Rabeprazole

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Rabeprazole: A comprehensive
profile
Ahmed H. Bakheita,b,*, Hamad M. Al-Kahtania, Salem Albraikia
a
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
b
Department of Chemistry, Faculty of Science and Technology, Al-Neelain University, Khartoum, Sudan
*Corresponding author: e-mail addresses: [email protected]; [email protected]
Contents
1. Description 2
1.1 Nomenclature 2
1.2 Formula 2
1.3 Elemental analysis 3
2. Methods of preparation 4
3. Physical characteristics 8
3.1 Physical description 8
3.2 Dissociation constants 8
3.3 Flash point, and vapor pressure 8
3.4 Solubility characteristics 8
3.5 Partition coefficient 8
3.6 Particle morphology 8
4. Characterization and identification 9
4.1 Thermal methods of analysis 9
4.2 UV/vis spectroscopy 10
4.3 Infrared spectroscopy 11
4.4 Mass spectrometry 12
5. Methods of analysis 18
5.1 Compendial methods of analysis 18
5.2 Reported methods of analysis 21
5.3 Determination in body fluids and tissues 29
6. Stability 30
6.1 Stability indicating method 30
6.2 Solid-state stability 31
6.3 Solution-phase stability 32
7. Uses 32
8. Pharmacology 33
8.1 Pharmacodynamic properties 33
8.2 Pharmacokinetic properties 36
8.3 Dosing 37
8.4 ADME profile 39
References 41
Profiles of Drug Substances, Excipients, and Related Methodology # 2020 Elsevier Inc. 1
ISSN 1871-5125 All rights reserved.
https://doi.org/10.1016/bs.podrm.2020.07.003
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2 Ahmed H. Bakheit et al.
1. Description
Rabeprazole is a benzimidazole substitution, proton pump inhibitor.
Sodium salt of rabeprazole is a proton pump inhibitor in the stomach, which
can suppress gastric acid secretion by inhibiting H+, K+-ATPase on the
secretory surface of the partial cellular cells without affecting cholinergic
or histamine H2-receptors. Sodium rabeprazole is usually used in combina-
tion prescriptions to eliminate Helicobacter pylori. Moreover, rabeprazole is
one of the treatments for duodenal ulcers. It is also used in the treatment
of gastroesophageal reflux and Zollinger-Ellison syndrome, which is the
conditions in which the stomach produces much acid. It is also used in cases
of gastric ulcers caused by bacteria where it is used with antibiotics [1].
1.1 Nomenclature
1.1.1 Systematic chemical names
1.1.1.1 Rabeprazole base
• 2-[[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1H-
benzimidazole.
• 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-
benzimidazole [2].
1.1.1.2 Rabeprazole sodium salt

• 1H-Benzimidazole, 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]
methyl]sulfinyl]-, sodium salt [3].
• 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]benz-
imidazole sodium salt [117976-90-6] [3].
1.1.2 Non-proprietary names

Generic:
Rabeprazole sodium, rabeprazole sodium hydrate.
1.1.3 Proprietary names (brand names)

Pareit; acephex, abbot-rabeprzole, apo-rabeprazole [4].
Aciphex; Clofezone; Pariet; Q9Z21M00M9; LY307640; C063129;
Chemistry 2153; DB01129.
E3810 [5].
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Rabeprazole: A comprehensive profile 3
1.2 Formula
1.2.1 Empirical formula, molecular weight, CAS number
Empirical formula, molecular weight, and CAS number are tabulated in
Table 1.
1.2.2 Structural formula

The structural formula of rabeprazole base and rabeprazole sodium salt is
performed in Fig. 1.
1.3 Elemental analysis

The elemental composition of rabeprazole base and sodium salt is written in
Table 2.
Table 1 Empirical formula, molecular weight, CAS number [6].

Compounds Empirical formula Molecular weight CAS number
Rabeprazole base C18H21N3O3S 359.44 117976-89-3
Rabeprazole sodium salt C18H20N3NaO3S 381.42 117976-90-6
Rabeprazole base Rabeprazole sodium salt
Fig. 1 Rabeprazole base and salt structure.
Table 2 The elemental composition of rabeprazole base and sodium salt [6].
Elements Rabeprazole base (%) Rabeprazole sodium salt (%)
C 60.15 56.68
H 5.89 5.29
N 11.69 11.02
O 13.35 12.58
S 8.92 8.41
Na 0 6.03
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2. Methods of preparation
The Rabeprazole and many other substituted benzimidazole-style
compounds with anti-ulcer activity are reported by Souda et al. [7]. This
patent further reveals the method of Rabeprazole preparation using 85%
m-chloroperabenzoic acid for oxidation of Rabeprazole sulfide 2, in a mix-
ture of dichloromethane and diethyl ether, after that, work is performed
to get product as oil. A dichloromethane/ether mixture is used to crystalize
the oil produced. In aqueous solution of sodium hydroxide the oily crude is
optionally dissolved. The solution is exposed to distillation of azeotropic via
ethanol to eliminate water and adding ether to give crystalline Rabeprazole
base (Scheme 1).
Ray et al. [4] prepared rabeprazole from reaction of the free base
2-(dichloraneyl)methyl)-4-(3-methoxypropoxy)-3-methylpyridine 2 with
m-chloroperabenzoic acid (mCPBA) in chloroform medium at 58 °C to give
2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine 3. The com-
pound 3 was condensed with 2-(chloromethyl)-4-(3-methoxypropoxy)-
3-methylpyridine 1-oxide 4 in N,N-dimethylformamide containing
potassium carbonate to yield a chlorine-free compound as 2-(((1H-benzo[d]
imidazol-2-yl)thio)methyl)-4-(3-methoxypropoxy)-3-methyl pyridine
1-oxide 6. The compound 6 was oxidized with mCPBA in dichloromethane
at 0 °C to give mixture of two compounds 7a and 7b, compound 7b was
Scheme 1 Synthesis of rabeprazole by Souda method.

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Scheme 2 Synthesis of rabeprazole by Ray method.
treated by m-Chloroperabenzoic acid at 58 °C for 85 min and maintained for

1 h to give compound 1 (Scheme 2).
Vardanyan and Hruby [8] synthesized rabeprazole 1. This method was
started from 4-nitro-2,3-dimethylpyridine-N-oxide 2, which on heating
with concentrated hydrochloric acid gave 4-chloro-2,3-dimethylpyridine-
N-oxide 3. A reaction with sodium 3-methoxypropan-1-olate in DMSO
yields the corresponding 4-alkoxy intermediate 4. The 4-alkoxy intermedi-
ate 4, on further reaction with acetic anhydride, underwent Boekelheide
rearrangement to produce O-acetyl intermediate 5, which, after alkaline
hydrolysis, produced pyridin-2-ylmethanol 6, which was chlorinated using
thionyl chloride to furnish a chloro intermediate 6. A condensation of the
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Scheme 3 Synthesis of rabeprazole by Vardanyan method.
Scheme 4 synthesis of 2-Mercapto[2-14C]-benzimidazole 4 by Amersham

International plc.
obtained compound with 2-mercapto benzimidazole 8 in the presence of

base produced a 2-((pyridin-2-ylmethyl)thio)-1H-benzo[d]imidazole deriv-
ative 9, which oxidized with meta-chloroperabenzoic acid, gave the final
rabeprazole 1 (Scheme 3).
Tagami et al. [9] synthesized rabeprazole as illustrated in Scheme 5.
2-Mercapto[2-14C]-benzimidazole 4, the starting material, was synthesized
by Amersham International plc, as shown in Scheme 4. [14C] carbon disulfide
was treated with phenylenediamine 2 in a solution of potassium hydroxide
followed by desalination via acetic acid to give compound 4. An equivalent
amount of the product from nonlabeled 2-mercapto-benzimidazole was
used for dilution.
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A mixture of an ethanolic solution containing of 2-mercapto[14C]

benzimidazole 4, Z-mercapto-benzimidazole, 2-chloromethyl-4-(3-met-
hoxypropoxy)-3-methylpyridine hydrochloride 5 and sodium hydroxide
were refluxed with stirring for 1 h. Then the mixture was cooled to room
temperature and filtered under vacuum to eliminate inorganic salt. The
compound 6 was extracted from the residue in the aqueous phase with dic-
hloromethane organic phase. Furthermore, compound 6 was isolated form
the residue with column chromatography on silica (first eluting with 66.7%
n-hexane/ethyl acetate, and then with 50% n-hexandethyl acetate), and
finally with 33.3% n-hexandethyl acetate as white crystals.
After cooling to !68 °C, the compound 6 dissolved in dichloromethane
was treated with ethyl ether and m-chloroperabenzoic acid followed by
stirred the mixture for 1 h. After that the mixture was treated by
triethylamine and stirred for 10 min, and then with 1N sodium hydroxide
aqueous solution. The solution was stirred for 30 min at room temperature.
In addition, dichloromethane was used to remove unreacted thioether 6
from the aqueous layer which was treated with 2 M ammonium acetate solu-
tion and dichloromethane. The collective organic layers were dried over
magnesium sulfate and the solution filtered. The resulting solution was
treated with ethyl ether and the solid produced was filtered off and air-dried
at room temperature to give compound 7, which was dissolved in alcoholic
sodium hydroxide and the solution was filtered and washed with ethanol and
dichloromethane. The solvent was removed under vacuum. The residue
was treated with Ethanol and the solvent was again removed. The residue
was dried under vacuum and then treated with ethyl ether to afford com-
pound 1 as a pale yellowish solid (Scheme 5).
Scheme 5 Synthetic process for sodium [14C] rabeprazole.

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3. Physical characteristics
3.1 Physical description
A white to yellowish-white solid in its pure form [10].
3.2 Dissociation constants

pKa1 ¼ 1.9.
pKa2 ¼ 3.2.
pKa3 ¼ 4.2 [11].
3.3 Flash point, and vapor pressure

Flash point: 319.1 # 34.3 °C.
Vapor pressure (mm Hg): 0.0 # 1.7 mmHg at 25 °C [12].
3.4 Solubility characteristics

Rabeprazole is highly soluble in water and methanol, freely soluble in eth-
anol and chloroform; ether and insoluble in N-hexane. [13].
3.5 Partition coefficient

The n-octyl alcohol/water partition coefficient is 214 [14].
3.6 Particle morphology

The powder of rabeprazole was characterized structurally by high-resolution
X-ray diffraction (XRD) using Rigaku Ultima IV diffractometer with scin-
tillation detector with reflection mode, Cu K{acute over (α)} 19.400 radi-
ation (1.5406 Å), Scanning range: 3–60°2θ, Step size: 0.02° 2θ and Time per
step: 1 s, monochromatized with a graphite crystal. The pattern was col-
lected at 40 kV of tube voltage and 40 mA of tube current in step scan mode.
The peaks (reflections) of Rabeprazole powder are obtained at Table 3 and
shown in Fig. 2.
Table 3 The X-ray powder diffraction pattern of rabeprazole.

