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3578 Ramipril / Official Monographs USP 41

ADDITIONAL REQUIREMENTS Residue on ignition 〈281〉: not more than 0.1%.

• PACKAGING AND STORAGE: Preserve in well-closed contain- Chromatographic purity—
ers, and store at controlled room temperature. Diluent, Mobile phase, Resolution solution, and Chromato-
• USP REFERENCE STANDARDS 〈11〉 graphic system—Proceed as directed in the Assay.
USP Ramipril RS
USP Ramipril Related Compound A RS Standard solution—Prepare as directed for Standard prepa-
(2S,3aS,6aS)-1-[(S)2-[[(S)-1-(Methoxycarbonyl)- ration in the Assay.
3-phenylpropyl]amino]-1-oxopropyl]-octahydro- Test solution—Prepare as directed for Assay preparation in
cyclopenta[b]pyrrole-2-carboxylic acid. the Assay.
C22H30N2O5 402.48 Procedure—Separately inject equal volumes (about 10 µL)
USP Ramipril Related Compound D RS of the Standard solution and the Test solution into the chro-
Ethyl (2S)2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-diox- matograph, record the chromatograms, and identify the
odecahydro-1H-cyclopenta[e]pyrrolo[1,2-a]pyrazin- ranitidine peak and the peaks due to impurities and degra-
2-yl]-4-phenyl-butanoate. dation products listed in the table below.
C23H30N2O4 398.50
Name Retention Time
Ranitidine simple nitroacetamide1 . 0.14
Ranitidine oxime2 0.21
Ranitidine Hydrochloride

Ranitidine amino alcohol3 . 0.45

Ranitidine diamine4 . 0.57
Ranitidine S-oxide5 . 0.64
Ranitidine N-oxide6 . 0.72
Ranitidine complex nitroacetamide7 . 0.84
C13H22N4O3S · HCl 350.86 Ranitidine formaldehyde adduct8 . 1.36
1,1-Ethenediamine, N-[2-[[[5-[(dimethylamino)methyl]- Ranitidine bis-compound9 . 1.75
2-furanyl]-methyl]thio]ethyl]-N′-methyl-2-nitro-, 1 N-Methyl-2-nitroacetamide.

2 3-(Methylamino)-5,6-dihydro-2H-1,4-thiazin-2-one oxime.

3 {5-[(Dimethylamino)methyl]furan-2-yl}methanol.

4 5-{[(2-Aminoethyl)thio]methyl}-N,N-dimethyl-2-furanmethanamine (rani-
ethenediamine, hydrochloride [66357-59-3]. .

tidine related compound A).

» Ranitidine Hydrochloride contains not less 5 N-{2-[({5-[(Dimethylamino)methyl]-2-furanyl}methyl)sulfinyl]ethyl}-N′-

methyl-2-nitro-1,1-ethenediamine (ranitidine related compound C).

than 97.5 percent and not more than 102.0 per- 6 N,N-Dimethyl(5-{[(2-{[1-(methylamino)-2-nitroethenyl]amino}ethyl)

cent of C13H22N4O3S · HCl, calculated on the


sulphanyl]methyl}furan-2-yl)methanamine N-oxide.
USP Monographs

dried basis. 7 N-{2-[({5-[(Dimethylamino)methyl]furan-2-yl}methyl)sulphanyl]ethyl}-2-ni-


Packaging and storage—Preserve in tight, light-resistant 8 2,2′-Methylenebis(N-{2-[({5-[(dimethylamino)methyl]furan-2-yl}methyl)-

containers. sulphanyl]ethyl}-N′-methyl-2-nitroethene-1,1-diamine).
9 N,N′-bis{2-[({5-[(Dimethylamino)methyl]-2-furanyl}methyl)thio]ethyl}-2-nitro-
USP Reference standards 〈11〉— .

1,1-ethenediamine (ranitidine related compound B).

