RABEPRAZOLE SODIUM

Rabeprazole is a substituted benzimidazole proton pump inhibitor (PPI) developed in the 1990s for the treatment of acid-related gastrointestinal disorders. 
It is most frequently supplied as the sodium salt (rabeprazole sodium) for oral dosage forms. Rabeprazole entered clinical use as an alternative PPI with a somewhat faster onset of acid suppression in some studies and particular metabolic characteristics compared with older PPIs.

CAS: 117976-90-6

SYNONYMS: 

Rabeprazole sodium; Rabeprazole sodium salt; Pariprazole; LY307640; E-3810; 2-([4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole sodium salt.

Chemical identity and physicochemical properties
Structure and formula
IUPAC (parent neutral base): 2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole (rabeprazole base).
Salt form: rabeprazole sodium (sodium salt of the sulfoxide).
Molecular formula (sodium salt): C₁₈H₂₀N₃NaO₃S. 

Molecular weight, solubility and pKa
Molecular weight (approx., sodium salt): ~381.41 g·mol⁻¹ (depends on hydration and crystalline form).
Rabeprazole is a weakly basic benzimidazole derivative; the sodium salt increases aqueous solubility compared with the free base. 
The compound is acid-labile and degrades rapidly under strongly acidic conditions; this necessitates acid-protective strategies in oral formulations (enteric coating, buffering agents). 

Solid state (crystalline / amorphous forms)
Multiple crystalline forms, hydrates, and amorphous states of rabeprazole sodium have been described; crystalline forms and controlled amorphous material influence stability and tablet/capsule manufacturability. 
Patent literature and analytical investigations describe processes to obtain crystalline vs amorphous sodium salt and methods to avoid solvent complexes (e.g., acetone complexes). 

Synthetic routes and manufacturing processes
Overview of medicinal chemistry route (general)
Synthetic approaches to rabeprazole center on construction of the benzimidazole core and introduction of the pyridinylmethylsulfinyl side chain (the sulfoxide linkage). 
Typical routes: (a) prepare the pyridinyl methanethiol/ sulfide precursor, (b) attach the benzimidazole methyl via alkylation, and (c) oxidize the sulfide to the sulfoxide in a controlled manner to yield the desired stereochemical/oxidation state (sulfoxide). 
Final conversion to the sodium salt is achieved by neutralization with a sodium base (NaOH) under controlled conditions, followed by isolation of a selected crystalline form or drying to amorphous salt. 
Patents describe many variants and process optimizations. 

Key process considerations
Control of sulfoxide oxidation: Over-oxidation to sulfone must be avoided; stereoselectivity is not a major clinical concern (sulfoxide is achiral unless stereogenic sulfur), but impurities at sulfur are critical quality attributes.
Solvent selection and complex formation: Some solvents (acetone) can form solvates/complexes with rabeprazole sodium; process patents describe solvent systems and temperature profiles to obtain amorphous or crystalline salt free of solvates. 

Impurities and degradants from synthesis
Common process-related impurities include unoxidized sulfide precursors, overoxidized sulfones, O- or N-alkylated side products, and residual solvents. 
Regulatory submissions require identification and control per ICH Q3A/B and validation of analytical methods capable of resolving these species.

Analytical methods and quality control
Assay and related substances
High-performance liquid chromatography (HPLC, often reversed-phase) with UV detection is the standard for potency and related substance assays. 
Methods must separate rabeprazole, its major known degradants (e.g., des-alkylated species, sulfone), and common process impurities. Impurities limits are defined in regulatory dossiers and pharmacopoeial monographs when present.

Characterization techniques
Mass spectrometry (LC–MS) for mass identity and impurity profiling.
NMR (¹H, ¹³C) for structure confirmation.
XRPD (X-ray powder diffraction) and DSC for solid-state form characterization (polymorph screening).
Karl Fischer titration for water content in hydrates.
Thermogravimetric analysis (TGA) to assess solvates and dehydration temperatures.

Dissolution testing and in vitro–in vivo correlation (IVIVC)
Because rabeprazole is acid-labile, dissolution tests for rabeprazole sodium formulations often use pH-adjusted or two-stage media that reflect the buffered/enteric release behaviour; pH 8 buffer is frequently used in development dissolution studies for the sodium salt. 
Formulation composition (use of buffering granules, enteric coating quality) strongly influences dissolution profiles. 