Peak no. 2theta Flex width d-Value Intensity I/Io
1 5.500 0.353 16.0548 147 9
2 19.400 0.353 4.5717 74 5
3 38.100 0.235 2.3600 1641 100
4 44.300 0.235 2.0430 571 35
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Intensity (cps)
2500
2000
2.360
1500
2000
2.043
500
16.055
4.572
0
10.0000 20.0000 30.0000 40.0000 50.0000
2theta (deg.)
Fig. 2 The X-ray powder diffraction pattern of rabeprazole.
4. Characterization and identification

4.1 Thermal methods of analysis
4.1.1 Melting behavior
Melting points of rabeprazole salt were measured using a B€
uchi melting
point B-545 apparatus, and the melting point range was found at
140–141 °C and decompose range at 153.2–154 °C which was agree with
Ref. [13].
4.1.2 Differential scanning calorimetry

Rabeprazole differential scanning (DSC) data were obtained by a differential
calorimeter Perkin-Elmer DSC-7 with a TAC 71DX thermal analysis con-
troller (Perkin-Elmer, Norwalk, CT). The samples were precisely weighed
(3.6 mg) in aluminum plates, and thermograms acquired at heating range of
10 °C per minute for a temperature range of 40–300 °C. The research was
carried out with Pyris Program 2.04 (Perkin-Elmer). Rabeparazole differen-
tial scanning calorimetry (DSC) (Fig. 3) shows a 222 °C exothermic process.
An exothermic process is followed immediately by weight loss due to
decomposition (mp 198–201 °C).
4.1.3 Thermogravimetric analysis

Thermal gravimetric analysis (TGA) of rabeprazole was obtained using a
Perkin Elmer pyris 1 apparatus. The samples (2.042 mg) were placed in alu-
minum pan, pierced prior to scan, and temperature profile 50–550 °C at a
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–8.761
0 Pe ak = 222.06 °C
10 Are a = –2164.495 mJ
D elta H = –441.7336 J/g
H e at Flow E ndo Down (mW)
20
30
40
50
60
71.86
55 100 150 200 250 300 350 400
Temperature (°C)
Fig. 3 DSC curves of rabeprazole RS.
100 –4.20%
90
Weight %
80
70
60
50 100 150 200 250 300

Temperature °C
Fig. 4 Thermogravimetric analysis (TGA) of rabeprazole.
rate of 10 °C/min under nitrogen purge (50 mL/min). The results show that
the powder of rabeprazole is chemically unstable above the melting point
temperatures and the compound was decompose at 153.2–154 °C as
shown in Fig. 4.
4.2 UV/vis spectroscopy

A Shimadzu UV-spectrophotometer (model no. UV-1800) was used to record
an ultraviolet absorption spectrum of methanolic solution of Rabeprazole
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1.832
1.500
1.000
Abs.
0.500
1
0.000
2
–0.165
200.00 250.00 300.00 350.00 400.00
nm.
Fig. 5 The UV-absorption spectrum of 20 μg/mL of rabeprazole in acetonitrile.
Fig. 6 IR spectrum of rabeprazole.
(20 μg/mL) in methanol. The absorption spectra are measured in a 1 cm quartz

cell within 200–400nm range. The ultraviolet spectrum is displayed in Fig. 5
with a two absorption maxima of Rabeprazole at 275 and 205 nm.
4.3 Infrared spectroscopy

A Fourier-transform infrared (FT-IR) absorption spectrum of rabeprazole
was recorded (as KBr disc) using the Perkin Elmer FT-IR Spectrum BX
apparatus. Fig. 6 shows the FT-IR of rabeprazole. The characteristic absorp-
tion band of rabeprazole is shown in Tables 4 and 5.
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Table 4 Interpretation of rabeprazole FT-IR spectra.

No. Functional group Standard value (cm21) Obtained value
1 C]C group 1600–1475 1584.99
2 CdN group 1350–1000 1094.79
3 CdO group 1000–1300 1010.69
4 S]O group 1050 1161.73
5 CdH group 2850–3000 2923.03
6 NdH group 3300–3500 3382
4.4 Mass spectrometry

The mass spectrum of Rabeprazole was obtained using a mass spectrom-
eter Agilent 6320 ion-trap (Agilent Technologies, USA) fitted with the
electrospray ionization interface (ESI). Instead of a column, a connector
was used. The mobile phase consisted of a combination of HPLC grade
water and acetonitrile (50:50). The rabeprazole powder (10 mg) was dis-
solved in acetonitrile and diluted to 10 mL with a mobile phase. Based on
the intensities of the ions the test solution was diluted to 10–30 μg mL!1 with
the mobile-phase. Rate of flow was 0.4 mL min!1 and 5 min is runtime. The
parameters of mass spectrometry were optimized. The scan was in ultra-scan
mode. In the mass range 50–1000 m/z, MS2 scans were performed. The ESI
was in a positive mode. The source temperatures were set to 350 °C. The
molecular ion peak at m/z ¼ 360 [M + 1]+ was observed with a nebulizer
gas pressure of 55,00 psi, dry gas flow rate of 12.00 L min. The full scan mass
spectra of rabeprazole demonstrated that the main rabeprazole peak was
present at m/z 351.2 (Fig. 7).
The spectra of product ion mass by these protonated molecular ions
(Fig. 8) demonstrated that the main rabeprazole product ion was present
at m/z 194.8, 73.0, 119, 169.9, 150 and 242.
The resulting MS data are similar to that of described in the literature
[15–18]. The ESI negative ion mode is also reported; the important fragments
(m/z) are 434.25 (M + H+), 390.1, 350.1, and 179.2 [19,20]. Both positive
and negative ion modes are used for determination of Rabeprazole by
LC-MS/MS.
The EI-MS of rabeprazole was reported by Hishinuma et al. [21]. The
important fragments (m/z) were 242.1 [M–118], 342 [M–18], 210 [M–150],
195.3 [M–164.7], and 73.2 [M–286.8].
Table 5 Summary of chromatographic methods of rabeprazole.
Detection
Sample Method Method mobile/flow rate (λ, nm) Stationary phase Linearity range References
Pure Rabeprazole Sodium HPLC Mobile phase composition: 280 nm size: l ¼ 0.25 m, – [23]
RS —mobile phase A: mix 5 volumes of acetonitrile R and Ø ¼ 4.6 mm
95 volumes of a 4.35 g/L solution of dipotassium
hydrogen phosphate R previously adjusted to pH 7.0
with phosphoric acid R
—mobile phase B: methanol R
—mobile phase C: acetonitrile R
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Time (min) 0 2 7 27 32
A% 100 100 85 30 15
B% 0 0 0 40 55
C% 0 0 15 30 30
-USP Rabeprazole HPLC Flow rate: 1 mL/min 280 nm 4.6-mm $ 25-cm; 5-μm – [22]
Sodium RS Mobile phase composition: packing L1
-Ssample of Rabeprazole Buffer 1: 4.35 g/L of dibasic potassium phosphate. Adjust
Sodium with phosphoric acid to a pH of 7.0
Solution A: Acetonitrile and buffer 1 (5:95)
Solution B: Methanol
Solution C: Acetonitrile
Time (min) 0 2 7 27 32
Solution A % 100 100 85 30 15
Solution B % 0 0 0 40 55
Solution C % 0 0 15 30 30
Continued
Table 5 Summary of chromatographic methods of rabeprazole.—cont’d
Detection
The rabeprazole and HPLC 0.01 M 6.5 pH ammonium acetate buffer– 276 nm Phenomenex C18 The range of [18]
mosapride in their methanol–acetonitrile (30:40:30, v/v) adjusted to pH column (250 mm $ 0.30–3.67% and
combined Pharmaceutical 5.70 # 0.02 with acetic acid–ammonia. (Flow rate of 4.6-mm i.d., 5-μm 1.03–3.58%,
dosage forms 1.0 mL/min) particle size) respectively
Rabeprazole enantiomers HPLC An isocratic elution: 280 nm Chiralpak IC 10–100 μg/mL for [44]
in commercial tablets hexane:ethanol:ethylenediamine (30:70:0.05, v/v) at a (150 $ 4.6 mm, 5 μm) each enantiomer
flow rate of 1.0 mL/min column
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Rabeprazole sodium RP- The optimized mobile phase consisted of a 10 mM 280 nm Pursuit C18 50–150 μg/mL [45]
HPLC potassium dihydrogen phosphate buffer, acetonitrile and column, i.e.,
methanol (50:18:32, v/v) 4.6 mm $ 25 cm, 5 μm
Tablet dosage form RP- phosphate buffer (pH 5.5), methanol (30:70) with flow 284 nm Symmetry C18 20–60 μg/mL [46]
HPLC rate at 0.9 mL/min at wavelength 284 nm (4.6 $ 150 mm, 5 mm,
Make: XTerra)
Human plasma RP- 5 mM ammonium acetate buffer (pH 7.4)/acetonitrile/ 284 nm Waters symmetry® C18 20–1000 ng/mL [47]
HPLC methanol (45/20/35, v/v) column
Human plasma NP- Diamonsil C18 analytical column Mass n-hexane– 2.0–800 ng/mL [48]
HPLC– detector dichloromethane–
MS/MS isopropanol
(20:10:1, v/v)
Marketed tablet samples RP- 0.1 M sodium phosphate buffer (pH 6.5) and acetonitrile 285 nm Lichrosphere RP-100 0.025–150% [49]
HPLC 65:35 with UV detection (285 nm) with a flow rate of C8 column
1.2 mL/min!1
Pure powder and tablet RP- Phosphate buffer (pH 6): acetonitrile (65:35, v/v) flow 280 nm Inertsil ODS 3 V, 80–120 μg/mL [50]
dosage form HPLC rate of 1.5 mL/min 150 $ 4.6 mm, 5 μ
Pharmaceutical dosage RP- Mixture of phosphate buffer (pH 7.4) and acetonitrile 290 nm. C-18 column 0.1–1.0 μg/mL [51]
forms HPLC (65:35, v/v) (4.6 mm $ 250 mm,
A flow rate of 1.5 mL/min 5 μm)
Rabeprazole and RP- 0.01 M, pH 6.5 ammonium acetate buffer:methanol: 287 nm Phenomenex C18 (2) 200–2000 ng/mL [52]
domperidone in their HPLC acetonitrile (40:30:30, v/v, pH 7.44) column
combined dosage forms flow rate of 1.0 mL/min (250 mm $ 4.6 mm i.d.,
5 μm)
Rabeprazole sodium in RP- Acetonitrile:phosphate buffer (70:30, v/v, pH 7.0) at a 228 nm C18 column [Use 0.1–30 μg/mL [53]
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pharmaceutical HPLC flow rate of 0.8 mL/min Inertsil C18, 5 μ,
formulations 150 mm $ 4.6 mm]
Rabeprazole sodium and HPLC Acetonitrile:buffer (35:65, v/v) and the pH 7 266 nm Luna C18 (5 μM, 2–16 μg/mL [54]
itopride hydrochloride in 25 cm $ 4.6 mm i.d)
solid dosage form phenomenex
Rabeprazole in bulk and HPLC Methanol and water (65:35, v/v), the flow rate is 284 nm RP-C18 column 0.25–20 μg/mL [55]
tablet dosage form. 0.8 mL/min (150 mm $ 4.6 mm I.D,
5 μm particle size)
Bulk drugs and RP- Triethyl amine buffer (pH 5):acetonitrile (50:50, v/v) 284 nm BDS Hypersil C8 5–25 μg/mL [56]
pharmaceutical dosage HPLC with flow rate 2 mL min!1 (250 mm $ 4.5 mm,
forms 5 μm)
Rabeprazole sodium and RP- Methanol:acetonitrile:water (60:10:30, v/v/v) at a flow 280 nm C-18 column methanol: 1–10 μg/mL [57]
Aceclofenac in a HPLC rate of 1.0 mL/min acetonitrile:water
combined dosage form (60:10:30, v/v/v)
Rabeprazole Sodium (RS) RP- 50 mM ammonium acetate in water (pH 8) with PDA YMC C18, ODS-AM 100–500 μg/mL [58]
in solid dosage HPLC ammonia and methanol detector stainless steel column
(250 mm $ 4.6 mm ID;
particle size 5 m)
Continued
Table 5 Summary of chromatographic methods of rabeprazole.—cont’d
Detection
Rabeprazole, RP- 10 mM potassium dihydrogen orthophosphate (adjusted 288 nm. Phenomenex C18 2.5–25 μg/mL [59]
pantoprazole, and itopride HPLC to pH 6.8):acetonitrile (70:30, v/v) at a flow rate of (Luna) column
in combined dosage form 1.0 mL/min (250 mm $ 4.6 mm,
dp ¼ 5 μm)
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Rabeprazole sodium in HPLC Acetonitrile and phosphate buffer (pH 7.4) in the ratio of 280 nm a Waters Acquity BEH 0.03–30 μg/mL [60]
tablet formulations 35:65 (v/v). The flow rate was 0.4 mL/min C18 (50 $ 2.1 mm,
particle size 1.7 μm)
Rabeprazole sodium in RP- Methanol:water (50:50; v/v) at the flow rate of 290 nm Waters C18 10–200 μg/mL [61]
bulk and its tablet dosage HPLC 1.0 mL/min (4.6 $ 150 mm, 5 μm)C
forms
Clidinium Bromide, RP- Phosphate buffer (pH 4.5):acetonitrile (80:20, v/v) and 215 nm ODS C18 RP 20–60 μg/mL [62]
Chlordiazepoxide, HPLC pH adjusted with 0.5% orthophosphoric acid column (250 mm $
Dicyclomine HCl and -At a flow rate of 1.0 mL/min 4.6 mm i.d., 5 μm)
Rabeprazole Sodium in
combined solid dosage
Naproxen and rabeprazole RP- Sodium dihydrogen phosphate buffer (pH 7.5 # 0.1) and 275 A phenomenex ODS 1.0–30.2 μg/mL [63]
sodium in pure and HPLC acetonitrile in the ratio of 70:30 (v/v) C18 column of
pharmaceutical dosage -The flow rate 1 mL/min dimension 4.6 mm $
250 mm, 10 μm
Rabeprazole and RP- Methanol and buffer (55:45%) [pH 4.0 adjusted with 276 An Inertsil-C18 20–80 μg/mL [64]
mosapride in bulk and HPLC triethylamine] ODS column
tablet dosage forms The flow rate 1.0 mL/min (250 $ 4.6 mm; 5 μ)
Rabeprazole and related HPLC- 0.02 M K2HPO4:acetonitrile:methanol (85:5:10, v/v), 285 nm (250 $ 4.6 mm), 5.0 μm, [65]
impurities in bulk PDA with gradient programmed at flow rate 1.0 mL/min Phenomenex C18
—mobile phase A: 0.02 M K2HPO4 column
—mobile phase A: Acetonitrile R
—mobile phase C: Methanol R
Time (min) 0 10 15 25 35 40
A% 85 60 30 30 85 85
B% 5 30 60 60 5 5
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C% 10 10 10 10 10 10
Rabeprazole sodium in RP- Buffer, methanol (30:70%, v/v) 284 nm Column C18 20–60 μg/mL [66]
raw material and tablet HPLC Flow rate 0.9 mL/min (4.6 $ 150 mm, 3.5 μm,
dosage form XTerra)
Rabeprazole in plasma HPLC 5.0 mM ammonium acetate buffer (pH adjusted to 7.4 290 nm Luna C18 column 20.0–1000.0 ng/mL [67]
with dilute ammonia solution) methanol and acetonitrile (5 mm, 250 mm $
at the ratio 45:35:20 (v/v/v) 4.6 mm i.d.; 5 μm
A flow rate of 1.0 mL/min Phenomenex, CA, USA)
with a guard column
(30 mm $ 4.6 mm i.d.;
Phenomenex, CA, USA)
Rabeprazole sodium in RP- pH 5 phosphate buffer, methanol (30:70%, v/v) 284 nm Column: C18 20–60 μg/mL [68]
raw material and tablet HPLC flow rate of 0.9 mL/min flow rate (4.6 $ 150 mm, 3.5 μm,
dosage form XTerra)
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x10 4 + Scan (0.435 min) S ample 2.d