USP Ranitidine Hydrochloride RS
USP Ranitidine Resolution Mixture RS Measure the responses for the major peaks, and calculate
It is a mixture of ranitidine hydrochloride and four re- the percentage of each impurity in the portion of Ranitidine
lated impurities: ranitidine-N-oxide, ranitidine complex Hydrochloride taken by the formula:
nitroacetamide, ranitidine diamine hemifumarate, and
ranitidine amino alcohol hemifumarate. 100CV/W(ri / rS)
Ranitidine-N-oxide: N,N-dimethyl[5-[[[2-[[1-(methyl-
amino)-2-nitroethenyl]amino]ethyl]sulphanyl]methyl] in which C is the concentration, in mg per mL, of ranitidine
furan-2-yl]methanamine N-oxide. hydrochloride in the Standard solution; V is the volume, in
Ranitidine complex nitroacetamide: N-[2-[[[5-[(dimethyl- mL, of the Test solution; W is the weight, in mg, of Rani-
amino)methyl]furan-2-yl]methyl]sulphanyl]ethyl]-2-ni- tidine Hydrochloride taken to prepare the Test solution; ri is
troacetamide. the peak response for each impurity obtained from the Test
Ranitidine diamine hemifumarate (related compound A): solution; and rS is the ranitidine peak response obtained from
5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl- the Standard solution: not more than 0.3% of ranitidine bis-
2-furanmethanamine, hemifumarate salt. compound is found, not more than 0.1% of any other sin-
Ranitidine amino alcohol hemifumarate: [5-[(dimethylami- gle impurity is found, and not more than 0.5% of total
no)methyl]furan-2-yl]methanol. impurities is found. The reporting level for impurities is
Identification— 0.05%.
A: Infrared Absorption 〈197M〉. Assay—
B: Ultraviolet Absorption 〈197U〉— Phosphate buffer—Place approximately 1900 mL of water
Solution: 10 µg per mL. in a 2.0-L volumetric flask, accurately add 6.8 mL of phos-
phoric acid, and mix. Accurately add 8.6 mL of 50% sodium
Medium: water. hydroxide solution, and dilute with water to volume. If nec-
Absorptivities at 229 nm and 315 nm, calculated on the essary, adjust with 50% sodium hydroxide solution or phos-
dried basis, do not differ by more than 3.0%. phoric acid to a pH of 7.1, and filter.
C: A solution of it meets the requirements of the tests for Solution A—Prepare a mixture of Phosphate buffer and ac-
Chloride 〈191〉. etonitrile (98:2).
pH 〈791〉: between 4.5 and 6.0, in a solution (1 in 100). Solution B—Prepare a mixture of Phosphate buffer and ac-
Loss on drying 〈731〉—Dry it in vacuum at 60° for 3 hours: etonitrile (78:22).
it loses not more than 0.75% of its weight.

Official from May 1, 2018

Copyright (c) 2018 The United States Pharmacopeial Convention. All rights reserved.
Accessed from by Amneal on Wed Apr 18 03:42:42 EDT 2018

USP 41 Official Monographs / Ranitidine 3579

Mobile phase—Use variable mixtures of Solution A and So- Labeling—Label Injection to state both the content of the
lution B as directed for Chromatographic system. Make ad- active moiety and the content of the salt used in formulat-
justments if necessary (see System Suitability under Chroma- ing the article.
tography 〈621〉). USP Reference standards 〈11〉—
Diluent—Use Solution A. USP Ranitidine Hydrochloride RS
Standard preparation—Dissolve an accurately weighed USP Ranitidine Related Compound A RS
quantity of USP Ranitidine Hydrochloride RS in Diluent to 5-[[(2-Aminoethyl)thio]methyl]-N,N-dimethyl-
obtain a solution having a known concentration of about 2-furanmethanamine, hemifumarate salt.
0.125 mg of ranitidine hydrochloride per mL. USP Ranitidine Related Compound C RS
Resolution solution—Transfer about 1.3 mg of USP Rani- N-{2-[({5-[(Dimethylamino)methyl]-2-furanyl}methyl)
tidine Resolution Mixture RS to a 10-mL volumetric flask, sulfinyl]ethyl}-N′-methyl-2-nitro-1,1-ethenediamine.
and dissolve in and dilute with Diluent to volume. [NOTE— Identification—
USP Ranitidine Resolution Mixture RS contains ranitidine hy- A: The RF value of the principal spot observed in the
drochloride and four related impurities: ranitidine amino al- chromatogram of the Test preparation obtained as directed
cohol hemifumarate, ranitidine diamine hemifumarate, rani- in the Chromatographic purity test corresponds to that ob-
tidine N-oxide, and ranitidine complex nitroacetamide.] tained from the Standard preparation.
Assay preparation—Transfer about 25 mg of Ranitidine B: The retention time of the major peak in the chromato-
Hydrochloride, accurately weighed, to a 200-mL volumetric gram of the Assay preparation corresponds to that in the
flask. Dissolve in and dilute with Diluent to volume, and mix. chromatogram of the Standard preparation, as obtained in
Chromatographic system (see Chromatography 〈621〉)—The the Assay.
liquid chromatograph is equipped with a 230-nm detector Bacterial Endotoxins Test 〈85〉—It contains not more
and a 4.6-mm × 10-cm column containing 3.5-µm packing than 7.00 USP Endotoxin Units per mg of ranitidine.
L1 that is stable from pH 1 to 12. The flow rate is about pH 〈791〉: between 6.7 and 7.3.
1.5 mL per minute. The column temperature is maintained
at 35°. The chromatograph is programmed as follows. Particulate Matter in Injections 〈788〉: meets the re-
quirements under small-volume injections.
Chromatographic purity—
Time Solution A Solution B
(minutes) (%) (%) Elution Test preparation—Dilute Injection quantitatively with
water, if necessary, to obtain a solution containing 25 mg of
0–10 100→0 0→100 linear gradient
ranitidine per mL. [NOTE—Use Injection of lower concentra-
10–15 0 100 isocratic tion without dilution as directed under Procedure.]
15–16 0→100 100→0 linear gradient Standard preparation—Dissolve USP Ranitidine Hydrochlo-
16–20 100 0 re-equilibration ride RS in water to obtain a solution having a known con-
centration of 560 µg per mL. Dilute portions of this Stan-
Chromatograph the Resolution solution, and identify the dard preparation quantitatively with water to obtain
peaks using the table of impurities and degradation prod- solutions having concentrations of 280 µg per mL (Diluted
ucts (found above): the resolution, R, between the peaks for

