Ranitidine

Chemical Name

N12-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyThN'-methyl-2-nitro-1,1- ethenediamine

Other Name

Zantac

Form Molecular Formula MW CAS

Ranitidine C13H22N403S 314.4 66357-35-5
Ranitidine hydrochloride C13H22N403S.HC1 350.9 66357-59-3

Appearance

Ranitidine hydrochloride is a white to pale yellow granular substance.

Solubility

Ranitidine hydrochloride has solubilities of 660 mg/mL in water and 190 mg/mL in alcohol.

PKa

Ranitidine has pKa values of 2.7 and 8.2.

Method 1

Munro and Walker developed an isocratic HPLC method for ranitidine analysis. The Thermo Separations
liquid chromatograph consisted of a model SCM1000 degasser, a model P4000 quaternary pump, a model
AS3000 variable-loop autosampler, and a model UV6000 photodiode-array detector. The stationary phase
was a YMC-Pack ODS-AM column (150 x 4.6 mm, 5-gm particle size) with a YMC guard column (20 x 4.0
mm, 5-gm particle size). The column temperature was 35 C. The mobile phase consisted of 57% buffer
solution and 43% methanol, where the buffer contained 10 mM sodium dodecyl sulfate and 50 mM
phosphoric acid, adjusted to pH 6.8 with triethylamine. The flow rate was 1.0 mL/min. UV detection was
228 nm. The injection volume was 25 gL. Under these conditions, the retention time of ranitidine was 5.5
minutes.

The method was demonstrated to be stability indicating by accelerated degradation. Ranitidine samples were
degraded in 1.0 M hydrochloric acid or 1.0 M sodium hydroxide solution for 1 day, were degraded in 1.0%
hydrogen peroxide for 4 hours, were heated in a 105 C oven for 7 days, or were exposed to 500-W UV light
for 30 days. Ranitidine was separated from all its degradation products.

A calibration curve for ranitidine was generated from 0.056 to 44.4 gg/mL. The correlation coefficient was
greater than 0.9996. The limit of detection was 0.028 sg/g. The limit of quantitation was 0.056 p.g/g.

Reference

Munro JS, Walker TA. Ranitidine hydrochloride: Development of an isocratic stability-indicating high-
performance liquid chromatographic separation. J Chromatogr A. 2001; 914: 13-21.
Method 2

Caufield and Stewart described an HPLC assay for the simultaneous analysis of meropenem and ranitidine in
intravenous fluid mixture. The instrument was a Hewlett-Packard model 1090 system including a pump, an
autosampler, and a Gilson model 117 variable-wavelength UV detector. A Waters model 996 photodiode-
array detector was used for the peak purity analysis. The stationary phase was a YMC ODS-AQ column (150
x 2.0 mm, 3-gm particle size). The mobile phase consisted of aqueous acetic acid solution (pH 3) and
acetonitrile (92:8, vol/vol). The flow rate was 0.2 mL/min. UV detection was performed at 317 nm.

Samples were diluted with the mobile phase. The sample injection volume was 5 !IL. Under these
conditions, retention times of ranitidine and meropenedwere about 4.7 and 7.7 minutes, respectively.

The method was evaluated to be stability indicating by accelerated degradation of ranitidine. Solutions of
ranitidine were treated with 0.1 N hydrochloric acid for 15 minutes, with 0.01 N sodium hydroxide solution
for 2 minutes, or with 0.03% hydrogen peroxide for 1.75 hours or were heated at 60 C for 4 hours. None of
the degradation product peaks interfered with the intact drug peak.

A standard curve for ranitidine was constructed from 131.25 to 525 gg/mL. The correlation coefficient was
0.9996-1.0. Intraday and interday coefficients of variation were 0.63 and 0.93%, respectively. The limit of
detection was 131 ng/mL.

Reference

Caufield WV, Stewart JT. HPLC separations of meropenem and selected pharmaceuticals using a polar
endcapped octadecylsilane naitow bore column. Chromatographia. 2000; 51: 308-14.

Method 3

Using an HPLC method, Nahata et al. investigated the stability of ranitidine hydrochloride in water for
injection in glass vials and plastic syringes. A Hewlett-Packard series 1050 liquid chromatograph included a
solvent-delivery pump, an autosampler, a variable-wavelength UV detector, and a Hewlett-Packard 3396A
integrator. The stationary phase was a Waters pBondapak Cig column (300 x 3.9 mm, 10-pm particle size).
The mobile phase was a mixture of acetonitrile and 0.1 M ammonium phosphate buffer. The pH of the
mobile phase was adjusted to 3.0 with phosphoric acid. The flow rate was 1.5 mL/min. UV detection was
performed at 228 nm. The autosampler vials were at 10 C whereas the analytical column remained at room
temperature. Caffeine 1 mg/mL was used as an internal standard.