1.2 351.2
1.1
1
0.9
0.8
0.7
0.6
0.5 100.0
0.4
0.3 140.0
0.2
114.0 165.0 326.9 371.0 432.3
0.1 88.9
0
60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440
C ounts vs. Mass-to-C harge (m/z)
Fig. 7 Traces show full scan mass spectra of rabeprazole.
5. Methods of analysis
5.1 Compendial methods of analysis
5.1.1 Identification
USP 41 [22] described two methods for identification of Rabeprazole
sodium bulk drug, i.e., IR absorption (197K), (197M), or (197A) may be
used. LC system (compare to the retention time) and a TLC method were
applied for identification of Rabeprazole. The sample and standard
(0.2 mg/mL) were prepared in in methanol and 10 μL of sample and standard
solution were added to thin layer chromatography plate. The mobile phase
was a mixture of 10 mM ammonium acetate in water. Adjust with glacial
acetic acid to a pH of 7.0:Acetonitrile (1:1). The Rf of the samples should
be identical to that of the standard solutions.
British Pharmacopeia 2019 [23] described three methods (A, B, and C)
for identification of Rabeprazole sodium: (A) Infrared absorption spectro-
photometry (2.2.24), the sample was dissolved in methanol and evaporated
to dryness then it was recorded the spectrum by the residue. The result spec-
trum was comparison with standard of rabeprazole sodium hydrate. (B) Loss
on drying and (C) It gives reaction (A) of sodium (2.3.1). The identification
must be conducted by using either methods A and B or A and C. Method
B consist many tests, first test, 0.1 g of Rabeprazole sodium sample was dis-
solved in carbon dioxide-free water R and diluted to 10 mL with same sol-
vent. The pH of this solution should be in range 9.5–11.5. Second test
should be performed by using LC system (see Table 3). The sample used
in this method contains impurity A and H. Finally method B tests,
0.200 g of sample was used to determine the water percentage in the sample
and it should be in range 1.5–7.0%. For method C, addition of a 150 g/L
x10 3 + Product Ion (0.441 min) (360.0 -> **) R B Z Pl.d
150.0
2.8
2.6
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2.4
2.2
2
1.8
1.6
1.4 45.1 136.2
1.2
1 73.0 107.2
0.8
0.6
0.4 169.9 242.2
194.8
0.2
0
20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400
C ounts vs. Mass-to-C harge (m/z)
Fig. 8 Traces show product ion spectra of rabeprazole.
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potassium carbonate R solution to a 0.05 g/mL of Rabeprazole sodium solu-

tion, then mixture solution was boiled after that, 4 mL of potassium
pyroantimonate solution R was added to the mixture and heated to boiling.
Next, the mixture was cold in ice water and A dense white precipitate was
formed detection for sodium ion.
5.1.2 Related compounds

USP 36 [22] described two limit tests for Rabeprazole-related compounds
using LC methods. Test 1 is the limit test for related compound A (RS A),
while test 2 is for related compound B (RS B), related compound C (RS C),
and other related compounds. The percentage of the related compounds
can be calculated by using the formula:
Result ¼ ðru =rs Þ $ ðCs =Cu Þ $ 100
in which Cs is the concentration (mg/mL) of the Rabeprazole-related com-
pound A in the standard solutions, while Cu is the concentration of
Rabeprazole (mg/mL) in the test solutions; ru and rs are the peak responses
of RS A from the test and standard solutions, respectively. The acceptability
limit is 1%. Details of LC methods are described in Table 3.
British Pharmacopeia 2019 [23] described an LC method for determina-
tion of the impurity in bulk drugs (see Table 3). The peak-to-valley ratio of
Rabeprazole should be minimum 1.5, where the peak height above (Hp) the
baseline due to impurity H and height above the baseline of the lowest point
of the curve separating this peak from the peak due to rabeprazole.
5.1.3 Assay
USP 41 [22] described LC methods for the determination of Rabeprazole
bulk drug. All LC methods used the same material for column (L1) but with
different dimensions and particle sizes, while mobile phases are identical.
A gradient elution was applied for analysis of Rabeprazole. Details of LC
conditions are presented in Table 3.
British Pharmacopeia 2019 [23] used Liquid chromatography for assay of
Rabeprazole in bulk drugs (see Table 3).
5.1.4 Impurities
USP [22] Rabeprazole Sodium RS
• USP Rabeprazole Related Compound A RS Sodium 1-(1H-
benzimidazol-2-yl)-3-methyl-4-oxo-1,4- dihydropyridine-2-carboxylate
(C14H10N3NaO3 291.24).
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• USP Rabeprazole Related Compound B RS 2-{[(1H-benzimidazol-

