| HS Code | 775238 |
| Product Name | Rifaximin Uterine Infusion Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Chemical Class | Semi-synthetic rifamycin antibiotic |
| Cas Number | 80621-81-4 |
| Molecular Formula | C43H51N3O11 |
| Molecular Weight | 785.88 g/mol |
| Appearance | Orange-red crystalline powder |
| Solubility | Practically insoluble in water; soluble in organic solvents such as acetone, chloroform, and ethyl acetate |
| Mechanism Of Action | Inhibits bacterial DNA-dependent RNA polymerase by binding to the beta-subunit, blocking RNA synthesis |
| Antimicrobial Spectrum | Broad-spectrum activity against Gram-positive and Gram-negative bacteria, including anaerobes associated with uterine infections |
| Veterinary Indication | For uterine infusion in the management of metritis and endometritis in veterinary species |
| Dosage Form Compatibility | Suitable as an active pharmaceutical ingredient for tablets, injections, capsules, powders, granules, premixes, and solutions |
| Storage Conditions | Store in a cool, dry place, protected from light, in a tightly closed container |
| Stability | Protect from moisture and high temperatures to preserve chemical stability |
| Administration Route Compatibility | Formulation-dependent; primary nominated veterinary route is uterine infusion |
As an accredited Rifaximin Uterine Infusion Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in sealed, sterilized double-lined aluminum bags with desiccant, 1 kg per bag, ensuring stability for veterinary formulations. |
| Container Loading (20′ FCL) | 20′ FCL loading of Rifaximin Veterinary Grade API: sealed drums/cartons, palletized, secured for safe transport of tablets, injections, powders, granules, premix, solutions. |
| Shipping | Rifaximin Uterine Infusion Veterinary Grade API ships in sealed, inert containers to protect against moisture and light. Shipment requires temperature-controlled transport, avoiding extreme heat or cold. Include full documentation: SDS, certificate of analysis, and origin declaration. Use expedited freight with tracking to ensure safe, compliant delivery. |
| Storage | Store Rifaximin Uterine Infusion Veterinary Grade API in a cool, dry, well-ventilated area, protected from light, moisture, and heat. Keep container tightly sealed and avoid exposure to air. Store away from incompatible materials and food. Follow local regulations; use within expiry date at controlled room temperature, ideally 15–30°C. |
| Shelf Life | Shelf life is typically 24 months when stored in original tightly sealed containers, protected from light, moisture, and heat. |
In postpartum dairy cows with clinical endometritis, rifaximin has been evaluated as a locally retained intrauterine antimicrobial because the compound is a poorly absorbed rifamycin derivative that remains largely confined to the uterine lumen and produces minimal systemic exposure after mucosal instillation. Formulation addition ratios in national veterinary master formulas for intrauterine suspensions generally fall between 1.0% w/v and 2.5% w/v, with single-dose volumes of 20–50 mL and total dose per animal from 200 mg to 750 mg; intrauterine foam tablets typically contain 100–250 mg rifaximin per unit. The regulatory basis includes Regulation (EU) 2019/6 for veterinary medicinal products, Commission Regulation (EU) No 37/2010 Table 1, under which a positive maximum residue limit and a species-specific milk and meat withdrawal period must be established before food-producing animal use, and VICH GL49 for metabolism and residue kinetics study design. Downstream manufacturing for the suspension requires aseptic dispersion of micronized rifaximin with a particle size D90 ≤ 15 µm into a sterile gel or physiological saline vehicle using a high-shear rotor-stator mixer at 3,000–5,000 rpm under vacuum to remove entrained air, followed by filling into individual intrauterine catheters or HDPE single-dose containers under ISO Class 5. Terminal moist-heat sterilization is generally unsuitable because aqueous rifaximin suspensions show crystal growth and polymorphic conversion above 30–40°C under high humidity; therefore, the process uses aseptic filtration of the vehicle and sterile API addition. Terminal product types include single-dose intrauterine suspensions, foaming intrauterine tablets, and gel-based applicator systems. A production-scale limitation observed in batch records involves settling of more than 20% of the suspended API within 4–6 h when pH drifts above 7.5; controlling pH with citrate buffer at 6.0–6.8 and adding colloidal silicon dioxide at 0.5–1.0% w/w reduces sediment volume. Lot-to-lot variation in raw rifaximin polymorph ratios can shift sedimentation volume by 10–15%; therefore, incoming API is verified by powder X-ray diffraction and particle size distribution per Ph. Eur. 2367 and the USP Rifaximin monograph. Release testing includes HPLC assay at 95–105% of label claim and related substances not more than 1.0% for any single impurity per Ph. Eur. 2367.
