| HS Code | 663442 |
| Product Name | Cefoperazone Sodium (Sterile) Pharma Grade API |
| Drug Category | Cephalosporin antibiotic (third generation) |
| Cas Number | 62893-20-3 |
| Molecular Formula | C25H26N9NaO8S2 |
| Molecular Weight | 667.65 g/mol |
| Description | White to off-white crystalline powder, sterile grade |
| Solubility | Freely soluble in water; sparingly soluble in methanol; practically insoluble in ethanol |
| Grade | Pharma Grade (sterile API) |
| Intended Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral and Injectable |
| Pharmacopoeia Compliance | Conforms to relevant pharmacopoeial standards (e.g., USP/Ph.Eur.) |
| Storage Conditions | Store below 25°C, protected from moisture and light, in airtight containers |
| Shelf Life | Typically 24 months when stored under recommended conditions |
As an accredited Cefoperazone Sodium (sterile) 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 | Sterile Cefoperazone Sodium API packed in sealed double polyethylene bags with aluminum foil inner liner, 25 kg per drum. |
| Container Loading (20′ FCL) | One 20′ FCL loaded with sterile Cefoperazone Sodium API drums, suitable for tablet, capsule, granule, and injectable pharmaceutical manufacturing. |
| Shipping | Shipment of Cefoperazone Sodium (sterile) Pharma Grade API must be conducted under controlled, cool, dry conditions, protected from light and moisture. Pack in sealed, moisture-resistant containers with tamper-evident seals. Use insulated, refrigerated transport if required. Include Certificate of Analysis and Material Safety Data Sheet, ensuring compliance with pharmaceutical logistics regulations. |
| Storage | Store Cefoperazone Sodium (sterile) in tightly sealed, light-resistant containers in a cool, dry place below 25°C (or as directed). Protect from moisture, heat, and direct sunlight. Do not freeze. Keep the container closed when not in use and use immediately after opening to maintain sterility and stability for oral and injectable formulations. |
| Shelf Life | Shelf Life: 24 months when stored in a cool, dry place, protected from light and moisture, in tightly sealed containers. |
Aseptic dry-powder filling of sterile cefoperazone sodium for parenteral administration is carried out in an ISO 14644-1 Class 5 zone with unidirectional airflow at 0.45 ± 0.05 m/s over the critical fill point. The API is received in double polyethylene bags inside an aluminium-laminated fibreboard drum, and transfer to the filling hopper occurs through a restricted access barrier system under continuous relative humidity control; the room is maintained at 20 ± 2 °C and ≤ 30% RH because the sodium salt is hygroscopic. Depyrogenated Type I borosilicate glass vials are washed and passed through a hot-air tunnel at 250 °C for 30 min, while chlorobutyl rubber stoppers are steam-sterilized at 121 °C for 15 min and dried under vacuum. Gravimetric dosators fill 1 g and 2 g cefoperazone free acid equivalent per vial, based on assayed anhydrous potency rather than as-is powder weight; the filled vials are then stoppered under a vacuum or nitrogen purge to limit residual oxygen and moisture. Container closure integrity is verified on-line by vacuum decay per USP <1207>, and release testing includes sterility by membrane filtration per USP <71>, bacterial endotoxin by kinetic chromogenic assay per USP <85>, subvisible particulate by light obscuration per USP <788>, and visible particulate by USP <790>. The product is not terminally sterilized; any breach of aseptic technique or extended exposure above the validated relative humidity limit will generate batch-to-batch moisture variation and may shift reconstitution time. Powder flow is monitored by ring shear testing, and the fill-weight relative standard deviation is normally held below 2% for a 1 g fill; if the API is not pre-sieved through a 500 µm screen, dosator overfill and intermittent stoppage become recurrent production bottlenecks.
Fixed-dose injectable formulations combine cefoperazone sodium and sulbactam sodium at 1:1 and 2:1 w/w ratios; the 1:1 commercial vial contains 1 g cefoperazone plus 1 g sulbactam, and the 2:1 vial contains 1 g cefoperazone plus 0.5 g sulbactam. Sulbactam irreversibly acylates Ambler class A serine beta-lactamases such as TEM-1 and SHV-1, but it does not inhibit class B metallo-beta-lactamases or class C AmpC cephalosporinases; this limitation defines the microbiological coverage expansion rather than a broad increase in Gram-negative activity. Reconstitution with sterile water for injection produces a solution with compendial pH typically in the range 4.5–6.5; alkalinisation above pH 7.5 accelerates hydrolysis of the beta-lactam ring, and acidification below pH 3.5 reduces solubility of the free acid. Dry-powder blending of the two APIs is performed at ≤ 30% RH; segregation risk is assessed by content uniformity testing per USP <905> and EP 2.9.40, with an acceptance value of ≤ 15 for individual units. Near-infrared moisture monitoring is commonly configured in the blend hopper, and the blend is rejected if residual moisture exceeds the validated control limit. The sodium load from both actives is dose-limiting in fluid-restricted or hypertensive patients, and the final intravenous admixture concentration must be adjusted by the hospital pharmacy according to the prescribed sodium allowance.
