| HS Code | 629271 |
| Product Name | 5-(Difluoromethoxy)-2-mercapto-1H-benzimidazole Pharma Grade API |
| Chemical Name | 5-(Difluoromethoxy)-1H-benzimidazole-2-thiol |
| Cas Number | 134592-94-8 |
| Molecular Formula | C8H6F2N2OS |
| Molecular Weight | 216.21 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay Hplc | ≥99.0% |
| Solubility | Soluble in DMF and DMSO; sparingly soluble in methanol; practically insoluble in water; soluble in dilute aqueous alkali |
| Storage Conditions | Store in a tightly sealed container in a cool, dry area protected from light and moisture |
| Pharmaceutical Use | Pharma grade API for oral and injectable dosage forms including tablets, capsules, granules, and injections |
As an accredited 5-(Difluoromethoxy)-2-mercapto-1H- benzimidazole Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaging: 25 kg net in double polyethylene-lined aluminium bag inside HDPE drum, suitable for oral and injectable pharmaceutical formulations. |
| Container Loading (20′ FCL) | 20′ FCL container loading of 5-(Difluoromethoxy)-2-mercapto-1H-benzimidazole Pharma Grade API, safely packed for oral and injectable use. |
| Shipping | Ship as a Pharma Grade API in sealed, light-resistant, moisture-proof containers (e.g., double PE-lined drums). Protect from heat, humidity, and direct sunlight. Transport under temperature-controlled conditions with secure, tamper-evident packaging. Include full documentation, MSDS, and regulatory certificates. Avoid contact with oxidizing agents or metals during transit and handling. |
| Storage | Store in tightly closed, original containers under dry, well-ventilated conditions at controlled room temperature (20–25°C), protected from light, moisture, and excessive heat. Avoid exposure to oxidizing agents. Keep away from incompatible materials. Ensure container is properly sealed after each use. Do not store near food or direct sunlight. |
| Shelf Life | Shelf life: 24 months when stored unopened in a cool, dry place, protected from light and moisture. |
5-(Difluoromethoxy)-2-mercapto-1H-benzimidazole functions as a pharmaceutical-grade benzimidazole thiol precursor and pharmacopoeial impurity marker rather than a finished active moiety that is directly tableted, granulated, encapsulated, or injected. Its largest downstream application is the industrial synthesis of pantoprazole sodium, where the thiol group is alkylated with 2-chloromethyl-3,4-dimethoxypyridine hydrochloride in aqueous alkaline media. A representative production sequence uses a two-phase methylene chloride or toluene system in a jacketed glass-lined reactor held at 20 °C to 25 °C. The organic phase is washed with dilute sodium hydroxide and water to remove unreacted 2-mercapto benzimidazole, and the resulting pantoprazole sulfide is then oxidized with hydrogen peroxide in the presence of sodium tungstate or with meta-chloroperbenzoic acid at controlled temperature in the range 0 °C to 5 °C. Over-oxidation to pantoprazole sulfone is limited by maintaining the peroxide charge near 1.0–1.1 molar equivalents relative to the sulfide and by quenching residual peroxide with sodium bisulfite before isolation. The wet pantoprazole base is converted to pantoprazole sodium sesquihydrate with sodium hydroxide in an aqueous acetone system and crystallized to controlled particle-size specifications. For delayed-release tablet manufacture, the pantoprazole sodium API originating from this thiol intermediate is processed under nitrogen because of moisture sensitivity, blended with an alkalizing excipient system in a high-shear granulator or dry-blend formulation, compressed on rotary tablet presses, and film-coated with a methacrylic acid copolymer such as Eudragit L 100-55 plasticized with triethyl citrate. Dissolution is evaluated according to USP <711> using Apparatus II at 50 rpm; the acid-stage release in 0.1 N hydrochloric acid is controlled to NMT 10% after 2 h, and the subsequent buffer-stage release at pH 6.8 is controlled to NLT 75% after 45 min. Residual 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole is monitored at the drug-substance stage by reversed-phase HPLC with a C18 column and UV detection near 290 nm, because unreacted free thiol can oxidize to disulfide species and affect impurity profiles during finished-tablet stability studies.
