Hindawi Publishing Corporation

ISRN Chromatography
Volume 2013, Article ID 484592, 7 pages
http://dx.doi.org/10.1155/2013/484592

Research Article
Determination of Ranitidine in Human Plasma by SPE and
ESI-LC-MS/MS for Use in Bioequivalence Studies

Karini B. Bellorio,1, 2 Maria Isabel R. Alves,1 and Nelson R. Antoniosi Filho1

1
Laboratório de Métodos de Extração e Separação (LAMES), Instituto de Química, Universidade Federal de Goiás,
Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil
2
Núcleo Integrado de Farmacocinética da Universidade Federal de Goiás e Instituto Melon de Estudos e Pesquisas/Instituto de Ciências
Farmacêuticas, CP 131, 74001-970 Goiânia, GO, Brazil

Correspondence should be addressed to Maria Isabel R. Alves; isaribeiroalves@yahoo.com.br

Received 9 November 2012; Accepted 16 December 2012

Academic Editors: J.-F. Jen, J. Millership, and A. Sanches Silva

Copyright © 2013 Karini B. Bellorio et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

A method for determining ranitidine in human plasma by ESI-LC-MS/MS was validated, using propranolol as internal standard.
e extraction method used was solid phase extraction (SPE). Chromatographic separation was performed in a Chromolith C18
(50 mm × 4.6 mm i.d.) analytical column, which provided good separation of ranitidine and propranolol peaks with an analysis
time of 2.5 minutes. Extraction yields of 94.4% for ranitidine and 89.4% for the internal standard were obtained. e lower limit
of quanti�cation (LLO�) was 3.00 ng/mL, and limit of detection (LOD) was 0.05 ng/mL, with linearity ranging from 3.00 to
500 ng/mL. e results, thus, showed that this method is suitable for application in bioequivalence studies of ranitidine in human
plasma.

1. Introduction and simple methods to determine drugs in biological matri-

ces has been intense. us, several methods for determining
e chemical structure of ranitidine hydrochloride (Figure ranitidine in human plasma have been reported. Zendelovska
1) consists of a �ve-membered furan heterocyclic ring and Sta�lov [4] developed a method for determining rani-
and a nitroethenodiaminic group. e molecular mass of tidine and cimetidine in human plasma using HPLC with a
ranitidine hydrochloride is 350.9 daltons (g/mol), and its diode array detector. In this study, the analysis time was 9
molecular formula is C13 H22 N4 O3 SHCl corresponding to minutes, with a 50.0 ng/mL limit of detection for ranitidine.
hydrochloride N[2-[[[5-[(dimethylamine)methyl)-2-furan] Famotidine was used as internal standard. In another study
methyl]thio]ethyl]-N′ -methyl-nitro2-1,1-ethenodiamine. using the same detector, an analysis time of 6.5 minutes was
Ranitidine hydrochloride appears as a crystalline powder, obtained in a C18 column (300 mm × 4.6 mm id, 5 𝜇𝜇m), with
practically odorless and white to light yellow. It is very a limit of quanti�cation of 20.0 ng/mL [5].
soluble in water, somewhat soluble in alcohol, and slightly Methods for analyzing ranitidine in plasma by LC-
soluble in chloroform. Furthermore, it should be stored in MS/MS have been reported in some studies [6–8]. e
hermetically sealed containers and protected from light [1]. limits of quanti�cation ranged from 1.0 ng/mL to 12.2 ng/mL.
Ranitidine is widely used in the treatment of gastric However, these methods use the protein precipitation pro-
pathologies, has a chemical structure that partially resembles cedure. is has the disadvantage of reducing the useful life
histamine, and acts primarily as a competitive histamine of the column due to the presence of compounds that are
inhibitor through the H2 receptors [2, 3]. not precipitates or that use liquid-liquid extraction, which
Since around two thousand analyses are conducted before requires large volumes of sample and has a higher limit of
bioequivalence studies can be concluded, the search for quick quanti�cation.
2 ISRN Chromatography