In hospital pharmacy central intravenous admixture units, the dry-powder vial is reconstituted with 10 mL sterile water for injection or 0.9% sodium chloride injection to a nominal concentration of 100 mg/mL cefoperazone free acid equivalent, then transferred into polyvinyl chloride or polyolefin infusion bags and diluted to a final concentration commonly not exceeding 20 mg/mL for intermittent infusion. Compounded sterile preparations are assigned beyond-use dates according to USP <797> risk-level categories; a low-risk preparation made from sterile ingredients under ISO Class 5 conditions may be assigned 48 h at controlled room temperature or 14 days refrigerated, but the manufacturer’s approved package insert may impose a shorter chemical stability interval because beta-lactam hydrolysis follows pH-dependent first-order kinetics. Aminoglycosides such as gentamicin or tobramycin must not be mixed in the same infusion container because the beta-lactam ring can inactivate the aminoglycoside in vitro; separate intravenous lines or staggered administration with adequate flushing is the standard operational rule. In-line filtration through a 0.22 µm low-protein-binding polyethersulfone or polyvinylidene fluoride filter is used to remove inadvertent particulate; any visible precipitation after mixing indicates incompatibility, and the admixture is discarded under USP <790> criteria. Published data for adsorption of cefoperazone sodium to specific filter membrane materials is limited; therefore the filtration step is validated by physical inspection and potency recovery before the hospital pharmacy adopts a new filter supply.
Cefoperazone sodium is not approved in any major pharmacopoeial territory as an oral systemic antibiotic because the beta-lactam ring is acid-labile in fasted gastric fluid at pH 1.2, and the ionized sodium salt is not transported by the human oligopeptide transporter PEPT1. Published data for the precise gastric half-life of cefoperazone sodium in simulated gastric fluid is limited; approved prescribing information documents negligible oral absorption. If oral tablet or capsule prototypes are produced for investigational non-systemic intestinal decontamination or clinical trial material, the preferred manufacturing route is dry granulation with 10–30% microcrystalline cellulose and 2–5% croscarmellose sodium as disintegrant; wet granulation is avoided because aqueous binder fluids accelerate hydrolysis of the beta-lactam ring and increase residual water. Enteric protection is achieved with methacrylic acid-ethyl acrylate copolymer applied to a weight gain of 8–12%, which resists dissolution in 0.1 N HCl for 2 h and releases above pH 5.5 in phosphate buffer per USP <711>. The hygroscopic sodium salt requires foil-foil blister packaging with desiccant rather than PVC/PVDC, and batch release must include residual solvent testing per USP <467> and ICH Q3C. There is no compendial oral tablet or capsule monograph for this API, so any such development is regulatorily exploratory and cannot be described as a commercial downstream segment without new clinical efficacy data.
When cefoperazone sodium is processed into oral granules or dry syrup sachets for non-systemic gut decontamination protocols, the granulation step is limited to non-aqueous or dry processes. A top-spray fluid-bed granulator using isopropyl alcohol and 2–5% povidone as binder can produce granules with a particle-size distribution of D90 ≤ 500 µm for uniform sachet fill weight; aqueous granulation is contraindicated because the beta-lactam ring hydrolyzes under elevated moisture and heat. Sachet filling is performed in an ISO Class 8 room with local humidity control at ≤ 25% RH, and the finished sachets are sealed with desiccant in polyethylene terephthalate/aluminium/low-density polyethylene laminates. Residual solvent limits for isopropyl alcohol follow ICH Q3C Class 3 acceptance criteria, and the granule loss on drying is controlled by halide-free Karl Fischer titration per USP <921>. No oral suspension or oral granule product containing cefoperazone sodium is marketed as a systemic antibiotic in the United States, European Union, or Japan; the clinical use of oral cefoperazone remains investigational and is limited to protocols where the absence of gastrointestinal absorption is deliberately exploited to suppress aerobic Gram-negative flora in the intestinal lumen. Published stability data for cefoperazone sodium granules in this specific configuration is limited, so bracketing studies under ICH Q1A(R2) are required before any clinical supply release.