Pantoprazole sodium for injection is manufactured from the same API stream that originates with the 2-mercapto benzimidazole precursor. The drug substance is dissolved in Water for Injection, adjusted to a mildly alkaline pH range of 9.0 to 10.5 with sodium hydroxide, sterile-filtered through a 0.22 µm PVDF or PES membrane, filled into Type I borosilicate glass vials, and freeze-dried in a cGMP lyophilizer with a shelf-temperature ramp profile controlled by product thermocouple data. Because residual free thiol can consume dissolved oxygen and promote oxidative by-product formation in the reconstituted solution, the compounding tank and filtration line are operated under a nitrogen gas overlay. Dissolved oxygen is monitored with an inline optical oxygen probe; the operating target is maintained below 2 mg/L before filtration. The lyophilized cake is reconstituted with 0.9% sodium chloride injection or 5% dextrose injection, and clarity is assessed against USP <790> particulate matter limits. Residual 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole and its disulfide oxidation product are controlled at the API release stage using the pharmacopoeial reference standard designated as pantoprazole related compound A. The analytical method is validated under ICH Q2(R1) requirements for specificity, linearity, accuracy, precision, and limit of quantitation; a reporting threshold of 0.05% applies under ICH Q3A(R2) for a maximum daily dose up to 2 g. Stability of the lyophilized injection is evaluated under ICH Q1A(R2) long-term conditions at 25 °C/60% RH and accelerated conditions at 40 °C/75% RH, with special attention to cake collapse, reconstitution time, pH drift, and brown discoloration caused by thiol-related oxidative degradation. If the upstream sulfide oxidation step is incomplete, residual mercapto benzimidazole can carry through to the injection drug substance and react with trace metals in stoppers or vial glass, producing visible discoloration; therefore, the API specification for this impurity is validated against the injection manufacturing process rather than only against oral solid-dose requirements.
Pantoprazole sodium oral granules and powders for oral suspension are produced as enteric-coated multiparticulates rather than monolithic single-unit dosage forms. The API derived from the 2-mercapto precursor is suspended with a binder and spray-layered onto sugar spheres or microcrystalline cellulose starter cores in a fluid-bed apparatus equipped with a Wurster insert. The drug layer is then sealed with a hydroxypropyl methylcellulose subcoat, followed by an enteric methacrylic acid-ethyl acrylate copolymer dispersion. In-process particle-size distribution is measured by sieve analysis according to USP <786> and, for sub-100 µm fine generation, by laser diffraction in accordance with ISO 13320:2020. The enteric-coated granules are dried to a moisture specification of NMT 2.0% by Karl Fischer titration under USP <921>; moisture above approximately 2.5% can plasticize the enteric film and reduce acid resistance during storage in unit-dose sachets. Dissolution testing for the oral granule product uses USP <711> delayed-release methodology, often with Apparatus III or modified Apparatus II, with the same acid-stage and buffer-stage performance targets applied to monolithic tablets. The residual 2-mercapto benzimidazole precursor is not separately tested in the granule formulation because it is routinely quantified at the API stage, but if an atypical odor, off-white discoloration, or sulfur-like smell is observed during development, the batch is analyzed by the same HPLC method used for the drug substance. Since the free thiol is consumed in the sulfide coupling step, its presence in the finished granule would indicate incomplete oxidation, insufficient washing of the thioether intermediate, or an API batch that failed the related-compound specification. The oral granule process therefore depends on the quality of the upstream thiol starting material, especially with respect to residual solvents controlled under ICH Q3C and elemental impurities controlled under ICH Q3D.