2-yl)sulfinyl]methyl}-4-(3-methoxypropoxy)-3-methylpyridine 1-oxide
(C18H21N3O4S 375.44).
• USP Rabeprazole Related Compound C RS 1H-benzimidazole-2-
thiol (C7H6N2S 150.20).
• USP Rabeprazole Related Compound D RS 2-({[4-G-meethotortor
3-methyl-2-pyridyl] reilly ay benzimidazole (C18H21N3O4S 375.44).
• USP Rabeprazole Related Compound E RS 2-{[4-(3-methoxypropoxy)-
3-methyI-2-pyridyl]methylthio}benzimidazole (C18H21N3O2S 343.44).
• USP Rabeprazole Related Compound F RS 2-{[4-chloro-3-methyl-
2-pyridyl]methyl]sulfinyl}benzimidazole (C14H12ClN3OS 305.78).
British Pharmacopeia 2019 [23] detected 10 impurities compound, the main
impurities specified impurities A. Other detectable impurities include: B, C,
D, E, F, G, H, I, K. It is not necessary to identify these impurities for dem-
onstration of compliance.
A. 2-[[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl]sulfonyl]-
1H-benzimidazole,
B. 2-[[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl]sulfanyl]-
1H-benzimidazole,
C. 1-(1H-benzimidazol-2-yl)-3-methyl-4-oxo-1,4-dihydropyridine-2-
carboxylic acid,
D. 2-[[(RS)-(1H-benzimidazol-2-yl)sulfinyl]methyl]-4-(3-methoxypro-
poxy)-3-methylpyridine 1-oxide,
E. 2-[(RS)-[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl]-1H-
benzimidazole,
F. 1H-benzimidazole-2-thiol,
G. 2-[[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfanyl]-1H-
benzimidazole,
H. 2-[(RS)-[(4-chloro-3-methylpyridin-2-yl)methyl]sulfinyl]-1H-
benzimidazole,
I. 2-[[(1H-benzimidazol-2-yl)sulfonyl]methyl]-4-(3-methoxypropoxy)-
3-methylpyridine 1-oxide,
K. 1H-benzimidazol-2-ol.
5.2 Reported methods of analysis

5.2.1 Electrochemical method
5.2.1.1 Voltammetric
Radi et al. [24] studied the oxidative behavior of rabeprazole at a glassy car-
bon electrode in Britton–Robinson (BR) buffer solutions using cyclic,
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linear sweep and differential-pulse voltammetry. The process of oxidation

was seen to be irreversible over the pH range (6.0–11.0) and managed dif-
fusion–adsorption. For the determination of rabeprazole as supporting elec-
trolyte in BR buffer solution (pH 8.0), an analytical method was established.
The linearly range of rabeprazole concentration is 1.0 $ 10!6 to 2.0 $ 10!5,
and the limit of detection was 4.0 $ 10!7 M.
Khashaba et al. [25] investigated the effect of adding transition metals
to the electrolyte containing proton pump inhibitors, such as rabeprazole
sodium (RAB sodium), on the voltammetric response of pencil graphite
electrode. Both square wave adsorptive voltammetry (SWAdSV) and
cyclic voltammetry (CV) were used to explain and validate the potential
complexation of the intermediate metal between RAB sodium and cobalt.
The current signal due to the oxidation process was a function of the
concentration of RAB sodium, pH of the medium, cobalt concentration,
scan rate, frequency, and deposition time at the electrode surface. The
oxidation peak current ranged from 0.05–9 to 10!9 M and 0.2–8.5 to
10!7 M, for SWAdSV and CV, respectively. The detected limits were
found to be 0.015 $ 10!9 M and 0.06 $ 10!7 M for SWAdSV and CV,
respectively.
Guo et al. [26] developed a carbon paste electrode (CPE) anodic adsorp-
tion voltammetric method for determination of rabeprazole. On the elec-
trode, the solution of Rabeprazole was concentrated and determined by
adsorptive voltammetry in supporting solution of 1.8 mol/L H2SO4. The
rabeprazole anthodic peak potential was at 0.498 V (vs SCE). The linear rela-
tionship between the rabeprazole concentration and the peak currents were
found in the range of 4.15 $ 10!7–3.73 $ 10!6 mol/L, with the detection
limit 6.705 $ 10!11 mol/L.
5.2.1.2 Polarography
Gartner et al. [27] reported a differential pulse polarography (DPP) method
for the electrochemical reduction of proton pump inhibitors (PPIs),
namely, lansoprazole and rabeprazole using a dropping mercury electrode
(DME). Both experiments were performed with pH values from 3.0 to 11.0
in the Britton-Robinson pump solutions. All PPIs were proved to be thor-
oughly decomposed, with pH values increasing, containing two principal
compounds, one cyclic sulfenamide and another dimer. In this case, pH 8.0
was determined to be stable with lansoprazole and pH 9.0 with rabeprazole.
Rabbeprazole was decomposed slightly faster than lansoprazole and hence
up to higher pH levels. High currents ranged from 1 $ 10!6 M to
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7 $ 10!5 M at the pH 9.0 linearly with concentrations of the two PPI. Both
compounds were displayed similarities in reaction and different variations
based on their respective chemical properties and structures.
5.2.2 Spectroscopic methods of analysis

5.2.2.1 Spectrophotometry
El-Gindy et al. [28] proposed three methods for evaluating Rabeprazole in
the presence of its degradation products. One of these methods was based on
the first derivative of the spectra ratio (1DD), which relied on the measure-
ment of amplitudes at 310.2 nm. The pH-rate profile of rabeprazole degra-
dation in Britton–Robinson buffer solutions within pH range 3–11 was
further investigated. In Britton–Robinson buffer solution pH 7, however,
the activation energy of rabeprazole degradation was determined. The cal-
ibration range of rabeprazole with the ratio first derivative of the spectra ratio
was 10–30 μg/mL, the detection limit was 0.019, and the quantitation limit
was 0.058.
Patel et al. [29] developed a spectrophotometric method for determi-
nation of rabeprazole in pharmaceutical bulk dosage form. The method
depended on the ion-pair complexes formation of rabeprazole with four
dyes, viz. bromo thymol blue, bromocresol green, bromophenol blue and
bromocresol purple in solution of acidic buffer, afterwards their chloro-
form extraction. The absorption of the organic layer was measured against
the corresponding blank reagent at the respective wavelength of the
maximum absorbance. The method was evaluated statistically and found
to be accurate and precise. Phosphate buffer (pH 2) and bromocresol green
dye phosphate buffer gave the maximum absorption of rabeprazole at
454 nm. The Beer law was found within the concentration range of
10–100 μg/mL.
A spectrophotometric derivative method for evaluating Rabeprazole
sodium was developed and validated by Garcia et al. [30] in drug formula-
tions. The procedure was performed with water as a diluent (pH 10.0).
The derivative spectra of the first order were obtained at N ¼ 5, Δλ ¼ 4.0 nm,
and determinations were made at wavelength 304 nm. In the present of drug
excipients, the procedure showed a good linearity of 6.0 and 18.0 μg/mL!1,
and the accuracy was 99.15%.
Sabnis et al. [31] developed a spectrophotometric ratio method of spectra
derivatives for simultaneous determination of rabeprazole sodium and
itopride hydrochlorides in theirs dosage forms. Amplifications were chosen
for the first derivatives of the respective at 231 nm (minimum) and 260 nm
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ratio range. Linearity, accuracy and precision, were validated. The Beer law
was found to be within the 4–20 μg/mL concentration range for rabeprazole.
Gul et al. [32] reported a UV spectrophotometric method for determina-
tion of rabeprazole in bulk using methanol as solvent. The solution was
scanned at 200–400 nm with a maximum absorption at 284 nm. The method
was validated according to ICH guidelines. Linearity was in the 12–18 μg/mL
range. A recovery was 99.86–100.14%. The %RSD for repeatability was
0.628% and for precision and inter was found at 0.488–0.77%. This method
indicated that rabeprazole was interactive with clorazepate dipotassium
at pH 7.4.
Garcia et al. [33] developed a UV spectrometric ultraviolet (UV) method
for determination of rabeprazole in pharmaceutical formulation and com-
pared the method with a previously accepted capillary electrophoresis
(CE) method. The proposed method was applied using water (pH 10.0)
as diluted at 291 nm. The method showed a good linearity (r ¼ 0.9997) in
the concentration range of 6.0–18.0 μg mL!1.
Gowri et al. [34] developed two new methods for estimation of
Rabeprazole in bulk and tablet dosage forms. In the first method, a Folin-
Ciocalteu reagent and sodium hydroxide were used. A Folin-Ciocalteu
reagent was reduced by Rabeprazole, in the presence of sodium hydroxide,
and blue colored chromogen was formed at a maximum absorption of
640 nm. The linearity range was obtained at concentration of 1–8 μg/mL
and a correlation coefficient (r2) was found to be 0.9983. In the second
method, the ferric nitrate was reduced by rabeprazole. The product ferrous
ions reacted with 2,2,bipyridine, showing maximum at 522 nm. The linear-
ity was obtained at range of concertation of 2–16 μg/mL with a correlation
coefficient (r2) of 0.9994. These two methods were validated according to
the ICH guidelines and they can be applied to determination of rabeprazole
in bulk and dosage form.
A simultaneous UV spectrophotometric method for determination of
Famotidine and Rabeprazole sodium in the laboratory mixture was devel-
oped and validated by Dsouza et al. [35]. The proposed method was per-
formed at a maximum absorption of 263 nm for Famotidine and 284 nm
for Rabeprazole sodium. The method obeyed Beer’s law in the concentra-
tion range of 5–30 μg/mL for both famotidine and rabeprazole.
5.2.2.2 Colorimeter
Two direct spectrophotometric methods for determining rabeprazole
sodium through complexation of charge transfer reactions were presented
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by Abdel-Hay et al. [36]. The first method was based on the reaction of the
drug with p-chloranilic acid (P-CA) in acetonitrile to produce a red colored
product with maximum absorption of 518 nm. The second method was
based on the reaction of 7.7,8,8-tetracyanoquinodimethane (TCNQ) with
Rabeprazole sodium in acetone. A blue-green complex was formed and
measured at 845 nm. The linearity range was obtained at concentration of
20–200 μg/mL for P-CA–rabeprazole and 2–16 μg/mL for TCNQ–
rabeprazole.
Validated colorimetric methods were developed by Kanekar et al. [37]
for the quantitative estimation of Rabeprazole in bulk and pharmaceutical
dosage form. Method A consisted of redox reaction of Rabeprazole in pres-
ence of acidic medium reacted with excess amount of Cerric ammonium
sulfate. The dye Safranin gave λmax of Rabeprazole at 516 nm. Method
B consisted of a redox reaction of Rabeprazole with ferric nitrate and the
reduced ferrous ion than reacted with 1,10 Phenanthroline giving maximum
absorbance at 511 nm. The methods were validated as per ICH guidelines.
Shaik et al. [38] developed two methods for estimating Rabeprazole
in bulk and tablet dosage form. In the first method, Folin-Ciocalteu
and hydroxide were used. In the presence of sodium hydroxide, Folin–
Ciocalteu reagent was reduced by the Rabeprazole and blue colored
chromogen was formed with a maximal absorption at 640 nm and a con-
centration of 1–8 μg/mL. Linearity was detected with correlation coeffi-
cient (r2) 0.9983. In the second method, rabeprazole reduced ferric nitrate.
The reduced ferric ions react with 2,2,bipyidine, exhibiting absorption
maximum at 522 and at concentration range 2–16 μg/mL. Linearity was
obtained with correlation (r2) 0.9994. These two method were validated
according to ICH guidelines and were suitable for estimation of rebaprazole
in bulk and pharmaceutical dosage form.
Two spectrophotometric methods for determination of rabeprazole sodium
in commercial dosage forms were developed and validated by Rahman
et al. [39]. In method A, Rabeprazole sodium was reacted with 3-methyl-
2-benzothiazolinone hydrazone hydrochloride (MBTH) in the presence of
ammonium cerium (IV) nitrate in acetic acid medium at room temperature
to form red-brown product which absorbs maximally at 470 nm. In method
B, Rabeprazole sodium was reacted with 1-chloro-2,4-dinitrobenzene
(CDNB) in dimethyl sulfoxide (DMSO) at 45 # 1 °C to form yellow col-
ored Meisenheimer complex. The band peak of the colored complex
was found at 420 nm. The concentration range of rabeprazole sodium
was 14–140 μg/mL and 7.5–165 for at method A and B, respectively.
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5.2.2.3 Chemiluminescence
Yousef zadeh et al. [40] reported a high-emission efficient chemilumines-
cence (CL) reaction based on a synergistic improvement effect of silver
nanocluster (AgNCs) and graphene quantum points (GQDs). First,
AgNCs and GQDs syntheses were carried out simply by reducing AgNO3
chemical material and by thermal treatment of glucose. The useful behav-
ior of the prepared nanomaterial in CL systems was investigated after the
characterization phase. A low CL emission was provided by the oxidation
reaction of KMnO4-rhodamine B. Nevertheless, the existence of AgNCs
and GQDs resulted in a synergetic increase in emissions. Using absorption
and fluorescence experiments, a potential mechanism for this effect was
studied. In addition, the effect of rabeprazole on the CL emission was
relatively selective. The linearity relation between intensity of CL and
the Rabeprazole was in concentration range of 4–133 ng/mL, with a detec-
tion limit (3Sb/m) of 1.1 ng/mL. The development of the CL method was
used to quantify Rabeprazole with acceptable precision and accuracy in
biological samples.
5.2.3 Chromatographic methods of analysis