Compendial release testing of sterile cefoperazone sodium dry-powder vials combines pharmacopoeial general chapters with regional filing requirements; the following matrix is typical for a parenteral powder fill.
| Attribute | Standard/code | Typical release criterion |
|---|---|---|
| Sterility | USP <71>, EP 2.6.1, JP 4.06 | No growth after 14 days incubation |
| Bacterial endotoxin | USP <85>, EP 2.6.14 | Not more than K/M-derived limit; K=5 EU/kg for intravenous route |
| Subvisible particulate | USP <788> Method 1 | ≥10 µm ≤ 6000/vial; ≥25 µm ≤ 600/vial |
| Visible particulate | USP <790> | Essentially free from visible particles |
| Water content | USP <921> Method 1a | Not more than 2.0% for dry powder |
| Content uniformity | USP <905>, EP 2.9.40 | Acceptance value ≤ 15 for first 10 units |
| Residual solvents | USP <467>, ICH Q3C | Class 1 solvents absent; Class 2 below partial daily exposure limits |
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Cefoperazone sodium (sterile) pharma grade API for tablet / capsule / granule / injection, oral & injectable is a sterile crystalline sodium salt of the third-generation cephalosporin cefoperazone. The molecular formula is C25H26N9NaO8S2, with a molecular weight of 667.66 g/mol and CAS registry 62893-19-0. The product is the salt of the free acid C25H27N9O8S2, molecular weight 645.67 g/mol. The sodium salt confers high aqueous solubility, making the material suitable for aseptic dry-powder filling and reconstitution into intravenous or intramuscular injections. Model designations are not harmonized in pharmacopeias; supplier-specific codes for sterile cefoperazone sodium often distinguish crystalline and micronized grades, but the compendial designation remains Cefoperazone Sodium. The label phrase “tablet / capsule / granule / injection, oral & injectable” indicates the manufacturer may supply the same API for diverse dosage-form development routes; it does not establish bioequivalence or therapeutic equivalence among those routes. For oral dosage forms, no current Ph. Eur., USP, or JP monograph provides release criteria or bioequivalence acceptance ranges for cefoperazone sodium tablets, capsules, or granules.
In aqueous solution, the β-lactam ring hydrolyzes by base- and acid-catalyzed pathways; maximum stability in solution is observed near pH 4.5–6.5. The dry sterile API is therefore handled under controlled relative humidity. Thermogravimetric and Karl Fischer data from supplier certificates of analysis typically report water below 2.0% w/w for sterile dry powder, though the pharmacopeial monograph may allow a higher limit for non-sterile bulk. Water activity is controlled below 0.15 at release to reduce hydrolysis and microbial risk. Bulk powder is filled in Grade A isolators or comparable unidirectional airflow systems that meet EU GMP Annex 1. Terminal steam sterilization at 121°C is not a compatible sterility assurance option because the cephalosporin ring degrades under saturated steam; aseptic crystallization, sterile filtration of the process solution through 0.22 µm membranes, and aseptic drying are used instead.
The primary barrier is the absence of a recognized oral bioavailability pathway for this salt. Cefoperazone sodium is acid-labile in gastric fluid; published human oral bioavailability data for the sodium salt is limited, and the molecule is not classified among orally absorbed cephalosporins such as cefixime or cefalexin. Direct compression of the sterile powder into tablets is further constrained by needle-like crystal habit and low bulk density, which produces poor die filling and variable weight on rotary tablet presses. Fluid-bed wet granulation with water is not appropriate because localized moisture initiates β-lactam hydrolysis; the β-lactam carbonyl is susceptible to nucleophilic attack by water, and free water in the granulating solvent can reduce assay during extended wet-mass holding. If granules for capsules or tablets are required, dry granulation or non-aqueous granulation with solvent control under ICH Q3C is the only feasible starting point. However, no harmonized dissolution or bioequivalence specification exists for cefoperazone sodium oral products, so tablet/capsule development remains outside compendial recognition.