Samples were diluted 1:10 with water. One hundred microliter portions of this dilution were mixed with 100
1.1.1, of the internal standard before analysis. The injection volume was 10 p.L. Under these conditions,
retention times for ranitidine and caffeine were 3.8 and 7.8 minutes, respectively.

To determine the stability-indicating nature of the assay, 1 mL of ranitidine 1 mg/mL was mixed with 1 mL
of 1.0 M sodium hydroxide and 1.0 M hydrochloric acid for 1 hour. Chromatograms of these solutions
showed that the quantification of the peak area of the intact ranitidine was not affected by the peaks of
degradation products.

A standard curve was generated for ranitidine from 0.25 to 3.50 mg/mL. Its linearity was determined by
linear regression analysis of the ranitidine concentration versus peak area ratios of ranitidine and caffeine.
The correlation coefficient was greater than 0.999. The intraday and interday coefficients of variation of the
assay were less than 2%.
Reference

Nahata MC, Morosco RS, Fox J. Stability of ranitidine hydrochloride in water for
injection in glass vials and plastic syringes. Am .1 Health Syst Pharm. 1996; 53: 1588-90.

Method 4

Inagaki et al. studied the stability of ranitidine hydrochloride with cefmetazole sodium during simulated Y-
site administration. The liquid chromatographic system consisted of a Hitachi model 6200 intelligent pump,
a Hitachi model L-4200 UV-visible detector, a Hitachi model AS-2000 autosampler, and a Hitachi model D-
2500 chromato-integrator.

The stationary phase was an Alltech Adsorbosphere C18 analytical column (250 x 4.6 mm, 5-gm particle
size) with a guard column of the same packing material. The mobile phase was a mixture of methanol and
0.1 M ammonium acetate (65:35, voUvol) and was delivered isocratically at 1.0 mL/min. UV detection was
performed at 322 nm and 0.128 AUFS.

Samples were diluted 1:20 with 0.9% sodium chloride injection. The injection volume was 50 pi. The
retention time for ranitidine was 6.5 minutes.

The assay was shown to be stability indicating by accelerated decomposition of ranitidine hydrochloride.
Solutions of the drug were degraded in 1 N hydrochloric acid,

1 N sodium hydroxide, and water for 10 hours at 80 C and in 1% hydrogen peroxide for

2 hours at room temperature. Solutions were also exposed to UV radiation for 20 hours at room temperature.
The resultant solutions were assayed by HPLC. Degradation product peaks did not interfere with the intact
ranitidine and cefmetazole peaks.

Standard curves were constructed from a linear plot of the peak area against the concentration from 0.05 to
1.0 mg/mL. The correlation coefficient was greater than 0.999.

A similar method was used by Crowther et al.

References

fnagaki K, Gill MA, Okamoto MP, et al. Chemical compatibility of cefmetazole sodium with ranitidine
hydrochloride during simulated Y-site administration. J Parenter Sci Technol. 1993; 47: 35-9.

Crowther RS, Bellanger R, Szauter KEM. In vitro stability of ranitidine hydrochloride in enteral nutrient
formulas. Ann Pharmacother. 1995; 29: 859-62.

Inagaki K, Gill MA, Okamoto MP, et al. Stability of ranitidine hydrochloride with aztreonam, ceftazidime,
or piperacillin sodium during simulated Y-site administration. Am J Hosp Pharm. 1992; 49: 2769-72.

Method 5

Williams et al. evaluated the stability of ranitidine hydrochloride in total parenteral nutrient mixtures. The
liquid chromatograph consisted of a Waters 6000A solvent-delivery system, a Waters Lambda-Max model
480 variable-wavelength UV detector, a Shimadzu SIL-6A autoinjector, a Shimadzu C-R3A Chromatopac
integrator, and a Chromanetics Scientific Spherisorb ODS-1 reversed phase analytical column (250 x 4.6
mm, 5-gm particle size) with an Applied Biosystems Brownlee NewGuard RP18 ODS guard column (1.5-cm
cartridge, 7-gm particle size). The mobile phase consisted of 24% 0.05 M sodium dibasic phosphate buffer at
pH 6 and 76% methanol. The flow rate was 1.0 mL/min. UV detection was performed at 228 nm and 0.005
AUFS. N43-[[3- (Dimethylamino)-methyl]phenoxy]propy1]-N' -methy1-2-nitro-1,1-ethenediamine
hydrochloride 1 mg/mL was used as an internal standard.

Ranitidine was extracted from the admixture witLchloroformmethanol (1:1, voUvol). The injection volume
was 25 p.L. Under these conditions, retention times for ranitidine and the internal standard were 5.8 and 8.9
minutes, respectively.