5.2.3.1 Electrophoresis
A capillary electrophoresis method for determining rabeprazole sodium in
coated tablets was developed and validated by Garcia et al. [41]. The con-
ditions were as following: a bare fused silica capillary with 48.0 cm length
(39.5 cm effective) and 75 μm id; a 10 mM, pH 9.0, sodium tetraborate
run buffer; a diode array detector set at 291 nm; hydrodynamic injection
(50 mbar/5 s); and a voltage of 20 kV. HP Chemstation CE rev. A.06.03 soft-
ware was used for system control, data acquisition, and analysis. A linear pro-
cedure was found to be within the 5.0–40.0 μg/mL concentration range
(r ¼ 0.9993), A standard deviation of interday relative was found 0.49.
Percentage of mean recovery was 103.1%. The limits of detection and quan-
titation were 1.29 and 3.91 μg/mL, respectively.
Ma et al. [15] reported an enantioseparation procedure for rabeprazole and
omeprazole in acetonitrile—method (60:40, v/v). An ephedrine-based chiral
ionic liquid, (+)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)
imidate ([DMP](+) [Tf(2) N](!)) was used as both a chiral selector and a
background electrolyte in nonaqueous capillary electrophoresis. The influ-
ences of separation conditions, including the concentration of [DMP](+)
[Tf(2) N](!), the electrophoretic media and the buffer, on enantioseparation
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were evaluated. [DMP]+[Tf2N]! concentration in acetonitrile-methanol

(60:40, v/v) was investigated between 30 and 70 mM.
Papp et al. [16] developed and validated capillary electrophoresis
methods using Cyclodextrins (CDs) for the chiral detection of lansoprazole
and rabeprazole. A preliminary analysis was performed on 14 separate neu-
tral and anionic CDs at pH 4 and 7. The most suitable chiral field for both
compounds was found to be sulfobutyl—with a number 6.5 and 10 substi-
tution at neutral pH. Specific dual CD systems were also compared and
probable enantiomer separation mechanisms were discussed. The most suit-
able method for separations was a dual selector method comprising
sulfobutyl-ether-β-CD substitution 6.5 and native γ-CD. Optimization
of the procedure was achieved by an experimental design method with
an initial fractional factor screening design and a core composite design to
achieve the desired analytical criteria. Optimized procedures (25 mM phos-
phate buffer, pH 7, 10 mM sulfobutyl-ether-β-CD/20 mM γ-CD, +20 kV
voltage; 17 °C temperature; 50 mbar/3 s injection, detection at 210 nm for
lansoprazole; 25 mM phosphate buffer, pH 7, 15 mM sulfobutyl-ether-β-
CD/30 mM γ-CD, +20 kV voltage; 18 °C temperature; 50 mbar/3 s injec-
tion, detection at 210 nm for rabeprazole) provided a baseline separation for
the enantiomers with desirable migration order of lansoprazole (Rs ¼ 2.91)
and rabeprazole (Rs ¼ 2.53). The developed methods were evaluated in
compliance with current guidance.
5.2.3.2 Thin layer chromatography

Raval et al. [17] established a thin layer chromatographic method for
the simultaneous estimation of combinations of the ondansetron in solid
dose form with omeprazole and rabeprazole. The procedure consisted of
separating components with TLC from pre-coated silica gel 60F254 using
a dichloromethane mixture:methanol (9:1) as a mobile phase. Spots of
ondansetron with omeprazole and rabeprazole were observed at 309 and
294 nm, respectively. The maximum ondansetron and omeprazole retarda-
tion factor were found to be 0.42 # 0.02, 0.54 # 0.03, respectively. The
average factor of retardation was 0.42 # 0.02, 0.54 # 0.03 for ondansetrone
and omeprazole, respectively. While for ondansetron and rabeprazole was
0.41 # 0.02 and 0.51 # 0.02, respectively. The linearity range of three
medications was 0.1–0.5 μg/spot.
Pateli et al. [18] was developed high liquid chromatography (HPLC) and
thin-layer chromatography (TLC) methods for the quantitative estimation of
rabeprazole and mosapride for their combined pharmaceutical formulation.
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In the TLC, ethyl acetate-methanol-benzene was used as the mobile phase

(2:0.5:2.5, v/v). The retention times of rabeprazole and mosapride were
found to be 4.93 # 0.01 and 9.79 # 0.02, respectively. The Rf values were
0.42 # 0.02, and 0.61 # 0.02, for rabeprazole and mosapride, respectively.
In TLC, the detection limit for rabeprazole and mosapride were 132.29
and 98.25 ng/point, respectively. In HPLC, the limit of detection was found
to be 97.7 ng/mL for rabeprazole and 97.6 ng/mL for mosapride. The pro-
posed methods can be applied to the determination of rabeprazole and
mosapride in pharmaceutical dosage forms.
In order to evaluate Rabeprazole sodium and its degradation compo-
nents, Osman et al. [19] was established and validated stability indicating
spectrofluorometric, TLC-densitometric and HPLC procedures. A TLC
procedure was based on acidic medium followed by densitometric estima-
tion of the spot’s intact drug at 284 nm. The separation was carried out on
Fluka TLC sheets of silica gel 60F254 using isopropyl alcohol–30% ammo-
nia (80 + 2, v/v) mobile phase.
The procedure for a simultaneous measurement of rabeprazole and
domperidone was described and validated by Patel et al. [20] using high-
performance thin-layer chromatography (HPTLC) in pure powder and in
capsule formulations. A HPTLC method was performed using ethyl
acetate-methanol-benzene-acetonitrile (30:20:30:20, v/v) as a mobile phase
in an aluminum plate of silica gel 60F254 with a UV detection at 287 nm.
Quantitation was performed over a 400–1200 and 600–1800 ng/spot con-
centration range with mean recovery of 99.82 # 0.74 and 99.43 # 0.68 for
rabeprazole and domperidone, respectively.
A chromatographic high-performance thin layer (HPTLC) approach for
simultaneous determination rabeprazol sodium and domperidone in com-
bined tablet dosage was developed and validated by Gandhi et al. [42].
The mobile phase was toluene-acetone-methanol (4.5 + 4.5 + 0.5, v/v/v)
with a UV detection at 285 nm. The rabeprazole sodium and domperidone
retention factors were 0.53 # 0.12 and 0.32 # 0.20. The approach was val-
idated in terms of linearity, accuracy, and robustness. The method was
complied with Beer’s law in the range of 50–800 ng/band, for both drugs.
5.2.3.3 High-performance liquid chromatography

Elkady et al. [43] developed and validated bio-analytical LC-MS/MS
method for the simultaneous extraction and determination of four pro-
ton pump inhibitors: esomeprazole, lansoprazole, pantoprazole and rabe-
prazole in human plasma using escitalopram as an internal standard.
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The analytes were extracted from plasma samples using precipitation of

proteins with acetonitrile. A mobile phase of 10 mM ammonium for-
mate:acetonitrile:methanol (20:40:40%, v/v) was used for separating at a
flow rate 0.8 mL/min. in isocratic mode on a reversed phase C18
INERTSIL ODS-3 (5 μm, 150 $ 4.6 mm) and column temperature of
40 °C. Positive mode electrospray ionization source was used prior to multiple
reaction monitoring (MRM) detection using parent and daughter ions: m/z
346.2 ! 198.1 for esomeprazole, m/z 370.1 ! 252 for lansoprazole, m/z
384.2 ! 200.2 for pantoprazole, m/z 360.1 ! 242.1 for rabeprazole and
m/z 325.2 ! 109 for escitalopram. The curves of calibration were linear
in a concentration range of 20–5000 ng/mL. The method was completely
validated in accordance with US-FDA and EMA guidelines. Further
methods of high-performance liquid chromatography are tabulated in
Table 5.
5.3 Determination in body fluids and tissues