H resolution of 9.0, HM2 resolution 9.0, ion 2 energy 2.5,

CH3
O NH NO2 multiplier at 650 V, 0.5 s dwell time, and 0.1 s delay time.
N S
· HCl
CH3
NHCH3 2.3. Preparation of the Stock and Standard Solutions. e
stock solutions of ranitidine and propranolol were prepared
F 1: Chemical structure of ranitidine hydrochloride. at a concentration of 0.5 mg/mL in methanol : water
(50 : 50 v/v). ese solutions were used to prepare
working solutions of ranitidine at concentrations of
30.00, 50.00, 100.00, 500.00, 1000.00, 2000.00, 4000.00,
us, the object of this paper was to develop an ana- and 5000.00 ng/mL. e working solutions of propranolol
lytical methodology for determining ranitidine in human were also prepared from stock solutions (0.5 mg/mL) at a
plasma using the solid phase extraction (SPE) technique concentration of 2000 ng/mL. All solutions were placed in
and high performance liquid chromatography coupled to Falcon-type tubes. e tubes with the ranitidine solutions
mass spectrometry (HPLC-MS/MS) in order to develop a were protected from light with aluminum foil and stored
fast, highly speci�c, and repeatable methodology for use in in a freezer at −20∘ C. e other solutions were stored in a
pharmaceutical bioequivalence studies. refrigerator at +4∘ C and replaced daily.

2. Experimental 2.4. Sample Preparation. Plasma samples were thawed at

room temperature, homogenized by vortexing and cen-
2.1. Chemicals and Reagents. Ultrapure water generated by trifuged at 3400 rpm for 4 minutes to precipitate materials
the Millipore Milli-Q Gradient 10 ultrapuri�cation system suspended in the plasma. Waters Oasis 1-cc HLB solid phase
was used in all processes. HPLC-grade reagents were supplied extraction (SPE) cartridges and 30 mg of adsorbent were
by Merck. We used the (United Stated Pharmacopeia) USP used. ese cartridges were previously conditioned with 1 mL
reference standard for ranitidine hydrochloride (lot G) and of methanol and 1 mL of ultrapure water for activation of the
the Brazilian Pharmacopoeia primary standard for propra- drug binding sites.
nolol hydrochloride (lot 1005). More ever, 250 𝜇𝜇L of human plasma, 100 𝜇𝜇L of propra-
nolol, and 500 𝜇𝜇L of ultrapure water were added to the SPE.
e cartridge was then placed inside a clean test tube, and the
2.2. Instrumentation and Chromatographic Conditions. cartridge-test tube combination was centrifuged at 3400 rpm
Chromatographic analyses were performed on a Shimadzu for 4 minutes for plasma elution and retention of the drug
AD Vp HPLC (Shimadzu, Japan) coupled to a Quattro LC in the cartridge. Subsequently, the eluate was discarded, and
(MS-MS) triple quadrupole mass spectrometer (Micromass, the analytes were eluted with 1000 𝜇𝜇L of water : methanol
UK) equipped with Z-spray operated in electrospray solution (20 : 80 v/v) with 0.1% of formic acid.
positive (ES +) mode, with argon as the collision gas.
e system was controlled by MassLynx soware version
3.4 for Windows NT. e chromatographic conditions 2.5. Analytical Curve. e analytical curve was prepared
were determined using a Merck Chromolith C18 analytical at concentration levels of 3.00, 5.00, 10.00, 50.00, 100.00,
column (50 mm × 4.6 mm i.d.) with a �ow rate of 0.5 mL/min 200.00, 400.00, and 500.00 ng/mL of ranitidine. Also 250 𝜇𝜇L
for a mobile phase consisting of aqueous 0.1% formic acid of human plasma, 100 𝜇𝜇L of each of the ranitidine solutions,
solution : methanol (50 : 50 v/v pH = 3.8) pumped by 100 𝜇𝜇L of propranolol, and 400 𝜇𝜇L of ultrapure water were
a VDP-10A LC pump (Shimadzu, Japan), using a 1 : 2 added to the SPE. en, the sample preparation proce-
postcolumn split. Solvents were �rst placed in ultrasound dure was carried out. e sample quality controls (QCs)
for 3 minutes and then put through a DGU-14A degassing were prepared at concentrations of 3.00, 5.00, 200.0, and
system (Shimadzu, Japan). e system operated at pressures 400.00 ng/mL by spiking of blank plasma and the subsequent
between 100 and 120 bar. e column and autosampler were extraction process.
kept at a temperature of 20∘ C, and the injection volume was
20 𝜇𝜇L. 2.6. Extraction Recovery. e extraction method’s recovery
e Quattro LC mass spectrometer (MS-MS) operated was determined by comparing ranitidine peak areas in sam-
in positive electrospray ionization mode (ES +) and MRM ples that did not undergo the extraction process considering
dual-channel mode. e following parameters were used for the extraction yield to be 100% and ranitidine peak areas
the electrospray source: capillary voltage 3.00 kV, cone voltage in extracted samples at concentrations of 3.00, 5.00, 10.00,
25.00 V for ranitidine and 30.00 V for propranolol, extractor 50.00, 100.00, 200.00, 400.00, and 500.00 ng/mL. For the
voltage 3.00 V, RF lens voltage 0.2 V, source temperature internal standard, the extraction yield of replicates at a
150∘ C, cone gas �ow 0.0 L/h, and desolvation gas �ow concentration of 200.00 ng/mL was determined.
439 L/h. e following conditions were established for the
quadrupoles of the Quattro LC mass spectrometer: LM1 2.7. Precision and Accuracy. e accuracy and precision of
resolution of 13.0, HM1 resolution of 13.0, ion 1 energy 0.2, the method were determined by the extraction of eight sam-
second hexapole input 5.0 V, collision energy at 25.00 eV for ples containing the internal standard and the ranitidine ana-
ranitidine and 17.00 eV for propranolol, 5.0 output, LM2 lyte at concentrations 3.00, 5.00, 200.00, and 400.00 ng/mL,
ISRN Chromatography 3