The assay was determined to be stability indicating by accelerated degradation of ranitidine hydrochloride.
Ranitidine hydrochloride solutions in deionized water, 1 N hydrochloric acid, and 1 N sodium hydroxide
were incubated at 70 C for 18 hours. In all cases, degradation product peaks did not interfere with the
ranitidine peak.

The interday coefficient of variation was 3.3%.

Reference

Williams MF, Hak LJ, Dukes G. In vitro evaluation of the stability of ranitidine
hydrochloride in total parenteral nutrient mixtures. Am J Hosp Pharm. 1990; 47: 1574-9.

Method 6

Stewart et al. used an HPLC method to evaluate the stability of ranitidine hydrochloride in intravenous
admixtures stored frozen, refrigerated, and at room temperature. The chromatograph consisted of a Beckman
model 110A pump, a Waters WISP autosampler, a Kratos model 757 UV detector, a Waters model 990
diode-array UV detector, and a Hewlett-Packard model 3392A integrator. The stationary phase was a
Keystone Spherisorb ODS 1 column (200 x 4.6 mm, 10-pm particle size). The mobile phase consisted of
methanol and 0.1 M aqueous ammonium acetate (85:15, vol/vol). The flow rate was 1.5 mL/min. UV
detection was performed at 322 nm. Samples were diluted to a ranitidine concentration of 0.1 mg/mL with
the mobile phase. The injection volume was 10 gL.

The stability-indicating capability of the method was demonstrated by accelerated decomposition of

ranitidine hydrochloride. Solutions of ranitidine hydrochloride 0.5 mg/mL were degraded in 1 N
hydrochloric acid and 1 N sodium hydroxide for 6 hours at 80 C. The purity of the ranitidine peak was
examined with a diode-array UV detector. Degradation product peaks did not interfere with the intact
ranitidine peak.

References

Stewart JT, Warren FW, Johnson SM, et al. Stability of ranitidine-in intravenous admixtures stored frozen,
refrigerated, and at room temperature. Am J Hosp Pharm. 1990; 47: 2043-6.

Galante LJ, Stewart JT, Warren FW, et al. Stability of ranitidine hydrochloride at dilute concentration in
intravenous infusion fluids at room temperature. Am J Hosp Pharm. 1990; 47: 1580-4.

Galante LJ, Stewart JT, Warren FW, et al. Stability of ranitidine hydrochloride with eight medications in
intravenous admixtures. Am J Hosp Pharm. 1990; 47: 1606-10.
Method 7

Cano et al. assessed the stability of ranitidine hydrochloride in total nutrient admixtures. A Perkin-Elmer
series 4 set high-performance liquid chromatograph was equipped with a 6-4 Rheodyne type injector, an LC-
85B UV detector, a Perkin-Elmer Sigma 15 integrator, and a 3-cm-long Perkin-Elmer HS-3 C18 column. The
mobile phase was a mixture of water, acetonitrile, and 5% ammonium hydroxide in isopropyl alcohol
(83:10:7, vol/vol/vol) that was delivered isocratically at 1 mL/min. UV detection was performed at 228 nm.
Cimetidine 200 pg/mL was used as an internal standard.

One milliliter of ranitidine hydrochloride sample was mixed with 1 mL of chloroformmethanol (1:1,
vol/vol) and 200 gL of the internal standard, vortexed for 5 minutes, and then centrifuged at 2500 x g for 5
minutes. The aqueous phase was filtered through a 0.45-pm Millipore HU filter. The injection volume was 6
pl.

To demonstrate that the method was stability indicating, ranitidine hydrochloride solutions 1 mg/mL in
water, 1 N hydrochloric acid, and 1 N sodium hydroxide were heated at 85 C for 10 hours. Another
ranitidine hydrochloride solution 1 mg/mL was exposed to UV radiation for 4 hours at room temperature. In
all cases, the degradation product peaks did not interfere with the intact ranitidine peak.

A standard curve for ranitidine hydrochloride was constructed from 10 to 200 g/mL.

Reference

Cano SM, Montoro JB, Pastor C, et al. Stability of ranitidine hydrochloride in total nutrient admixtures. Am J
Hosp Pharm. 1988; 45: 1100-2.

Method 8

Gupta et al. determined the chemical stabilities of famotidine and ranitidine hydrochloride in intravenous
admixtures using HPLC methods. The chromatographic system consisted of a Waters ALC 202 system, a
Schoeffel SF 770 multiple-wavelength detector, and a Houston Omniscribe recorder. The stationary phase
was a Waters pondapak C18 nonpolar column (300 x 3.9 mm). The mobile phase consisted of 10% methanol,
7% acetonitrile in 0.01 M aqueous phosphate buffer with the pH adjusted to 5.85 with either 0.1 N sodium
hydroxide or 0.1 N hydrochloric acid. The flow rate was 2.0 mL/min. UV detection was performed at 262
nm and 0.04 AUFS. Caffeine was used as an internal standard.