5.3.1 Chromatographic methods
Zhang et al. [48] developed and validated a liquid chromatography analytical
method, combined with tandem mass detection for estimation of rabeprazole
in human plasma using omeprazole as an internal standard. N-hexane–
dichloromethane–isopropanol (20:10:1, v/v) was used to extract both
rabeprazole and omeprazole (internal standard) and was isocratically
chromatographed on a column for the Diamonsil C19. The mobile phase
was methanol in order to prevent rabeprazole decomposition. The com-
pound was detected using an atmospheric pressure chemical ionization
method in the chosen reaction monitoring mode. The cycle was linear
in the 2.0–800 ng/mL concentration range. The lower limits were
2.0 ng/mL. The intra- and interday precision, measured using samples
from quality control (QC), was less than 9.8%. The accuracy was within
#1.1%. Following oral application of 20 mg of rabeprazole to 18 healthy
volunteers the procedure was used in a pharmacokinetic analysis.
Su et al. [69] developed and applied a super-critical fluid chromatography
chiral method tandem mass spectrometry to determine (R)-rabeprazole in
dog plasma and (S)-rabeprazole. After the addition of (R)-lansoprazole as
internal standard, the sample preparation was precipitated by protein with
acetonitrile. The simple separation of enantiomers within a time of
4.5 min was performed with an Acquity UPC2 method using a 60 °C col-
umn ACQUITY UPC2 Trefoil CEL2. The mobile phase was methanol:
CO2 (30:70, v/v) delivered at flow rate of 2.5 mL/min. The transitions at
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m/z 360.0–242.2 (rabeprazole) and 370.3–2252.0 (internal standard) were

observed by multiple reaction monitoring methods in the positive ion
mode. Inter-day precision in the range of !2.6% to 3.1% was less than
10.0% with accuracy. After the administration of a single oral dose of beagle
racemates in 10 mg, the procedure was successfully extended in a pharma-
cokinetic analysis of rabeprazole enantiomers.
5.3.2 Radioiodination methods

Sanad and Challan [70] used 131I to label Rabeprazole to give
131
I-rabeprazole in 98% yield. The optimum conditions were as follows:
pH 8, 100 μg of chloramine-T, 30 min, and 0.2 mg of rabeprazole. The
labeled Rabeprazole was stable for 24 h. After intravenous injection, bio-
distribution in mice was analyzed of 131I-rabeprazole and its high absorp-
tion in the stomach ulcer, reaching about 38% ID/g at 1 h after injection,
was reported. The concentration of the labeled compound was appropriate
for ulcer imaging in the stomach ulcer. Easy labeling, high protocol yield
and ulcer imaging are the advantages of the method.
6. Stability
6.1 Stability indicating method
In the presence of both impurities and degradation products resulting from
decomposition of rabeprazole, Buchireddy et al. [71] developed a stability-
indicating reverse-phase high-level liquid chromatographic system for
rabeprazole analyzes. As acid hydrolysis, oxidation, photolytic and thermal
stress was encountered, degradation, and aqueous hydrolysis were observed.
The medication was found to be stable against other stress conditions.
Kuchana et al. [72] developed a stability indicating method for a simul-
taneous determination of four active pharmaceutical ingredients, namely,
Pantaprazole (PAN), Rabeprazole (RAB), Lansaprazole (LAN) and
Domperidone (DOM) in their bulk and dosage forms by a RP-HPLC-
DAD method. The separation was executed using reverse phase chroma-
tography on X Bridge (3 $ 100 mm; 3.9 μm) C18 column with a gradient
program. Solvent A was consisted of Triethylamine in phosphate buffer at
pH 7.5 adjusted with ortho-phosphoric acid. Solvent B consisted of a mix-
ture of methanol:acetonitrile (85:15). The mobile Phase A was prepared by
mixing solvent A with solvent B in the 90:10 (v/v) ratio. The Mobile
Phase B was prepared by mixing the Solvent A with Solvent B in the
20:80 (v/v) ratio. The mobile phase-A (0–3 min:70–70; 3–7 min:70–40;
7–20 min:40–40; 20–21 min:40–40; 21–25 min:70–70) with gradient
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composition and the mobile flow was 0.6 mL/min. The temperature of col-
umn oven was maintained at 21–24 °C, run time was 25 min. Quantification
was achieved by the PDA detector and the effluents at 283 nm were mon-
itored for four drugs and their combination drug products were exposed to
various stress conditions. The correlation coefficient (r2) of all the calibra-
tion curves of four drugs was found to be 0.999. The Limit of detection for
Pantaprazole, Rabeprazole, Lansaprazole and Domperidone were found to
be 0.782, 0.897, 0.142 and 0.185 μg/mL, respectively. The Limit of quan-
titation for studied drugs were found to be 2.524, 2.894, 0.459 and
0.599 μg/mL, respectively.
In compliance with ICH Guidelines Q1A (R2), Bhandi et al. [73] stud-
ied force degradation products of rabeprazole. A Purospher STAR, C-18
(250–4.5 mm, 5 μ) with 10 mM ammonium acetate (pH !7.0) was used to
achieve a chromatographical separation of the compound and its degener-
ation products. A mixture of 10 degradation products (R1–R10) was iden-
tified and characterized by experiments with LC-ESI-MS/MS and precise
mass measurements. A study of the fragmentations of rabeprazole [M + H]+
ions and of their degradation products was suggested as the most possibly
formation method of the DPs. Semi preparatory HPLCs were isolated using
Water’s X-bridge Prep C18 (250–10 mm, 5 μ) for major degradation prod-
ucts (R3, R4, and R7). In vitro-toxicity measurement, more than 50% cell
inhibition in HepG2 cell and PANC-1 cell lines showed isolated degrada-
tion products at concentrations less than 1 μM. Studies of DNA binding
using spectroscopic techniques demonstrated that the ligand molecules
R3, R4, and R7 binded to the double-stranded DNA surface and stabilized
the DNA complex.
6.2 Solid-state stability

Ren et al. [74] reported that Rabeprazole Sodium (RPN) was highly unstable
in acid conditions or some acidic pharmaceutical excipients, such as acrylic
acid polymers (carbomer 934) with carboxylic acids. Therefore, a Fourier
transform infrared (FT-IR) spectroscopy was used to investigate the degrada-
tion process of binary rabeprazole blends in a solid state, without the use
of solvents in three different ratios (3:1, 1:1, and 1:3). A comparison was also
performed with alkalizers (MgO), neutral hydroxypropymethylcellulose
(HPMC 4000). The binary compositions were stored under speedy condi-
tions (40 °C/75 percentage relative moisture) for 2 weeks. When the
rabeprazole concentration reduced, concentrations of Thioether rabeprazol
in binary blends of acidic Carbomer 934 increased. Furthermore, the
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rabeprazole degradation half-life besides the relative peak area ratios

obtained from FTIR spectra of S]O stretching at 1094.1 cm!1 decreased
consistently as the fraction of carbomer 934 increased due to its sensitivity
between the basic benzimidazole nitrogen and carboxylic acid group of car-
bomer 934. In the presence of carbomer 934, the physical appearance
turned to a solid brown color. In comparison, the kinetics of rabeprazole
degradation with MgO and HPMC 4000 did not improve substantially
in their solid state. This current research indicated that the chromatographic
HPLC and FT-IR spectral analysis for solid state compatibility testing may
provide a valuable technique to evaluate appropriate pharmaceutical excip-
ients and elucidate the role of degradation in early formulation of drug for-
mulations through RPN.
6.3 Solution-phase stability

Ren et al. [75] investigated the chemical stability of a rabeprazole sodium,
which was evaluated in a simulated intestinal fluid (pH 6.8) containing
various “Generally Recognized As Safe (GRAS)”-listed excipients, includ-
ing Brij® 58, Poloxamer 188, Cremophor RH40, Gelucire 44/14 and
PEG 6000. The quantities of rabeprazole and the thioether-rabeprazole
product were quantified by HPLC after incubation at 37 and 60 °C. The
major degradation component was isolated and characterized by LC/MS.
Rabeprazole degradation followed kinetics of the first order. The rate con-
stants (k) obtained at 37 and 60 °C was 0.75 and 2.78 h!1, respectively. By
comparison, its stability was enhanced by incorporating excipients. Brij®58
had the greatest stabilizing effect of several excipients tested in this experi-
ment. At 37 and 60 °C, for instance, the k values of Brij®58 decreased to 0.22
and 0.53 h!1. In terms of their solubilizing performance and micellar formu-
lation of thioether rabeprazole, the stability mechanisms of these hydrophilic
polymer was excellent devices with optimum Hydrophile-lipophile balance
(HLB) values explained in detail. In addition, formulations containing suf-
ficient excipients of rabeprazole would improve the stability and bioavail-
ability of the intestinal tract.
7. Uses
Rabeprazole is used for gastric acid suppression, like other proton
pump inhibitors such as omeprazole. This effect helps to treat and prevent
conditions in which gastric acid directly aggravates symptoms such as duo-
denal and gastric ulcers. Acid suppression may provide symptomatic relief in
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the setting of gastroesophageal reflux disease (GERDs), which has long-term

gastric exposition in the esophageal because of changes in the stomach or
esophageal anatomy such as those due to abdominal obesity. The suppres-
sion of acid is also helpful in increasing a gastric acid production including
over secretion of gastric acid (excess gastric acid conditions) such as
Zollinger-Ellison, several endocrine adenomas and systemic mastocytoses.
In addition to antibiotic therapy, Rabeprazole is used in the treatment of
Helicobacter pylori pathogen, which otherwise thrives in acidic environments.
A randomized trial in high risk South Korean people with endoscopically
treated early stomach cancer has also demonstrated that H. pylori elimination
with antibiotics and Rabeprazole prevented developing a second stomach
cancer. Rabeprazole is FDA approved for treating symptomatic GERD
for adolescents and adults, healing duodenal ulcers in adults and the eradi-
cation of Helicobacter pylori [76–78].
8. Pharmacology
8.1 Pharmacodynamic properties
In fact, all PPIs that are substituted for benzimidazoles, have the same anti-
secretory pathways, which is the most effective means for raising the pH in
the stomach and hence for achieving the therapeutic level for GERD. They
concentrate on the secretory canaliculus in paretic cell. A conversion to an
active sulfenamide compound (the rate-restricting phase) is carried out in the
protonated molecules which form covalent disulfide-inhibiting bonds with
H+/K+ ATPases surface-exposed cell cysteines. In terms of acid stability, the
PPIs differ as the modified functional replacements in two ring structures
provide the highest pKa (approximately 5.0, the pH at which a drug
becomes 50% protonated), and hence the molecule can be activated at
higher pH levels much faster than other PPI: Raboprazole took 1.3 min
to be half-activated at pH 1.2 (channel room pH after meals), compared
to 2.0, 2.8 and 4.6 min for both lansoprazole, omeprazole and pantoprazole,
respectively. At pH 5.1 (the pH during fasting), the activation half-life for
rabeprazole, lansoprazole, omeprazole and pantoprazole was 7.2, 90, 84,
and 282 min, respectively [79].
Rabeprazole has demonstrated its efficient and fast action in an isolated
hog vesicle model: the proton pump has been almost completely inhibited
within 5 min of Rabeprazole treatment. Lansoprazole and omeprazole
achieved the same target after 30 min but only 50% could be blocked by pan-
toprazole at the end of the 50-min test [80]. Consequently, rabeprazole
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prevents basal and peptone food-stimulated gastric acid production as a result