USP Monographs
standard preparation A), 140 µg per mL (Diluted standard
ranitidine N-oxide and ranitidine complex nitroacetamide is preparation B), 84 µg per mL (Diluted standard preparation
not less than 1.5. Chromatograph the Standard preparation, C), 28 µg per mL (Diluted standard preparation D), and
and record the peak responses as directed for Procedure: the 14 µg per mL (Diluted standard preparation E), respectively.
relative standard deviation for replicate injections is not
more than 1.0%. Resolution preparation—Dissolve USP Ranitidine Related
Compound A RS in methanol to obtain a solution having a
Procedure—Separately inject equal volumes (about 10 µL) known concentration of 1.27 mg per mL.
of the Standard preparation and the Assay preparation into
the chromatograph, record the chromatograms, and meas- Procedure—Apply separately 10 µL of the Standard prepa-
ure the areas for the major peaks. Calculate the percentage ration, Diluted standard preparations A, B, C, D and E, and
of C13H22N4O3S · HCl in the portion of Ranitidine Hydrochlo- the required volume of the Test preparation, equivalent to
ride taken by the formula: 250 µg of ranitidine, to a suitable thin-layer chromato-
graphic plate (see Chromatography 〈621〉) coated with a
100(CS / CU)(rU / rS) 0.25-mm layer of chromatographic silica gel mixture. In ad-
dition, apply separately a further loading of the same vol-
in which CS and CU are the concentrations, in mg per mL, ume of the Test preparation to the same plate, and on top
of ranitidine hydrochloride in the Standard preparation and of this application, apply 10 µL of the Resolution preparation.
the Assay preparation, respectively; and rU and rS are the Allow the spots to dry, and develop the chromatograms in a
peak responses obtained from the Assay preparation and the solvent system consisting of a mixture of ethyl acetate, iso-
Standard preparation, respectively. propyl alcohol, ammonium hydroxide, and water
(25:15:5:1) until the solvent front has moved not less than
15 cm from the origin. Remove the plate from the develop-
ing chamber, mark the solvent front, and allow to air-dry.
Expose the plate to iodine vapors in a closed chamber until
the chromatogram is fully revealed. Examine the plate and
Ranitidine Injection

compare the intensities of any secondary spots observed in

the chromatogram of the Test preparation with those of the
» Ranitidine Injection is a sterile solution of Rani- principal spots in the chromatograms of the Standard prepa-
tidine Hydrochloride in Water for Injection. It ration and Diluted standard preparations (A, B, C, D, and E):
contains the equivalent of not less than 90.0 per- the system suitability requirements are met when there is
complete resolution between the primary spots of the Test
cent and not more than 110.0 percent of the la- preparation, and the Resolution preparation and if a spot is
beled amount of ranitidine (C13H22N4O3S). observed in the chromatogram of Diluted standard prepara-
tion E. The major secondary spot is not greater in size or
Packaging and storage—Preserve in single-dose or in intensity than the principal spot produced by the Standard
multiple-dose containers of Type I glass, protected from preparation (2.0%), and no other secondary spot is greater
light. Store below 30°. Do not freeze. in size or intensity than the principal spot produced by Di-
luted standard preparation A (1.0%). The sum of the intensi-

Official from May 1, 2018

Copyright (c) 2018 The United States Pharmacopeial Convention. All rights reserved.