Samples were diluted 1:10 with water. The injection volume was 20 Under

these conditions, retention times for ranitidine and the internal standard were about 4.5 and 6.5 minutes,
respectively (estimated from the published chromatogram).

The analytical method was demonstrated to be stability indicating by accelerated decomposition of ranitidine
hydrochloride. Stock solutions of ranitidine hydrochloride were mixed with either 1 N sulfuric acid or 1 N
sodium hydroxide and were then boiled for about 15 minutes. Degradation product peaks did not interfere
with the intact ranitidine peak.

Reference

Gupta VD, Parasrampuria J, Bethea C. Chemical stabilities of famotidine and ranitidine hydrochloride in
intravenous admixtures. J Clin Pharm Ther. 1988; 13: 329-34.
Method 9

Lampasona et al. studied the stability of ranitidine hydrochloride admixtures frozen and refrigerated in
minibags. The chromatograph consisted of a Perkin-Elmer 4B HPLC pump, a Valco six-port injector, a
Perkin-Elmer LC 75 variable-wavelength UV detector, and a Waters C18 Nova-Pak radial compression
cartridge. The mobile phase contained 184 mL of 0.1 M monobasic potassium phosphate, 5 mM
pentanesulfonic acid, and 240 mL of acetonitrile in a final volume of 2 L in deionized water. The mobile
phase was adjusted to pH 6.3 with 1 N potassium hydroxide. The flow rate was 1.5 mL/min. UV detection
was performed at 228 nm and 0.16 AUFS. Caffeine was used as the internal standard.

Samples were diluted 1:10 with deionized water. The injection volume was 60 p.L. Under these conditions,
retention times for caffeine and ranitidine were about 5.8 and 7.3 minutes, respectively (estimated from the
published chromatogram).

The stability-indicating nature of the assay was shown by accelerated decomposition of ranitidine. Solutions
of ranitidine hydrochloride 1 mg/mL in water, 1 N hydrochloric acid, and 1 N sodium hydroxide were heated
at 90 C for 10 hours. Another solution of ranitidine hydrochloride 1 mg/mL in 1% hydrogen peroxide was
exposed to UV radiation at 21 C for 4 hours. In all cases, the intact ranitidine peak was well separated from
its degradation product peaks.

A standard curve for ranitidine was generated from 0.25 to 2.50 mg/mL. The interday coefficient of variation
was 3.3%.

References

Lampasona V, Mullins RE, Parks RB. Stability of ranitidine admixtures frozen and refrigerated in minibags.
Am J Hosp Pharm. 1986; 43: 921-5.

L, Parks RB, Lampasona V, et al. Stability of ranitidine hydrochloride and aminoacids in parenteral nutrient
solutions. Am J Hosp Pharm. 1985; 42: 2683-7.

Method 10

Walker et al. determined the stability of ranitidine hydrochloride in a total parenteral nutrient solution. The
liquid chromatograph consisted of a Spectra-Physics model SP8700 solvent-delivery system, a Waters model
710B WISP autosampler, a Schoeffel SF 770 variable-wavelength UV detector, and a Spectra-Physics model
SP4270 integrator. The stationary phase was a Brownlee C2 reversed phase column (10-gm particle size).
The mobile phase consisted of acetonitrile and 0.5 M potassium phosphate buffer (34:66, vol/vol) at pH 6.8.
The flow rate was 2.0 mL/min. UV detection was performed at 235 nm.

Two hundred microliters of ranitidine hydrochloride samples were mixed with 100 gL of the internal
standard solution (n-propyl p-hydroxybenzoate 275 gg/mL) and then diluted with 4.0 mL of water. The
injection volume was 200 FL.

The method was determined to be stability indicating by accelerated decomposition of ranitidine

hydrochoride. Ranitidine hydrochloride was exposed to 6 M hydrochloric acid and 6 M sodium hydroxide at
60 C for 18 hours. Degradation product peaks did not interfere with the intact ranitidine peak.

A similar method was used by Sarkar et al.

References

Sarkar MA, Rogers E, Reinhard M, et al. Stability of clindamycin phosphate, ranitidine, hydrochloride, and
piperacillin sodium in polyolefin containers. Am J Hosp Pharm. 1991; 48: 2184-6.

SE, Kirby K. Stability of ranitidine hydrochloride admixtures refrigerated in polyvinyl chloride minibags.
Can J Hosp Pharm. 1988; 41: 105-8.