of dose-related continuous inhibition [81,82].
The antisecretory function of PPIs is well known to predict their success
in conditions associated with antacids. The correlation of Double ulcer
treatment was found with an intragastric pH > 3 lasting 18–20 h, whereas
erosive GERD cure with a pH roughly 24 h > 4 staying time [83,84].
Latest research has established in vivo previous evidence that after first
administration, rabeprazole can achieve adequate acid depression and sustain
this benefit over the next days of treatment. This results in a mean higher
intragastric pH of 24 h and longer spans of pH > 3 and >4 compared to
omeprazole [85].
It concluded, in the first 24 h after the dose, the higher pKa of rabeprazole
could justify its significant anti-screening effect compared with the other
tested of PPI formulations. Comparative 18H test in a multiple conver-
gence. Adults with pylorio-negative, rabeprazole 20 mg will have a 24-h
average gastric pH of 3.4, compared to 2.9 for 30 mg lansoprazole, 2.2
for 40 mg pantoprazole; 1.9 for 20 mg omeprazole; 1.8 for omeprazole
20 mg MUPS, and 1.3 for placebo (P < 0.05 vs all other PPI and placebo).
Moreover, rabeprazole holds pH > 4 for a longer duration of (8 h) than other
agents (7.4, 4.9, 2.9, 3.0 and 0.9 h, respectively, P ' 0.04 for rabeprazole vs
other agents) [86].
The acid suppression levels of lansoprazol 15 and 30 mg are greater than
those of rabeprazole 10 and 20 mg for hours 0–5 for days 1 and 5, respec-
tively, while rabeprazole is a comparable or a more effective for hours
11–24 on both days. Exactly 72 healthy patients received four PPIs therapies
in an open-label, randomized combination trial for 5 days with 2-week
washout periods and underwent on-going 24-h intragastric pH, 1 and 5 days,
on baseline. The mean pH period >4 was comparable with the mean 24-h
pH for both PPIs on days 1 and 5, but rabeprazole 10 mg statistically higher
than 15 mg lansoprazole [87].
8.1.1 Mechanism of action

Rabeprazole sodium is in the family of anti-secretory drugs, substituted for
benzimidazols, which do not have antagonistic effects with anticholine or
H2 histamine but which inhibit the secretions of gastric acid by causing
H+/K+-ATPase (acid or proton pump) in particular. Dose-connected effect
allows both basal and induced acid secretion to be blocked independent of
stimulation. Animal tests demonstrate that rabeprazole sodium easily disap-
pears both from plasma and gastric mucosa following administration.
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Rabeprazole is consumed easily after any dose as a depleted base and con-
centrates in the parietal cell acid region. Rabeprazole is converted by pro-
tonation into the active sulphenamide form and interacts with the available
cysteines on the proton pump afterwards [88].
8.1.2 Clinical efficacy and safety

The anti-secretive effect occurs about 1 h of orally administration of a 20 mg
rabeprazole sodium dose, with the full effect-taking place about 2–4 h. The
basal-and nutritionally induced secretion of acid is reduced for up to 48 h and
is 69–82% 23 h after the first dose of rabeprazole sodium. For repeated once-
daily doses, rabeprazole sodium has an inhibitor effect on the secretion of
acid, resulting in a steady state inhibition after 3 days. The confidentiality
operation normalizes within 2–3 days after the medication is stopped [88].
Reduced stomach acidity by some means, even rabeprazole, reduces the
bacteria levels usually present in the gastrointestinal tract. Therapy of PPIs
may raise the chance of GI infection including Salmonella, Campylobacter
and Clostridium difficile. Therapy may improve. Patients treated with
rabeprazole sodium (10 or 20 mg) once daily for up to 43 months in clinical
trials leading to rise the levels of serum gastrine during the first 2–8 weeks,
indicating the inhibitory effects on acid secretion. The values of gastrine ret-
urned to rates of pretreatment normally in 1–2 weeks after therapy stop [88].
Serum gastrine improves in response to the decrease in acid secretion
when treated with antisecretory medicines. CgA also improves owing to
a reduced acidity in stomach. The higher CgA level will interfere with neu-
roendocrine tumor studies. Published literature suggests that the antagonists
of proton pumps will be stopped between 5 days and 2 weeks before calcu-
lating CgA. This is to enable CgA levels to return to the reference range
which may be spuriously elevated during PPI treatment. The ECL histol-
ogy, the degree of gastritis, the effect of gastritis on atrophies, intestinal meta-
plasia, or distribution of H has not been observed in human gastric biopsies
from antrum and fundus in 500 patients under rabeprazole or comparator for
up to 8 weeks. There was no substantial improvement in the results present
at baseline in over 250 patients who endured 36 months of ongoing therapy.
Other impacts: CNS, digestive and respiratory processes have not yet been
proven to have a cumulative effect by rabeprazole sodium.
Rabeprazole sodium, administered at an oral intake of 20 mg for 2 weeks,
had no effect upon thyroid activity, metabolism of carbohydrates or circula-
tory levels of parathyroid hormones, cortisol, estrogen, testosterone, prolactin,
cholecystokininine, secretin, glucagon, follicular stimulating hormone (FSH).
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Studies in healthy voluntaries found that rabeprazole sodium does not inter-
fere with amoxicillin clinically substantially. When co-administrated to
extract the upper gastrointestinal H., rabeprazole does not negatively influ-
ence the plasma concentrations of amoxaicillin or clarithromycin Infection
of the H. pylori [88].
8.2 Pharmacokinetic properties

Rabeprazole is an enterically coated formulation since all PPIs are unstable
in acidic environments. This is consumed fairly rapidly after oral intake, as
the maximum plasma concentration (Cmax) is reached between 2.8 and 5.1
post-dose [89].
The molecular pharmacokinetics were shown to be linear in the
10–80 mg range, with a total bioavailability of 52%, seen with rabeprazole
20 mg. While Cmax and AUC are proportional to the dosage taken to the
plasma concentration, Cmax duration and half-life are dosage-independent.
The findings suggest that the first-pass metabolism of the rabeprazole is
unsaturated and can be absorbed in high doses [89]. However if food sources
prolonged the absorption of rabeprazole 20 mg by about 1.7 h and decreased
apparent removal halving-life owing to a potentially prolonged gastric
emptying, no acid or diet affect the bioavailability of the molecule [89].
The delivery amount of rabeprazole in different tissues, including gastric
mucosa, intestine, lung, blood cord, liver, bowel and thyroid have been
shown by preclinical studies. It has been shown that bound to plasma
proteins are 94.8–97.5% in healthy volunteers [89].
During repetitive administration, no major accumulation occurs as the
elimination half-life of 1 h after single administration is 1.5 h after several
administrations. A 20 mg dosage of rabeprazole (thioether iron, glucuronide
and mercaptopurine metabolites) is excreted in the urine at about 90% and in
faces 10% [89–91].
Rabeprazole is unique in its elimination. Whereas other PPIs including
omeprazole, lansoprazole, esomeprazole and pantoprazole are mainly
metabolized in the liver by CYP2C19, Rabeprazole is mainly metabolized
by a non-enzymatic pathway to rabeprazole thioether and, to a lesser extent,
by the cytochrome P450 isoenzymes CYP2C19 (demethylated rabeprazole)
and CYP3A4 (rabeprazole-sulfone). It is understood that variations in the
function of this enzyme are genetically determined. CYP2C19 genotypes
have been classified into three groups: rapid extensive metabolism (RM),
intermediate metabolism (IM) and poor metabolism (PM). PPIs depend
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on CYP2C19 genotype status in pharmacokinetics or pharmacodynamics.

Plasma PPI concentrations and intragastric pHs are lowest in the RM group
during the PPI procedure, the IM group is nearest, and the PM group
is highest of the three groups. The variations in CYP2C19 in PPI pharma-
cokinetics and pharmacodynamics, depending on the genotype, influence
the cure levels of gastroesophageal reflux and therapy-based H. pylori infec-
tion. Dose and dosage schemes of PPIs should be modified depending on
the genotype status of CYP2C19 for better PPI-dependent care [92].
The unusual catabolic mechanism suggests that rabeprazole is less sensitive
to the effects of genetic polymorphism on CYP2C19, leading to limited
pharmacokinetic and pharmacodynamic effects.
While the rabeprazole pharmacokinetic profile is altered in older people
(Cmax increased 60%, and AUC doubled after 7-day rabeprazole treatment
by 20 mg), and in patients with mild to moderate hepatic dysfunction (Cmax
increased by 50% and AUC by 20 mg). Nonetheless, no dosage change is
required in different populations, despite the evidence that these pharmaco-
kinetic changes were not associated with clinically relevant laboratory
parameters or severe adverse overnight effects in patients with renal defects
(after a dosage of rabeprazole 20 mg the day after hemodialysis and the
second dose after a period of 2 weeks throughout dialysis) [90].
Such results are not the case for antagonists of H2 receptor, where dose
changes were reported if the patients have mild to seriously compromised
renal function [93] but not associated with those of other PPIs [94].
8.3 Dosing
8.3.1 Dosing: adult
Duodenal ulcer: Tablets: Oral: 20 mg once daily for '4 weeks; additional
therapy to achieve healing may be required for some patients.
Dyspepsia (off-label use): Oral: 20 mg once daily for up to 8 weeks
[95,96].
Gastric ulcer (treatment) (off-label use): Oral: 20 mg once daily [97,98]
for generally 8 weeks based on healing and/or ulcer complications [99,100].
8.3.1.1 Gastroesophageal reflux disease (GERD)

Tablets: Oral: Erosive or ulcerative GERD: Treatment: 20 mg once daily for
4–8 weeks; if inadequate response, may repeat up to an additional 8 weeks;
maintenance: 20 mg once daily.
Symptomatic GERD (nonerosive): Treatment: 20 mg once daily for
'4 weeks; if inadequate response, may repeat for an additional 4 weeks.
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Helicobacter pylori eradication: Tablets: Oral:

