Levomenthol EUROPEAN PHARMACOPOEIA 11.

STORAGE
Protected from light.

IMPURITIES
Specified impurities : A, B, F.
Other detectable impurities (the following substances would, F. (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-
if present at a sufficient level, be detected by one or other of pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid,
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical
use (2034). It is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use) : C,
D, E, G, H, I.

G. (3S)-9-fluoro-3-methyl-10-[[2-(methylamino)ethyl]-
amino]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-
benzoxazine-6-carboxylic acid,

A. (3R)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-
oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-
carboxylic acid (enantiomer of levofloxacin),
H. ethyl (3S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-
7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-
6-carboxylate,

B. (3S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-2,3-
dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic
acid, I. (3S)-10-fluoro-3-methyl-9-(4-methylpiperazin-1-yl)-7-
oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-
carboxylic acid.

01/2008:0619

C. 4-[(3S)-6-carboxy-9-fluoro-3-methyl-7-oxo-2,3- LEVOMENTHOL
dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl]-1-
methylpiperazine 1-oxide, Levomentholum

C10H20O Mr 156.3
[2216-51-5]
D. (3S)-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3- DEFINITION
dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic (1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexanol.
acid,
CHARACTERS
Appearance : prismatic or acicular, colourless, shiny crystals.
Solubility : practically insoluble in water, very soluble in
ethanol (96 per cent) and in light petroleum, freely soluble in
fatty oils and in liquid paraffin, very slightly soluble in glycerol.
mp : about 43 °C.
IDENTIFICATION
E. (3S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2,3- First identification : A, C.
dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazin-7-one, Second identification : B, D.

3228 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 11.0 Levomepromazine hydrochloride

A. Specific optical rotation (see Tests). – stationary phase : diatomaceous earth for gas
B. Thin-layer chromatography (2.2.27). chromatography R impregnated with 15 per cent m/m of
macrogol 1500 R.
Test solution. Dissolve 25 mg of the substance to be
examined in methanol R and dilute to 5 mL with the same Carrier gas : nitrogen for chromatography R.
solvent. Flow rate : 30 mL/min.
Reference solution. Dissolve 25 mg of menthol CRS in Temperature :
methanol R and dilute to 5 mL with the same solvent. – column : 120 °C ;
Plate : TLC silica gel G plate R. – injection port : 150 °C ;
Mobile phase : ethyl acetate R, toluene R (5:95 V/V). – detector : 200 °C.
Detection : flame ionisation.
Application : 2 μL.
Injection : 1 μL.
Development : over a path of 15 cm.
Run time : twice the retention time of menthol.
Drying : in air, until the solvents have evaporated.
System suitability :
Detection : spray with anisaldehyde solution R and heat at – resolution : minimum 1.4 between the peaks due to menthol
100-105 °C for 5-10 min. and isomenthol in the chromatogram obtained with
Results : the principal spot in the chromatogram obtained reference solution (a);
with the test solution is similar in position, colour and size – signal-to-noise ratio : minimum 5 for the principal peak in
to the principal spot in the chromatogram obtained with the chromatogram obtained with reference solution (b).
the reference solution. Limits : test solution (a) :
C. Examine the chromatograms obtained in the test for – total : not more than 1 per cent of the area of the principal
related substances. peak ;
Results : the principal peak in the chromatogram obtained – disregard limit : 0.05 per cent of the area of the principal
with test solution (b) is similar in position and approximate peak.
dimensions to the principal peak in the chromatogram
obtained with reference solution (c). Residue on evaporation : maximum 0.05 per cent.
Evaporate 2.00 g on a water-bath and heat in an oven at
D. Dissolve 0.20 g in 0.5 mL of anhydrous pyridine R. Add 100-105 °C for 1 h. The residue weighs not more than 1.0 mg.
3 mL of a 150 g/L solution of dinitrobenzoyl chloride R in
anhydrous pyridine R. Heat on a water-bath for 10 min. 04/2021:0505
Add 7.0 mL of water R in small quantities with stirring
and allow to stand in iced water for 30 min. A precipitate
is formed. Allow to stand and decant the supernatant.
Wash the precipitate with 2 quantities, each of 5 mL, of iced
water R, recrystallise from 10 mL of acetone R, wash with
iced acetone R and dry at 75 °C at a pressure not exceeding LEVOMEPROMAZINE
2.7 kPa for 30 min. The crystals melt (2.2.14) at 154 °C to HYDROCHLORIDE
157 °C.
TESTS Levomepromazini hydrochloridum
Solution S. Dissolve 2.50 g in 10 mL of ethanol (96 per cent) R
and dilute to 25.0 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and
colourless (2.2.2, Method II).
Acidity or alkalinity. Dissolve 1.0 g in ethanol (96 per cent) R
and dilute to 10 mL with the same solvent. Add 0.1 mL of
phenolphthalein solution R. The solution is colourless. Not C19H25ClN2OS Mr 364.9
more than 0.5 mL of 0.01 M sodium hydroxide is required to [1236-99-3]
change the colour of the indicator to pink.
Specific optical rotation (2.2.7) : − 48 to − 51, determined DEFINITION
on solution S. (2R)-3-(2-Methoxy-10H-phenothiazin-10-yl)-N,N,2-
Related substances. Gas chromatography (2.2.28). trimethylpropan-1-amine hydrochloride.
Content : 98.5 per cent to 101.0 per cent (dried substance).
Test solution (a). Dissolve 0.20 g of the substance to be
examined in methylene chloride R and dilute to 50.0 mL with CHARACTERS
the same solvent. Appearance : white or very slightly yellow, crystalline powder,
Test solution (b). Dilute 1.0 mL of test solution (a) to 10.0 mL slightly hygroscopic.
with methylene chloride R. Solubility : freely soluble in water and in ethanol (96 per cent).
Reference solution (a). Dissolve 40.0 mg of the substance to be It deteriorates when exposed to air and light.
examined and 40.0 mg of isomenthol R in methylene chloride R It shows polymorphism (5.9). It exists in 2 forms, one melting
and dilute to 100.0 mL with the same solvent. at about 142 °C and the other at about 162 °C.
Reference solution (b). Dilute 0.10 mL of test solution (a) to
100.0 mL with methylene chloride R. IDENTIFICATION
A. Ultraviolet and visible absorption spectrophotometry
Reference solution (c). Dissolve 40.0 mg of menthol CRS in
(2.2.25). Prepare the solution protected from bright light
methylene chloride R and dilute to 100.0 mL with the same
and carry out the measurements immediately.
solvent.
Test solution. Dissolve 50.0 mg in water R and dilute to
Column : 500.0 mL with the same solvent. Dilute 10.0 mL of the
– material : glass ; solution to 100.0 mL with water R.
– size : l = 2.0 m, Ø = 2 mm ; Spectral range : 230-340 nm.

General Notices (1) apply to all monographs and other texts 3229