use with highly aqueous mobile phases R (5μm),
—temperature:45°C.
Mobile phase:
—mobile phase A:4.0g/L solution of potassium dihydrogen phosphate R adjusted to pH3.2with dilute phosphoric
acid R;
—mobile phase B:mobile phase A,acetonitrile R (300:700V/V);
Time
(min)
Mobile phase A
(per cent V/V)
Mobile phase B
(per cent V/V) 0-2050→750→93
20-30793
Flow rate:1.5mL/min.
Detection:spectrophotometer at240nm.
Injection:10μL.
Relative retention with reference to repaglinide
(retention time=about10min):impurity A=about0.2; impurity B=about0.3;impurity C=about0.4;
impurity D=about1.5.
System suitability:reference solution(b):
—resolution:minimum5.0between the peaks due to impurity B and impurity C,
—the chromatogram obtained is similar to the chromatogram supplied with repaglinide for system suitability CRS. Limits:
—correction factors:for the calculation of contents, multiply the peak areas of the following impurities by
the corresponding correction factor:impurity A=0.6;
impurity B=0.7;impurity C=3.1;
—impurities A,B,C,D:for each impurity,not more than the area of the principal peak in the chromatogram obtained
with reference solution(a)(0.1per cent);
—any other impurity:for each impurity,not more than the area of the principal peak in the chromatogram obtained
with reference solution(a)(0.1per cent);
—total:not more than5times the area of the principal peak in the chromatogram obtained with reference solution(a)
(0.5per cent);
—disregard limit:0.5times the area of the principal peak in the chromatogram obtained with reference solution(a)
(0.05per cent).
Loss on drying(2.2.32):maximum0.5per cent,determined on 1.000g by drying in an oven at105°C.
Sulfated ash(2.4.14):maximum0.1per cent,determined on 1.0g.
2848See the information section on general monographs(cover pages)
EUROPEAN PHARMACOPOEIA 7.0
Reserpine ASSAY Dissolve 0.320g in 10mL methanol R and add 60mL of anhydrous acetic acid R .Titrate with 0.1M perchloric acid ,determining the end-point potentiometrically (2.2.20).1mL of 0.1M perchloric acid is equivalent to 45.26mg of C 27H 36N 2O 4.STORAGE Protected from light.IMPURITIES Specified impurities:A,B,C,D,
E.A.R =H:4-(carboxymethyl)-2-ethoxybenzoic acid,B.R =C 2H 5:[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic
acid,C.(1S
)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butan-1-amine,D.ethyl 2-ethoxy-4-[2-[[(1S )-3-methyl-1-[2-(piperidin-1-
yl)phenyl]butyl]amino]-2-oxoethyl]benzoate,E.2-ethoxy-4-[2-[[(1R )-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid.01/2008:0528RESERPINE
Reserpinum C 33H 40N 2O 9M r 609[50-55-5]DEFINITION Methyl 11,17α-dimethoxy-18β-[(3,4,5-trimethoxy-benzoyl)oxy]-3β,20α-yohimban-16β-carboxylate.Content :—reserpine :98.0per cent to 102.0per cent (dried substance),—total
alkaloids :99.0per cent to 101.0per cent (dried substance).CHARACTERS
Appearance
:white or slightly yellow,small crystals or crystalline powder,darkening slowly on exposure to light.
Solubility :practically insoluble in water,very slightly soluble in ethanol (96per cent).IDENTIFICATION
First identification:B .
Second identification:A,C,D,E .
A.Ultraviolet and visible absorption spectrophotometry
(2.2.25).Test solution .Dissolve 20.0mg in chloroform R and dilute
to 10.0mL with the same solvent.Dilute 1.0mL of this
solution to 100.0mL with ethanol (96per cent)R .Examine immediately.
Spectral range :230-350nm.
Absorption maximum :at 268nm.
Specific absorbance at the absorption maximum :265to
285.Over the range
288-295
nm,the
curve
shows
a slight absorption minimum followed by a shoulder or a slight
absorption maximum;over this range,the specific absorbance is about 170.
B.Infrared absorption spectrophotometry (2.2.24).
Preparation :discs.
Comparison :reserpine CRS .
C.To about 1mg add 0.1mL of a 1g/L solution of sodium molybdate R in sulfuric acid R .A yellow colour is produced
which becomes blue within 2min.D.To about 1mg add 0.2mL of a freshly prepared 10g/L solution of vanillin R in hydrochloric acid R .A pink colour
develops within 2min.E.Mix about 0.5mg with 5mg of dimethylaminobenz-aldehyde R and 0.2mL of glacial acetic
acid
R and add
0.2mL of sulfuric acid R .A green colour is produced.Add
1mL of glacial acetic acid R .The colour becomes red.TESTS
Specific optical rotation (2.2.7):−116to −128(dried substance).
Dissolve 0.250g in chloroform R and dilute to 25.0
mL with
the same solvent.Examine immediately.Oxidation products .Dissolve 20mg in glacial acetic acid R
and dilute to 100.0mL with the same acid.The absorbance (
2.2.25)measured immediately at the absorption maximum at
388nm is not greater than 0.10.Loss on drying (2.2.32):maximum 0.5per cent,determined on
0.500g by drying at 60°C over diphosphorus pentoxide R at a pressure not exceeding 667Pa for 3h.
Sulfated ash (2.4.14):maximum 0.1per cent,determined on
0.5g.ASSAY
Total alkaloids .Dissolve 0.500g in a mixture of 6mL
of acetic anhydride
R and 40mL
of anhydrous acetic acid R .
Titrate with 0.1M perchloric acid ,determining the end-point potentiometrically (2.2.20).1mL of 0.1M perchloric acid is equivalent to 60.9mg of total alkaloids.Reserpine .Protect the solutions from light .Moisten 25.0mg
with 2mL of ethanol (96per cent)R ,add 2mL of 0.25M sulfuric acid and 10mL of ethanol (96per cent)R ,and warm
gently to dissolve.Cool and dilute to 100.0mL with ethanol (96per cent)R .Dilute 5.0mL of this solution to 50.0mL with ethanol (96per cent)R .Prepare a reference solution in the General Notices (1)apply to all monographs and other texts 2849。