The sterile API is released by HPLC assay against the current monograph. The assay acceptance criterion is based on anhydrous cefoperazone content; for the sodium salt the range is 870–1015 μg/mg. Identification is confirmed by infrared absorption and chromatographic retention time. Water content is determined by Karl Fischer titration according to USP<921> or Ph. Eur. 2.5.12; low water is a critical control because cefoperazone sodium is hygroscopic and hydrolysis follows water activity. Residual solvents are controlled according to ICH Q3C. For injectable manufacture, bacterial endotoxins and sterility are release attributes; the parenteral limit is calculated using the K=5 EU/kg threshold and the maximum adult dose, which yields an upper limit near 0.20 EU/mg for common dosing schedules.
| Attribute | Method / standard | Acceptance range or limit |
|---|---|---|
| Assay on anhydrous basis | USP HPLC, Ph. Eur. 2.2.29 | 870–1015 μg/mg as C25H27N9O8S2 |
| Water content | Karl Fischer titration, USP<921>, Ph. Eur. 2.5.12 | Sterile powder dried to <2.0% w/w; non-sterile bulk may have a different monograph limit |
| pH of 10% aqueous solution | Potentiometry, Ph. Eur. 2.2.3 | 4.5–6.5 |
| Bacterial endotoxins | Ph. Eur. 2.6.14, USP<85> | ≤ 0.20 EU/mg based on parenteral dose calc |
| Particulate matter in reconstituted solution | USP<788>, Ph. Eur. 2.9.19 | ≥ 10 µm: NMT 6000/container; ≥ 25 µm: NMT 600/container |
| Sterility | Membrane filtration, Ph. Eur. 2.6.1, USP<71> | No growth after 14 days |
On production-scale aseptic filling lines, the powder’s flow properties dominate fill-weight variability. Suppliers may report bulk density between 0.30 g/mL and 0.50 g/mL and tapped density up to 0.60 g/mL. These values vary with crystal habit and residual solvent profile; published data for this specific configuration is limited. Filling is performed in an isolator maintained at relative humidity below 25% and temperature below 25°C. Use of a vibratory hopper at low amplitude prevents bridging; inert nitrogen purge reduces moisture ingress and static charge. The product is not stored in unlined glass containers because moisture exchange at the stopper can raise water activity and accelerate ring opening.
Reconstitution of the sterile powder for injectable use is performed with water for injection, 0.9% sodium chloride injection, or 5% dextrose injection in an aseptic environment. The resulting solution is not preserved and must be used within the time validated by the hospital pharmacy; if stored, it is kept at 2–8°C for no more than 24 h unless a stability study supports a longer hold. Filtration through an in-line 0.22 µm filter is recommended for final administration in intravenous lines. For intramuscular injection, bacteriostatic water or lidocaine may be used only where licensed and where compatibility data exist; published compatibility data for cefoperazone sodium and certain buffered diluents is limited.
Compared with cefoperazone acid, the sodium salt exists as a freely soluble crystalline solid suitable for injection; the free acid is poorly soluble at neutral pH and is not the form used in parenteral manufacturing. The sodium salt should not be confused with cefoperazone sodium + sulbactam sodium fixed-dose powder; that product contains a β-lactamase inhibitor that extends coverage against selected β-lactamase-producing Enterobacterales and Bacteroides spp., while the single API does not. Among third-generation cephalosporins, cefoperazone sodium differs from ceftriaxone sodium in that it has clinically relevant activity against Pseudomonas aeruginosa and is substantially excreted in bile. However, the N-methylthiotetrazole substituent at position 3 is associated with hypoprothrombinemia and disulfiram-type reactions when alcohol is ingested; this substituent is not present in ceftazidime or cefepime. Cefoperazone sodium also differs from cefotaxime sodium because cefotaxime is partially metabolized to desacetylcefotaxime, whereas cefoperazone is eliminated primarily as unchanged drug in bile. These structural and metabolic differences affect manufacturing controls, particularly for related-substance profiling and compatibility with alcohol-containing cleaning agents.
Roller compaction of the sterile powder for granule dosage forms requires dry conditions and a closed contained system because the material is a cephalosporin allergen. Compression force and roll speed must be correlated with compact hardness; excessive shear can produce amorphous domains that accelerate water uptake and degradation. Published data for cefoperazone sodium roller compaction is limited; preformulation studies should map the minimum pressure needed to avoid lamination against the particle-size reduction caused by milling. For capsule filling, low bulk density can cause fill-weight variation on tamping-pin machines; vacuum-dosator or auger fillers are generally preferred. If the intended use is injectable, these oral dosage-form adaptations are unnecessary, and the material is handled as a sterile powder with controlled bioburden, low endotoxin, and water content below the limit specified by the supplier’s process validation. The API is not interchangeable with cefoperazone sodium + sulbactam sodium or with cefoperazone acid in manufacturing records without an approved change control.