which were analyzed in replicates. is procedure was carried Ranitidine 200 ng/mL SPE MRM of 2 channels ES +
out intraday and between-day. e approval criterion for 052001VA
315.1 > 129.9
1.66 1.52 5
relative standard deviation (RSD) was 15%. 100 36222 Area
Ranitidine

(%)
2.8. Stability. Stability studies of ranitidine in plasma were
performed under three conditions. First, stability was eval- 0
uated in three freezing cycles over 24 h at −20∘ C, followed 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
by thawing. Subsequently, we evaluated the stability of Time
ranitidine which was kept at room temperature for eight (a)
hours. Long-term stability was evaluated over a forty-day
MRM of 2 channels ES +
storage period. e acceptance criteria were a deviation from 052001VA
260.2 > 116.1
nominal concentration that was less than or equal to 15% and 100 2.13
38160 1.66 5
Propranolol
precision and accuracy less than or equal to 15%. Area
e long-term stability of the standard drug solutions

(%)
and the internal standard in the biological liquid at room
temperature was evaluated aer 12 h of preparation. ese 0
solutions were kept frozen at −20∘ C for seven days before the 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
analyses were carried out. Time
(b)

2.9. Biological Samples. e samples for bioequivalence tests F 2: Total ion chromatogram (TIC) for ranitidine and propra-
were collected at the Cardiology Institute of Anápolis in the nolol.
state of Goiás, Brazil. e study involved 24 volunteers and
was conducted aer approval of the study protocol by the
Research Ethics Committee of the Universidade Federal de spectra coincide with those obtained by Schellen et al. [9] and
Goiás. Ranitidine was assessed for bioequivalence in 150 mg Xia et al. [11].
tablet form.
Blood samples were collected with a total volume of 4. Method Validation
10 mL. e blood was centrifuged and the plasma removed.
Plasma samples were frozen at −20∘ C. e collection times 4.1. Selectivity�Speci�city. Figure 4 shows chromatograms of
were 15 min, 30 min, 45 min, 1:00 h, 1:15 h, 1:30 h, 2:00 h, normal blank plasma for ranitidine and the internal standard
2:30 h, 3:00 h, 4:00 h, 5:00 h, 6:00 h, 8:00 h, and 12:00 h. All (propranolol) aer the blank plasma samples were tested
samples collected were placed in test tubes containing 2 drops using the same procedure and under the same conditions
of heparin and then sent to the hospital analysis laboratory for as for sample analysis. As can be seen, no metabolites or
plasma extraction. interferents signi�cant for the retention time of the drug or
of the internal standard were found.
3. Results and Discussion 4.2. Analytical Curve. e mean determination coefficient
3.1. Analyses by HPLC-MS-MS. e chromatographic of the calibration curve for ranitidine was 0.9989. Linearity
method which was used allowed the ranitidine and the varied from 3.00 to 500.00 ng/mL. Relative error values
internal standard (propranolol) to elute with a resolution ranged from −6.60 to 8.66%, which indicates an analytical
of 1.23, with a retention time of 1.66 min for ranitidine and curve of excellent linearity, broad linear dynamic range and
2.13 min for the internal standard (Figure 2). e retention adequate accuracy. is provides the quanti�cation process
time obtained was similar to that found in a study by Zhang with analytical reliability.
et al. [7] and was lower than that reported by Sun et al. [8] e lower limit of quanti�cation (LLOQ) was 3.00 ng/mL,
who obtained an elution time of 4.5 minutes for ranitidine. with precision of 4.61% and accuracy of 100.62%. e limit
Ranitidine and propranolol were identi�ed through anal- of detection (LOD) was 0.05 ng/mL, a concentration whose
ysis of mass spectra obtained during the �rst and second signal-to-noise ratio was 3.98. e limit of quanti�cation was
ionizations of these analytes, as illustrated in Figure 3. lower than the LLOQ obtained by Zhang et al. [7] and Sun
Ranitidine underwent protonation in the �rst mass spec- et al. [8] and near that obtained by Wang et al. [6] who used
trometer, generating a quasimolecular ion [M+H]+ 𝑚𝑚𝑚𝑚𝑚 of the protein precipitation method and obtained an LLOQ of
315.1. rough collision with argon gas, this generates the 1 ng/mL. us, the precision values are adequate and provide
fragment (daughter ion) 𝑚𝑚𝑚𝑚𝑚 129.9 determined in the second analytical reliability for LLOQ determination and validation.
mass spectrometer. ese mass spectra coincide with those
obtained by Schellen et al. [9] and Kataoka et al. [10]. 4.3. Method Recovery. e absolute recovery of ranitidine
e quasimolecular ion generated by the internal stan- was evaluated for eight concentrations (𝑛𝑛 𝑛 𝑛). e recov-
dard (propranolol) [M+H]+ has 𝑚𝑚𝑚𝑚𝑚 of 260.3 which produces eries were 90.74 ± 3.22% for a nominal concentration of
the fragment (daughter ion) 𝑚𝑚𝑚𝑚𝑚 116.1 (Figure 3). ese 3.00 ng/mL; 87.49 ± 1.34% for 5.00 ng/mL; 86.18 ± 2.88% for
4 ISRN Chromatography