The 2-mercapto benzimidazole compound itself is not filled directly into hard capsule shells. In the downstream finished-dosage application space, pantoprazole sodium prepared from the thiol intermediate may be handled in compounding pharmacies or clinical manufacturing as enteric-coated granules or delayed-release tablet particles placed into hard gelatin or HPMC capsules. Capsule operations are governed by USP <795> for nonsterile compounding and, where applicable, USP <800> handling requirements for hazardous drug evaluation. HPMC capsule shells are preferred when ambient relative humidity exceeds 60% RH because gelatin shells can become brittle or undergo crosslinking; however, the acid-labile pantoprazole sodium core requires an intact enteric coat, so capsule-filling equipment must operate at low compaction pressure to avoid cracking the methacrylate film. Content uniformity of compounded capsules is assessed under USP <905>, with an acceptance value of ≤15 for 10 dosage units. Residual free thiol is not a routine lot-release test for compounded preparations, but the HPLC method using the pharmacopoeial related-compound A reference standard can be applied to investigate discoloration, vinyl-stopper interaction, or incompatibility with excipient aldehydes. The operational boundary for any capsule-based formulation is that pantoprazole sodium is acid-labile; therefore, uncoated particles or crushed delayed-release tablets should not be combined with acidic fruit vehicles or low-pH suspending agents before administration.
As a pharmacopoeial impurity marker, 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole is used in analytical method development, system suitability testing, and batch release of pantoprazole sodium API and finished dosage forms. The substance is characterized by its relative retention time against pantoprazole sodium in reversed-phase HPLC systems, by its UV spectral match near 290 nm, and by its distinct thiol reactivity toward iodine or hydrogen peroxide. In quality control laboratories, the reference standard is prepared at concentrations bracketing the ICH Q3A(R2) reporting threshold; method sensitivity is demonstrated by a limit of quantitation below 0.05% relative to the API peak. The table below summarizes the ICH Q3A(R2) thresholds that apply to residual 2-mercapto benzimidazole in the drug substance when the downstream drug product is a tablet, capsule, granule, or lyophilized injection.
| Maximum Daily Dose | Reporting Threshold | Identification Threshold | Qualification Threshold |
|---|---|---|---|
| ≤2 g | 0.05% | 0.1% or 1 mg/day | 0.15% or 1 mg/day |
| >2 g | 0.03% | 0.05% | 0.05% |
For injection-compatible pantoprazole sodium, the same impurity threshold logic is applied at the drug-substance release stage, while the finished lyophilized product is also examined for degradation products under ICH Q3B(R2). The free thiol marker is particularly useful in forced degradation studies because it can distinguish an incomplete synthetic step from oxidative or thermal degradation of the sulfoxide API. During method transfers between manufacturing sites, the reference standard is run in system suitability solutions to verify column selectivity and mobile-phase pH precision, and the retention time window is fixed against a freshly prepared standard at 24 h intervals under autosampler stability conditions. The compound is shipped in amber glass containers under inert gas, and analytical stock solutions are protected from light because the benzimidazole thiol function is susceptible to oxidation in oxygenated solvents. Published data for this specific configuration is limited for non-pantoprazole dosage forms; therefore, the analytical use remains anchored to benzimidazole-sulfoxide drug substance manufacturing and release rather than to unrelated therapeutic categories.