Pharmaceutical formulations & stability
Formulation strategies
Rabeprazole sodium is sensitive to gastric acidity and many excipients; common oral dosage forms include enteric-coated delayed-release tablets and capsules, or pellets/micropellets enclosed in enteric shells. 
Some strategies:

Enteric coating of core tablet/capsules or pellets to bypass stomach acid;
Buffered formulations (e.g., co-formulation with sodium bicarbonate) that transiently raise local pH;
Dry-coating or layered pellet technologies to isolate active from moisture/excipients; patents and formulation papers discuss micro-encapsulation and multiparticulate systems to improve stability and bioavailability. 

Stability concerns
Acid hydrolysis: rapid degradation at low pH; enteric protection essential.
Moisture sensitivity: some forms/hydrates can exhibit sensitivity leading to reduced potency or altered dissolution.
Thermal and oxidative stress: must be controlled during manufacturing and packaging. 
Stability studies must include forced degradation to define degradation pathways and suitable analytical markers.

Packaging and shelf life
Blister packs (aluminum/aluminum), HDPE bottles with desiccant and oxygen/moisture barriers are common. 
Shelf life is product-dependent and established through ICH stability programs.

SAFETY INFORMATION ABOUT RABEPRAZOLE SODIUM

 
First aid measures:
Description of first aid measures:
General advice:
Consult a physician. 
Show this safety data sheet to the doctor in attendance.
Move out of dangerous area:
 
If inhaled:
If breathed in, move person into fresh air. 
If not breathing, give artificial respiration.
Consult a physician.
In case of skin contact:
Take off contaminated clothing and shoes immediately. 
Wash off with soap and plenty of water.
Consult a physician.
 
In case of eye contact:
Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.
Continue rinsing eyes during transport to hospital.
 
If swallowed:
Do NOT induce vomiting. 
Never give anything by mouth to an unconscious person. 
Rinse mouth with water. 
Consult a physician.
 
Firefighting measures:
Extinguishing media:
Suitable extinguishing media:
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas
 
Advice for firefighters:
Wear self-contained breathing apparatus for firefighting if necessary.
Accidental release measures:
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. 
 
Avoid breathing vapours, mist or gas. 
Evacuate personnel to safe areas.
 
Environmental precautions:
Prevent further leakage or spillage if safe to do so.
Do not let product enter drains.
Discharge into the environment must be avoided.
 
Methods and materials for containment and cleaning up:
Soak up with inert absorbent material and dispose of as hazardous waste. 
Keep in suitable, closed containers for disposal.
 
Handling and storage:
Precautions for safe handling:
Avoid inhalation of vapour or mist.
 
Conditions for safe storage, including any incompatibilities:
Keep container tightly closed in a dry and well-ventilated place. 
Containers which are opened must be carefully resealed and kept upright to prevent leakage.
Storage class (TRGS 510): 8A: Combustible, corrosive hazardous materials
 
Exposure controls/personal protection:
Control parameters:
Components with workplace control parameters
Contains no substances with occupational exposure limit values.
Exposure controls:
Appropriate engineering controls:
Handle in accordance with good industrial hygiene and safety practice.
Wash hands before breaks and at the end of workday.
 
Personal protective equipment:
Eye/face protection:
Tightly fitting safety goggles. 
Faceshield (8-inch minimum). 
Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
 
Skin protection:
Handle with gloves. 
Gloves must be inspected prior to use. 
Use proper glove
removal technique (without touching glove's outer surface) to avoid skin contact with this product. 
Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. 
Wash and dry hands.
 
Full contact:
Material: Nitrile rubber
Minimum layer thickness: 0.11 mm
Break through time: 480 min
Material tested:Dermatril (KCL 740 / Aldrich Z677272, Size M)
Splash contact
Material: Nitrile rubber
Minimum layer thickness: 0.11 mm
Break through time: 480 min
Material tested:Dermatril (KCL 740 / Aldrich Z677272, Size M)
It should not be construed as offering an approval for any specific use scenario.
 
Body Protection:
Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection:
Where risk assessment shows air-purifying respirators are appropriate use a fullface respirator with multi-purpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. 
 
If the respirator is the sole means of protection, use a full-face supplied air respirator. 
Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
Control of environmental exposure
Prevent further leakage or spillage if safe to do so. 
Do not let product enter drains.
Discharge into the environment must be avoided.
 
Stability and reactivity:
Chemical stability:
Stable under recommended storage conditions.
Incompatible materials:
Strong oxidizing agents:
Hazardous decomposition products:
Hazardous decomposition products formed under fire conditions. 
Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas.
 
Disposal considerations:
Waste treatment methods:
Product:
Offer surplus and non-recyclable solutions to a licensed disposal company. 
Contact a licensed professional waste disposal service to dispose of this material.
Contaminated packaging:
Dispose of as unused product