Set
Ranitidine 2 1 (2.065) Scan ES +
315.1
100
1.31 8
H+
H
CH3 O NH NO2
N S Ranitidine (A)
CH3 HNCH3
(%)

316.3 392.6
365.2
65.2 260.4 270.3 305.3 321.2 348.4 379.3 394.5
184.7
0
60 100 140 180 220 260 300 340 380

(a)
Set
Daughters of 315ES +
Ranitidine 1 1 (2.065)
1.3 7
129.9
100
H
CH3 O NH NO2
N S
CH3
F HNCH3
(%)

98.1 125 176

102.1 Ranitidine (B)

124 191.1
97 110.1 165.1 224
88.2 137.9
0
60 100 140 180 220 260 300 340 380

(b)
Set
Propranolol scan 200 1 (2.065)
Scan ES +
100 7.12 8
H+
OH
O NH CH3

CH3
(%)

Propranolol (A)

0
60 100 140 180 220 260 300 340 380

(c)
Set
Propranolol 1 (2.065) Scan ES +
116.1 2.24e9
100
OH
O NH CH3
(%)

CH3
F
59.2
Propranolol (B)
260.3
83 138.9 156 196.9
0
60 80 100 120 140 160 180 200 220 240 260 280 300
(m/z)
(d)

F 3: �a�� �p�ctr�m o� ra��t�d��� a�d propra�o�o�� (a) �� �r�t ma�� �p�ctrom�t�r� (b) �� ��co�d ma�� �p�ctrom�t�r�
ISRN Chromatography 5

Plasma normal lot:103793AC MRM of 2 channels ES +

052001 Tb 002 315.1 > 129.9
100 112
Area

(%)
0
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5
Time
(a)
MRM of 2 channels ES +
260.2 > 116.1
052001 Tb 002
100 853
Area
(%)

0
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5
Time
(b)

F 4: Chromatograms of normal blank plasma monitoring ranitidine and propranolol.

T 1: Intraday and between-day precision and accuracy for the determination of ranitidine in plasma.