The coupling reaction between 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole and the pyridylmethyl chloride intermediate is mildly exothermic but becomes a critical scale-up operation when batch size moves from 5 L pilot vessels to 2000 L glass-lined production reactors. The thiol intermediate is charged as an aqueous sodium hydroxide solution, while the pyridylmethyl chloride hydrochloride is added as a controlled methylene chloride stream over 60–120 min to avoid local pH drift below the range that maintains the thiolate nucleophile. Agitation speed, jacket temperature, and organic-phase sampling are managed under cGMP equipment-control records; inline pH probes and thermocouples are calibrated according to each site’s master instrument schedule under 21 CFR 211.68. After phase separation, residual unreacted thiol is extracted into dilute sodium hydroxide and measured by HPLC area percent with a method detection limit below 0.01%. The oxidation step downstream is more sensitive to scale than the coupling step: peroxide dosing into a 2000 L reactor creates a thermally non-uniform zone if mixing is insufficient, leading to over-oxidation to the sulfone. Production batches therefore use a peroxide feed-line positioned below the liquid surface, a jacket set point of 0–5 °C, and sequential sodium bisulfite quench with residual peroxide tested by starch-iodide strip or titrimetry. Batch-to-batch variability in the residual free thiol before oxidation is tracked against the final pantoprazole sodium related-compound specification; if the free thiol value exceeds the ICH Q3A(R2) reporting threshold at the thioether stage, the lot is rejected or reprocessed before it reaches tablet, capsule, granule, or injection manufacturing. This traceability from the initial mercapto benzimidazole charge through the oxidation, salt conversion, and final dosage-form release is the central technical control for all downstream applications of this substance.
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5-(Difluoromethoxy)-2-mercapto-1H-benzimidazole, CAS 97963-62-9, is supplied as a pharmaceutical-grade organic solid with molecular formula C8H6F2N2OS and molecular weight 216.21 g mol−1. The product model descriptor recognizes the free-thiol base rather than a salt; commercial lots are available as crystalline, air-jet-micronized, or low-endotoxin lyophilized physical forms for oral tablet, capsule, granule, and injectable processing. The 5-position difluoromethoxy substituent and the 2-position mercapto group are primarily relevant to synthetic route control, impurity profiling, and stability-indicating method development in benzimidazole-based pharmaceutical processes. Typical release documentation includes HPLC area percent assay, Fourier-transform infrared identification against a qualified reference spectrum, water content by Karl Fischer titration, residue on ignition, headspace gas chromatography for residual solvents, and elemental impurity data aligned to ICH Q3D. Lots manufactured for injectable development are released with additional bacterial endotoxin and bioburden controls. The material is packaged under nitrogen in double low-density polyethylene liners within aluminum-foil laminate drums or fiberboard outer containers to reduce oxidative and moisture ingress. Manufacture and control are performed under a pharmaceutical quality system consistent with FDA 21 CFR 210 and 211 expectations; however, this substance appears in pharmacopeial contexts principally as a related compound or intermediate, and published finished-dose clinical data for the free thiol as a therapeutic API are limited.
The 2-mercapto substituent in this benzimidazole exists as a pH-dependent thiol-thione equilibrium, and that equilibrium affects both chemical stability and excipient compatibility during tablet and capsule manufacturing. Direct compression is considered only after powder flow data generated according to USP 1174 demonstrate a Carr index not greater than 25 and a Hausner ratio not greater than 1.35. Values above those limits require dry or wet granulation. Because the thiol form can oxidize at metal contact surfaces, tablet press tooling is preferentially cleaned and maintained to avoid residual iron or copper, and stainless steel or electroless nickel-coated contact parts are used. Excipient compatibility studies under ICH Q8 screening designs typically include microcrystalline cellulose, dibasic calcium phosphate anhydrous, pregelatinized starch, crospovidone, and sodium stearyl fumarate. Magnesium stearate is not introduced without data showing no free-thiol complexation or dissolution retardation; hydrophobic film formation from magnesium stearate may become process-relevant above 1.0% w/w, although published data for this specific compound are limited. For capsule filling, dry granulation by roller compaction commonly improves flow without adding granulation water that would mobilize the thiol-thione system. Roller compaction applicability must be established for this API because the compaction profile of a high-surface-area benzimidazole thiol can vary with feed rate and roll force. Weighing areas should be maintained at 25 ± 2 °C and 45–55% RH unless dynamic vapor sorption data show significant moisture uptake below that humidity range.