| Standard / Regulation | Scope | Cited Provision |
|---|---|---|
| Regulation (EU) 2019/6 | Veterinary medicinal product authorization | Article 106–112, Annex I manufacturing |
| Commission Regulation (EU) No 37/2010 | MRL and withdrawal classification for food-producing species | Table 1 |
| Ph. Eur. 2367 | Rifaximin raw material monograph | Identification, related substances, assay |
| USP General Chapter <795> | Nonsterile compounding of capsules and tablets | Content uniformity, beyond-use dating |
| ISO 6497:2002 | Sampling of animal feed for premix homogeneity verification | Section 7 |
| VICH GL49 | Residue metabolism and marker residue studies in food animals | Study design, marker residue selection |
Premix production for swine enteric conditions begins with a 10% w/w rifaximin intermediate blended with lactose monohydrate or calcium carbonate in a V-blender at 60 rpm for 20 min; this pre-blend is then diluted in a horizontal ribbon mixer to achieve a final feed concentration of 100–300 ppm in complete feed. The compliance chain for medicated premixes requires adherence to Regulation (EC) No 183/2005 for feed hygiene, ISO 6497:2002 for sampling and homogeneity verification, and the residue withdrawal framework of Commission Regulation (EU) No 37/2010 where swine are intended for human consumption. The formulation addition ratio at the farm gate is determined not by a fixed pharmacopoeial monograph but by a validated target dose per kilogram body weight; published data for this specific veterinary configuration is limited, but master formula validation commonly spans 0.5–2.0 kg rifaximin per tonne of complete feed, with a maximum carryover limit below 1% of the active substance in subsequently produced non-medicated feed. Downstream manufacturing requires stepwise geometric dilution because direct addition of micronized rifaximin to a ribbon mixer causes non-uniform distribution and segregation in the high-shear zone. The first dilution step uses a V-blender with intensifier bar at 10% w/w, followed by a hammer mill pass at 1,500–3,000 rpm to break API agglomerates. The diluted intermediate is then transferred into a 300 kg capacity horizontal ribbon mixer and blended for 15 min at 40–60% fill volume; 12 stratified samples are collected according to ISO 6497 and assayed by HPLC with a relative standard deviation target ≤ 5%. Terminal product types include medicated feed premix, oral granules, and water-dispersible oral suspension powder. A true aqueous oral solution is not feasible because rifaximin water solubility at 25°C is below 1 mg/mL; liquid forms require co-solvents such as propylene glycol or suspending agents. A process conflict observed on commercial premix lines is the tendency of rifaximin to adhere to stainless steel surfaces under relative humidity above 60%; pre-drying of lactose monohydrate at 105°C for 4 h and packaging in desiccant-lined bags is necessary to maintain flowability. Rifaximin should not be combined with alkaline feed additives such as sodium bicarbonate in the same premix due to accelerated hydrolysis of the rifamycin ring at pH above 8.0.
Because rifaximin is not approved for canine chronic enteropathy in most jurisdictions, compounded capsules are prepared under extralabel provisions governed by FDA 21 CFR 530 in the United States and by national compounding rules under veterinary prescription elsewhere. The formulation addition ratio in nonsterile compounding typically uses a 10% w/w rifaximin triturate in lactose monohydrate or microcrystalline cellulose, with final capsule strengths of 75 mg, 150 mg, or 200 mg filled into size 2 or size 3 hard gelatin capsules. Compliance relies on USP General Chapter <795> for nonsterile compounding, USP <800> where occupational handling is relevant, and the prescribing veterinarian’s extralabel drug use records. The downstream process requires geometric dilution of the API in a mortar or tumble blender for not less than 5 min per dilution step, followed by filling on a benchtop capsule machine or a semi-automatic tamping-pin capsule filler such as a Zanasi 6K or equivalent. Content uniformity is tested by UV or HPLC against a calibration curve, with acceptance criteria of 85–115% of label claim and RSD ≤ 6%. Disintegration testing is performed per Ph. Eur. 2.9.1 in water at 37 ± 1°C, with complete disintegration expected within 15 min. Terminal product types are hard gelatin capsules and, where a non-capsule form is required, immediate-release tablets prepared by direct compression with croscarmellose sodium at 3–5% w/w. A known operational boundary is the hygroscopicity of rifaximin: exposure to relative humidity above 60% during capsule filling increases stickiness on the tamping pins and leads to weight variation above ±7.5%, so the compounding room must be maintained at 40–50% RH. A limitation for this indication is that controlled clinical outcome data for rifaximin in canine chronic enteropathy are sparse; published case series report clinical response but no randomized equivalence to standard therapies.