Concentration (𝜇𝜇g/mL) 𝑛𝑛 𝑛 𝑛
Nominal Intraday Between-days
Determined RSD (%) Accuracy Determined RSD (%) Accuracy
3.00 2.79 9.75 93.2 2.92 4.04 97.3
5.00 4.67 2.99 93.5 4.64 0.99 92.8
200.00 197.19 3.29 98.6 202.43 2.41 101.2
400.00 406.26 3.37 101.6 419.38 2.73 104.8

10.00 ng/mL; 95.28 ± 3.9% for 50.00 ng/mL; 93.79 ± 5.81% ranitidine nor propranolol was degraded by the in�uence of
for 100.00 ng/mL; 96.20 ± 2.10% for 200.00 ng/mL; 100.23 ± various storage temperature �uctuations, which ensures that
3.38% for 400.00 ng/mL; 105.44 ± 10.1% for 500 ng/mL. e these samples may undergo several cycles of freezing and
recovery of the internal standard was 89.4 ± 4.37%, and the thawing with no loss in analyte concentration. In addition,
mean recovery of ranitidine in plasma by SPE was 94.41%, the drugs are not degraded during the period in which the
a result that demonstrates the effectiveness of the method in sample remains in the equipment to be analyzed. e long-
bioequivalence studies. term stability assessment has shown that the samples remain
stable over the forty-day period.
4.4. Accuracy and Precision. e intra-day and between-
day accuracy and precision results for the determination of 4.6. Pharmacokinetic Study. e method was effectively
ranitidine in human plasma are presented in Table 1. e applied in the bioequivalence study. Figure 5 displays mean
results indicate that the proposed method provides intra- plasma concentration of ranitidine versus time, comparing
day and between-day accuracy and precision within the the test drug (T) to the reference (R), for the 24 volunteers
parameters desirable for an analytical method for the study who participated in the study. e test ranitidine showed a
of drug bioequivalence. pro�le similar to that of the reference drug, with a ma�imum
plasma concentration (𝐶𝐶max ) of 90.0 ng/mL occurring at
4.5. Stability. Table 2 presents data on the stability of 1.8 h.
ranitidine and propranolol under different conditions. e For some volunteers, there were two plasma concentra-
acceptance criteria were a deviation from the nominal con- tion peaks for ranitidine. Several other studies have also
centration and precision less than or equal to 15%. Neither reported this [12–14�. Some authors attribute this �nding
6 ISRN Chromatography

T 2: Stability of ranitidine and propranolol under different conditions (𝑛𝑛 𝑛 𝑛).

Concentration (ng/mL)
Conditions
Drug Nominal Determined mean
5.06 5.46 ± 1.39%
Freezing and thawing cycles Ranitidine
407.13 429.99 ± 1.17%
4.97 5.05 ± 2.63%
Ranitidine
Room temperature for 8 h 411.44 423.99 ± 2.01%
Propranolol 214 195 ± 7.06%
∘ 4.8 5.28 ± 3.23%
Storage at −20 C for 40 days Ranitidine
390.79 400.33 ± 4.05%
5.00 5.15 ± 0.87%
Ranitidine
Standard solutions for 12 h 404.66 429.78 ± 1.89%
Propanolol 185.2 181.2 ± 7.06