Granulation and blending unit operations for this product are usually specified through batch records that include a deagglomeration step through a 0.5 mm or 0.8 mm conical mill, followed by high-shear granulation or fluid-bed top-spray granulation with purified water, ethanol/water, or a binder solution. Binder concentrations are screened by granule growth and friability, with povidone K30 at 2–5% w/w or hypromellose E5 at 3–5% w/w as common starting points. Drying is performed in a fluid-bed dryer at inlet air temperature below 45 °C until loss on drying is controlled within 0.5–1.0% w/w; higher residual moisture may accelerate thiol oxidation and discoloration in the presence of trace metals. Final milled granules are blended with extragranular disintegrant and lubricant for short periods, typically 3–5 min, to avoid overlubrication. Tablet compression is then run on a rotary tablet press with precompression force, main compression force, ejection force, and press speed recorded for each batch. Capsule filling on dosator or tamping-pin machines requires a blend angle of repose below 40° and acceptable flow index values; filled capsules are checked for gross weight, shell closure, and content uniformity according to USP 905. All parameters are finalized after a design-of-experiments study demonstrates robust content uniformity and dissolution performance using a discriminating method.
Injectable manufacture requires additional controls beyond solid oral processing even when the same chemical entity is used. The filling area must maintain ISO 14644-1 class 5 conditions at the point of fill, and aseptic connections must be validated to prevent microbial ingress. Solutions are prepared by dissolving the free thiol in Water for Injection after pH adjustment with sodium hydroxide, tromethamine, or a suitable buffering system; the target pH is selected to maintain complete dissolution of the thiol-thione equilibrium while avoiding unnecessary alkaline degradation. The bulk solution is clarified through 0.45 µm and 0.22 µm polyethersulfone or polyvinylidene fluoride filters. Disodium edetate at 0.01–0.1% w/v may be added to chelate trace metal ions that accelerate thiol oxidation. Bacterial endotoxin limits are set from the intended maximum dose and route using USP 85: a general parenteral limit of 5 EU/kg body weight per hour is used for large-volume products, while intrathecal products require a default limit of 0.2 EU/kg body weight. Finished injectable particulate matter is controlled by USP 788: small-volume parenterals must contain not more than 6000 particles ≥10 µm and 600 particles ≥25 µm per container; large-volume parenterals must contain not more than 25 particles ≥10 µm per mL and 3 particles ≥25 µm per mL. If terminal sterilization is considered, steam exposure at 121 °C for 15 min is evaluated for assay loss and related substance shifts. Where the free thiol is thermally labile or prone to headspace oxidation, aseptic filtration is preferred. Container closure compatibility is evaluated using Type I borosilicate glass vials and bromobutyl rubber stoppers with fluoropolymer coating; long-term oxygen permeation through the closure is monitored because the thiol is oxygen-sensitive.
Compared with unsubstituted 2-mercaptobenzimidazole, the 5-difluoromethoxy substituent introduces two C–F bonds that alter the aromatic ring electronics and modulate the thiol-thione equilibrium. Replacement of the terminal methyl hydrogens by fluorines increases molecular weight from 180.23 g mol−1 for 5-methoxy-2-mercaptobenzimidazole to 216.21 g mol−1 for the difluoromethoxy analog. This structural change also increases lipophilicity relative to the 5-hydroxy and 5-methoxy congeners, although published pharmacokinetic data for this specific free thiol are limited. In synthetic sequences, the 2-mercapto group is alkylated or oxidized to produce substituted sulfides and sulfoxides; residual free thiol is therefore controlled by stability-indicating HPLC methods capable of resolving the thiol from its S-alkylated and S-oxidized derivatives. The product differs from pantoprazole sulfoxide because it lacks the pyridine methylsulfinyl side chain required for proton-pump inhibition. This distinction has direct analytical consequences: an HPLC method used for release must be specific for 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole and must not misclassify the 5-methoxy analog, the 5-hydroxy analog, or the disulfide oxidation product. Headspace oxygen in primary packaging should be held at not more than 5% v/v where long-term storage is required.