Manufacturer labeling: 20 mg twice daily administered with amoxicillin
1000 mg and clarithromycin 500 mg twice daily for 7 days.
American College of Gastroenterology guidelines ACG [101,102].
Clarithromycin triple regimen: 20–40 mg twice daily in combination
with clarithromycin 500 mg twice daily and either amoxicillin 1 g twice daily
or metronidazole 500 mg three times per day; continue regimen for 14 days.
Note: Avoid use of clarithromycin triple therapy in patients with risk factors
for macrolide resistance (e.g., prior macrolide exposure, local clarithromycin
resistance rates (15%, eradication rates with clarithromycin-based regimens
'85%) [101,103].
Bismuth quadruple regimen: 20 mg twice daily in combination with tet-
racycline 500 mg four times per day, metronidazole 250 mg four times per
day or 500 mg three or four times per day, and either bismuth subcitrate
120–300 mg four times per day or bismuth subsalicylate 300 mg four times
per day; continue regimen for 10–14 days.
Concomitant regimen: 20 mg twice daily in combination with amox-
icillin 1 g twice daily, clarithromycin 500 mg twice daily, and either
metronidazole or tinidazole 500 mg twice daily; continue regimen for
10–14 days.
Sequential regimen: 20 mg twice daily plus amoxicillin 1 g twice daily for
5–7 days; then continue rabeprazole along with clarithromycin 500 mg
twice daily, and either metronidazole or tinidazole 500 mg twice daily for
5–7 days.
Hybrid regimen: 20 mg twice daily plus amoxicillin 1 g twice daily for
7 days; then continue rabeprazole and amoxicillin along with clarithromycin
500 mg twice daily, and either metronidazole or tinidazole 500 mg twice
daily for 7 days.
Levofloxacin triple regimen: 20 mg twice daily in combination with
amoxicillin 1 g twice daily and levofloxacin 500 mg once daily; continue
regimen for 10–14 days.
Hypersecretory conditions (including Zollinger-Ellison syndrome):
Tablets: Oral: Initial: 60 mg once daily; adjust dose to patient needs (some
may require divided doses). Doses as high as 100 mg once daily and 60 mg
twice daily have been used; continue as long as clinically indicated.
NSAID-induced ulcer prophylaxis (off-label use): Oral: 5–20 mg once
daily for 12–24 weeks [104,105].
Prevention of recurrent gastric or duodenal ulcer bleeding post-
endoscopy (off-label use): Oral: 20 mg twice daily for 72 h [106].
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8.3.2 Dosing: Pediatric

GERD, symptomatic:
Children '11 years: Oral: Sprinkle capsules:
<15 kg: 5 mg once daily for '12 weeks; if inadequate response may
increase to 10 mg once daily.
(15 kg: 10 mg once daily for '12 weeks.
Children (12 years and adolescents: Oral: Tablets: 20 mg once daily for
up to 8 weeks [107].
8.4 ADME profile

ADME: Oral administration
Rabeprazole’s bioavailability is approximately 52%, meaning that 52% of
orally administered dose is expected to enter systemic circulation (the blood-
stream). The bioavailability of rabeprazole is not affected by either food or
ant acids [108].
8.4.1 Absorption
Rabeprazole sodium is an enteric-coated (gastro-resistant) tablet formula-
tion of rabeprazole sodium. This is necessary because rabeprazole is
acid-labile. Absorption of rabeprazole therefore begins only after the tablet
leaves the stomach. Absorption is rapid, with peak plasma levels of
rabeprazole occurring approximately 3.5 h after a 20 mg dose. Peak plasma
concentrations (Cmax) of rabeprazole and AUC are linear over the dose
range of 10–40 mg. Absolute bioavailability of an oral 20 mg dose (com-
pared to intravenous administration) is about 52% due in large part to
pre-systemic metabolism. Additionally, the bioavailability does not appear
to increase with repeat administration. In healthy subjects the plasma half-
life is approximately 1 h (range 0.7–1.5 h), and the total body clearance is
estimated to be 283 # 98 mL/min. There was no clinically relevant inter-
action with food. Neither food nor the time of day of administration of the
treatment affect the absorption of rabeprazole sodium [88].
8.4.2 Distribution
Rabeprazole is approximately 97% bound to human plasma proteins [88].
8.4.3 Metabolism and elimination

Rabeprazole sodium, as is the case with other members of the proton pump
inhibitor (PPI) class of compounds, is metabolized through the cytochrome
P450 (CYP450) hepatic drug metabolizing system. In vitro studies with
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human liver microsomes indicated that rabeprazole sodium is metabolized

by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at
expected human plasma concentrations rabeprazole neither induces nor
inhibits CYP3A4; and although in vitro studies may not always be predictive
of in vivo status these findings indicate that no interaction is expected
between rabeprazole and cyclosporin. In humans the thioether (M1) and car-
boxylic acid (M6) are the main plasma metabolites with the sulfone (M2),
desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor
metabolites observed at lower levels. Only the desmethyl metabolite
(M3) has a small amount of anti-secretory activity, but it is not present in
plasma. Following a single 20 mg 14C labeled oral dose of rabeprazole sodium,
no unchanged drug was excreted in the urine. Approximately 90% of the dose
was eliminated in urine mainly as the two Metabolites: a mercapturic acid
conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites.
The remainder of the dose was recovered in faces.
Gender: Adjusted for body mass and height, there are no significant gen-
der differences in pharmacokinetic parameters following a single 20 mg dose
of rabeprazole.
Renal dysfunction: In patients with stable, end-stage, renal failure
requiring maintenance hemodialysis (creatinine clearance '5 mL/min/
1.73 m2), the disposition of rabeprazole was very similar to that in healthy
volunteers. The AUC and the Cmax in these patients was about 35% lower
than the corresponding parameters in healthy volunteers. The mean half-life
of rabeprazole was 0.82 h in healthy volunteers, 0.95 h in patients during
hemodialysis and 3.6 h post dialysis. The clearance of the drug in patients
with renal disease requiring maintenance hemodialysis was approximately
twice that in healthy volunteers.
Hepatic dysfunction: Following a single 20 mg dose of rabeprazole to
patients with chronic mild to moderate hepatic impairment the AUC dou-
bled and there was a 2–3-fold increase in half-life of rabeprazole compared to
the healthy volunteers. However, following a 20 mg dose daily for 7 days the
AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-
life of rabeprazole in patients with hepatic impairment was 12.3 h compared
to 2.1 h in healthy volunteers. The pharmacodynamic response (gastric pH
control) in the two groups was clinically comparable [88].
8.4.3.1 Elderly
Elimination of rabeprazole was somewhat decreased in the elderly.
Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the
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AUC approximately doubled, the Cmax increased by 60% and t½ increased

by approximately 30% as compared to young healthy volunteers. However,
there was no evidence of rabeprazole accumulation.
CYP2C19 Polymorphism: Following a 20 mg daily dose of rabeprazole
for 7 days, CYP2C19 slow metabolizers, had AUC and t½ which were
approximately 1.9 and 1.6 times the corresponding parameters in extensive
metabolizers while Cmax had increased by only 40% [88].
8.4.4 Preclinical safety data

The most common metabolites excreted in the urine are the mercapturic
acid conjugate and carboxylic acid [109].
Only at exposures which exceeded the maximum human exposure was not
observed enough to cause human safety concerns in relation to animal data
were non-clinical effects noted. Studies on mutagenicity gave equivocal results.
Tests in mouse lymphoma cell line were positive, but in vivo micronucleus
and in vivo and in vitro DNA repair tests were negative. Carcinogenicity
studies revealed no special hazard for humans. Mutagenicity tests have
provided equivocal data. Tests were successful on the cell line of mouse
lymphoma, but the in vitro and in situ DNA repair were poor. Trials on
mouse lymphoma cells, there was no special threat for humans found in
carcinogenicity tests [88].
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2 Ahmed H. Bakheit et al.

1.1.1.2 Rabeprazole sodium salt

1.1.2 Non-proprietary names

1.1.3 Proprietary names (brand names)

Rabeprazole: A comprehensive profile 3

1.2.2 Structural formula

1.3 Elemental analysis

Table 1 Empirical formula, molecular weight, CAS number [6].

Rabeprazole base Rabeprazole sodium salt

Fig. 1 Rabeprazole base and salt structure.

4 Ahmed H. Bakheit et al.

Scheme 1 Synthesis of rabeprazole by Souda method.

Rabeprazole: A comprehensive profile 5

Scheme 2 Synthesis of rabeprazole by Ray method.

treated by m-Chloroperabenzoic acid at 58 °C for 85 min and maintained for

6 Ahmed H. Bakheit et al.

Scheme 3 Synthesis of rabeprazole by Vardanyan method.

Scheme 4 synthesis of 2-Mercapto[2-14C]-benzimidazole 4 by Amersham

obtained compound with 2-mercapto benzimidazole 8 in the presence of

Rabeprazole: A comprehensive profile 7

A mixture of an ethanolic solution containing of 2-mercapto[14C]

Scheme 5 Synthetic process for sodium [14C] rabeprazole.

8 Ahmed H. Bakheit et al.

3.2 Dissociation constants

3.3 Flash point, and vapor pressure

3.4 Solubility characteristics

3.5 Partition coefficient

3.6 Particle morphology

Table 3 The X-ray powder diffraction pattern of rabeprazole.

Rabeprazole: A comprehensive profile 9

Fig. 2 The X-ray powder diffraction pattern of rabeprazole.

4. Characterization and identification

4.1.2 Differential scanning calorimetry

4.1.3 Thermogravimetric analysis

10 Ahmed H. Bakheit et al.

Fig. 3 DSC curves of rabeprazole RS.

50 100 150 200 250 300

4.2 UV/vis spectroscopy

Rabeprazole: A comprehensive profile 11

Fig. 5 The UV-absorption spectrum of 20 μg/mL of rabeprazole in acetonitrile.

Fig. 6 IR spectrum of rabeprazole.

(20 μg/mL) in methanol. The absorption spectra are measured in a 1 cm quartz

4.3 Infrared spectroscopy

12 Ahmed H. Bakheit et al.

Table 4 Interpretation of rabeprazole FT-IR spectra.

4.4 Mass spectrometry

18 Ahmed H. Bakheit et al.

x10 4 + Scan (0.435 min) S ample 2.d

Fig. 7 Traces show full scan mass spectra of rabeprazole.

20 Ahmed H. Bakheit et al.

potassium carbonate R solution to a 0.05 g/mL of Rabeprazole sodium solu-

5.1.2 Related compounds

Rabeprazole: A comprehensive profile 21

• USP Rabeprazole Related Compound B RS 2-{[(1H-benzimidazol-

5.2 Reported methods of analysis

22 Ahmed H. Bakheit et al.