100 Acknowledgments
Concentration (ng/mL)

80
e authors acknowledge MCT, FINEP, FUNAPE, and CNPq
60 for the �nancial support, and CAPES CNPq for the produc-
40 tivity fellowship to N. R. A. Filho (Process no. 309832/2010-
1).
20
0
0 2 4 6 8 10 12 References
Time (h)
[1] United States Pharmacopeial Convention, U.S. Pharmacopeia
T & National Formulary, National Publishing, Philadelphia, Pa,
R USA, 24th edition, 2000.
F 5: Mean plasma concentration of ranitidine versus time for [2] M. A. Rocha Júnior, “Histamina e Anti-histamínicos,” in Far-
test (T) and reference (R) products. macologia, P. Silva, Ed., p. 54, Guanabara Koogan, Rio de
Janeiro, Brazil, 5th edition, 1998.
[3] J. Dawson, D. A. Richards, and R. Stables, “Ranitidine—
pharmacology and clinical use,” Journal of Clinical and Hospital
to the mechanism of enterohepatic recirculation [15], while
Pharmacy, vol. 8, no. 1, pp. 1–13, 1983.
others attribute it to the existence of multiple drug binding
sites along the gastrointestinal tract [16]. [4] D. Zendelovska and T. Sta�lov, “Development of an HPLC
method for the determination of ranitidine and cimetidine in
human plasma following SPE,” Journal of Pharmaceutical and
5. Conclusions Biomedical Analysis, vol. 33, no. 2, pp. 165–173, 2003.
[5] T. G. Do Nascimento, E. De Jesus Oliveira, and R. O. Macêdo,
e analytical method for determining ranitidine in human
“Simultaneous determination of ranitidine and metronidazole
plasma using SPE and LC-MS/MS offers high recovery,
in human plasma using high performance liquid chromatogra-
excellent linearity, accuracy, and precision, and a lower phy with diode array detection,” Journal of Pharmaceutical and
limit of quanti�cation that is adequate for checking the Biomedical Analysis, vol. 37, no. 4, pp. 777–783, 2005.
remaining plasma concentration of ranitidine. In addition,
the procedure offers fast execution and chromatographic [6] L. Wang, L.-M. Zhao, Y.-T. Sun, and J.-K. Gu, “Rapid determina-
tion of ranitidine in human plasma by liquid chromatography-
analysis, with excellent resolution.
tandem mass spectrometry and its application to a clinical phar-
is methodology is appropriate for assessing the stability macokinetic study,” Chemical Research in Chinese Universities,
of ranitidine under various conditions. Ranitidine was stable vol. 26, no. 6, pp. 910–914, 2010.
in all the processes used to assess the stability of these drugs
in biological matrices. Analysis of these drugs is therefore [7] Y. Zhang, N. Mehrotra, N. R. Budha, M. L. Christensen, and B.
Meibohm, “A tandem mass spectrometry assay for the simul-
possible aer long periods of adequate storage at −20∘ C.
taneous determination of acetaminophen, caffeine, phenytoin,
us, the method is fully applicable to bioequivalence and ranitidine, and theophylline in small volume pediatric plasma
bioavailability studies of ranitidine. specimens,” Clinica Chimica Acta, vol. 398, no. 1-2, pp. 105–112,
2008.
Con�ict of �nterests [8] X. Sun, Y. Tian, Z. Zhang, and Y. Chen, “A single LC-tandem
mass spectrometry method for the simultaneous determination
e authors declare that they do not have a direct �nancial of four H2 antagonists in human plasma,” Journal of Chromatog-
relation with Merck and Millipore (Milli-Q). raphy B, vol. 877, no. 31, pp. 3953–3959, 2009.
ISRN Chromatography 7

[9] A. Schellen, B. Ooms, D. Van De Lagemaat, R. Vreeken,

and W. D. Van Dongen, “Generic solid phase extraction-
liquid chromatography-tandem mass spectrometry method for
fast determination of drugs in biological �uids,” Journal of
Chromatography B, vol. 788, no. 2, pp. 251–259, 2003.
[10] H. Kataoka, H. L. Lord, and J. Pawliszyn, “Automated
in-tube solid-phase microextraction-liquid chromatography-
electrospray ionization mass spectrometry for the determina-
tion of ranitidine,” Journal of Chromatography B, vol. 731, no. 2,
pp. 353–359, 1999.
[11] Y. Q. Xia, R. Bakhtiar, and R. B. Franklin, “Automated
online dual-column extraction coupled with teicoplanin sta-
tionary phase for simultaneous determination of (R)- and (S)-
propranolol in rat plasma using liquid chromatography-tandem
mass spectrometry,” Journal of Chromatography B, vol. 788, no.
2, pp. 317–329, 2003.
[12] M. A. Campanero, A. Lopez-Ocariz, E. García-Quetglás, B. Sád-
aba, and A. De La Maza, “Rapid determination of ranitidine in
human plasma by high-performance liquid chromatography,”
Chromatographia, vol. 47, no. 7-8, pp. 391–395, 1998.
[13] G. Mullersman and H. Derendorf, “Rapid analysis of raniti-
dine in biological �uids and determination of its erythrocyte
partitioning,” Journal of Chromatography, vol. 381, no. 2, pp.
385–391, 1986.
[14] K. S. Reynolds, M. H. Song, W. D. Heizer, C. B. Burns, D.
A. Sica, and K. L. R. Brouwer, “Effect of pancreatico-biliary
secretions and GI transit time on the absorption and phar-
macokinetic pro�le of ranitidine in humans,” Pharmaceutical
Research, vol. 15, no. 8, pp. 1281–1285, 1998.
[15] R. Miller, “Pharmacokinetics and bioavailability of ranitidine in
humans,” Journal of Pharmaceutical Sciences, vol. 73, no. 10, pp.
1376–1379, 1984.
[16] P. Schaiquevich, A. Niselman, and M. Rubio, “Comparison of
two compartmental models for describing ranitidine’s plasmatic
pro�les,” Pharmacological Research, vol. 45, no. 5, pp. 399–405,
2002.
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