Thermal stress studies at 105 °C and 121 °C for 30 min should monitor oxidative coupling of the free thiol to a disulfide dimer and any hydrolytic cleavage of the difluoromethoxy ether to the 5-hydroxy analog under acidic steam condensate. HPLC methods used for this evaluation should include these potential degradation products as system-suitability markers with resolution factors not less than 1.5. If measured assay loss exceeds the ICH Q3B reporting threshold for the intended maximum daily dose, terminal steam sterilization is unsuitable and aseptic filtration becomes the default manufacturing route. Autoclave load validation should include thermocouple mapping with cold spots controlled to ±1 °C from the set point at the chamber drain and hot spot. Oxygen removal by nitrogen sparging before heat exposure reduces oxidative degradation, but sealed ampoules under nitrogen may still generate headspace moisture during sterilization. For lyophilized injectable presentations, the freeze-drying cycle is designed around the collapse temperature of the freeze concentrate and the glass transition of the formulation. Because the free thiol can shift collapse temperature, cycle development should use freeze-drying microscopy and manometric temperature measurement before scale-up.
Residual solvent analysis by headspace gas chromatography is performed according to USP 467 or Ph Eur 2.4.24. ICH Q3C(R8) limits are applied using Option 1 unless process-specific Option 2 daily exposure calculations are justified. Elemental impurities are controlled under ICH Q3D; parenteral limits are tighter than oral limits, and a risk assessment must consider catalysts, process water, and container-closure contributions. A release control matrix for the oral and injectable processing grades is shown below.
| Quality control attribute | Reference procedure | Processing-grade release expectation |
|---|---|---|
| Identification | Infrared absorption, Ph Eur 2.2.24 | Concordant with reference spectrum |
| Assay by HPLC | USP 621 | 98.0–102.0% on dried basis as a representative release range |
| Water content | USP 921, Ph Eur 2.5.12 | ≤0.5% w/w unless sorption data justify alternative |
| Residue on ignition | USP 281, Ph Eur 2.4.14 | ≤0.1% w/w |
| Bacterial endotoxins | USP 85, Ph Eur 2.6.14 | Established from dose and route; injectable grade requires route-justified limit |
| Particulate matter in injection solution | USP 788, Ph Eur 2.9.19 | Small-volume parenteral limits apply for development-grade solutions |
| Residual solvent benzene | USP 467 | ≤2 ppm if benzene is used or likely present |
| Residual solvent methylene chloride | USP 467 | ≤600 ppm |
| Residual solvent ethanol | USP 467 | ≤5000 ppm |
In pantoprazole sodium manufacture, 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole is specified as an intermediate and potential related substance rather than a therapeutic active ingredient. This creates a defined control burden: residual free thiol must be measured by a stability-indicating HPLC method capable of resolving it from the pantoprazole sulfoxide and sulfide. For a 40 mg daily dose, ICH Q3A thresholds apply as follows: reporting threshold 0.05%, identification threshold 0.10%, and qualification threshold 0.15%. When this material is released as a pharmaceutical-grade processing chemical, its own impurity profile must be characterized under the same ICH Q3A framework if it is later incorporated into a development batch. Ultraviolet detection for benzimidazole thiols and their oxidized congeners is selected from the acquired spectrum of the compound; HPLC system suitability should demonstrate baseline resolution of the free thiol, disulfide, and any 5-substituted analog in the retention window. The difluoromethoxy group also requires careful mass spectral confirmation because the two fluorine atoms produce a characteristic isotope pattern that distinguishes this compound from the 5-methoxy and 5-hydroxy analogs in LC-MS impurity screening. Storage and incoming-lot evaluation should include appearance, retention time, peak purity, and water content because the free thiol can absorb moisture and oxidize during routine handling.