Equine oral paste formulations necessitate a non-aqueous matrix because rifaximin exhibits hydrolytic degradation in aqueous solution at pH below 4.0 or above 8.0 and polymorphic conversion in the presence of free water. The formulation addition ratio in extemporaneous equine paste is usually 5–10 g rifaximin per 100 g paste, with a single foal dose of 200–500 mg delivered from a graduated dial-a-dose syringe. The compliance environment for this extralabel application includes veterinary prescription and compounding requirements under national law; the relevant quality standard for the API remains Ph. Eur. 2367, while the finished oral paste is tested for uniformity of mass per Ph. Eur. 2.9.5 and for microbial quality per Ph. Eur. 5.1.4. The downstream process uses a vacuum planetary mixer: aluminum stearate or hydrogenated castor oil is pre-melted at 60–70°C and blended into a non-aqueous vehicle such as corn oil or propylene glycol dicaprylate, then cooled to 30–35°C before rifaximin is added under vacuum at −0.6 bar to prevent air entrapment. Colloidal silicon dioxide is added at 2–3% w/w to maintain suspension and ensure extrusion force below 80 N from the syringe. Terminal product types include oral paste, non-aqueous oral suspension, and coated granules for direct oral administration. Because equine data for rifaximin are limited, formulation development batches require pilot stability at 25°C/60% RH and 40°C/75% RH for 6 months to verify polymorph stability and API assay retention above 95%. A specific incompatibility exists with α-tocopherol above 1% w/w, which accelerates oxidative degradation of the rifamycin ring under storage.
When a sterile uterine injection dosage form is specified for rifaximin, the processing route must distinguish between parenteral intravenous administration and local lumen instillation because rifaximin has negligible systemic absorption and is not suitable for systemic therapy. The formulation addition ratio for a sterile intrauterine injection or instillation is commonly 10–20 mg/mL in an oil-in-water emulsion or a viscosified aqueous suspension, with a single uterine dose of 20–50 mL. Compliance for sterile veterinary products follows Regulation (EU) 2019/6 Annex I manufacturing requirements, EU GMP Annex 1 for sterile manufacture, and USP <71> for sterility testing; endotoxin limits are controlled per Ph. Eur. 2.6.14 to below 0.5 EU/mg. The downstream process requires pre-sterilization of the vehicle by moist heat at 121°C for 15 min and aseptic addition of micronized rifaximin API under ISO Class 5, because rifaximin is heat-labile in aqueous suspension at temperatures above 80°C. The primary emulsion is formed with a high-pressure homogenizer at 800–1,200 bar for 3–5 passes to achieve a droplet size D50 below 2 µm; for suspension forms, high-shear mixing is followed by wet milling to D90 ≤ 10 µm. Filling is performed under ISO Class 5 in sterile glass vials or pre-filled uterine applicators, and release testing includes sterility, bacterial endotoxins, pH 6.0–6.8, and extractable volume per Ph. Eur. 2.9.17. Terminal product types are sterile injection vials for local uterine instillation, pre-filled single-dose intrauterine syringes, and sterile emulsion applicators. A process failure mode observed during development is crystal bridging in the nozzle when the suspension viscosity falls below 150 mPa·s at 25°C; addition of sodium hyaluronate at 0.1–0.3% w/w maintains continuous filling. Sterile filtration of the entire suspension is not feasible because rifaximin D90 exceeds the 0.22 µm filter pore size, so the process must rely on validated aseptic handling rather than terminal filtration.
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Rifaximin Uterine Infusion Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is manufactured and released under product code RIF-UT-VET-API-25 for traceability; the code is a manufacturer-specific designation and does not correspond to a pharmacopoeial monograph title. The active substance is a rifamycin derivative identified as C43H51N3O11 with molecular weight 785.88 g/mol. The unprocessed API is a red-orange to brick-red crystalline powder. The release specification for assay is 98.0–102.0% on the dried, solvent-free basis determined by high-performance liquid chromatography; chromatographic system suitability is aligned with USP <621> and Ph. Eur. 2.2.46. The same API lot can be designated for tablets, injections, capsules, powders, granules, premix, or solutions only after the applicable polymorph identity, particle-size distribution, residual solvent class, elemental impurity profile, and microbiological quality criterion are assigned. No single certificate of analysis format is adequate for all finished-dosage conversions.
Polymorph identity is confirmed by X-ray powder diffraction against the approved rifaximin reference diffractogram; the approved pattern is controlled because amorphous content alters tablet dissolution and suspension flocculation. The differential scanning calorimetry thermogram is reviewed for the characteristic endotherm and any low-temperature shoulders that indicate imperfect crystallinity. Loss on drying is determined by Ph. Eur. 2.2.32; the registered limit is product-specific and reflects drying temperature, residual solvent class, and the hygroscopicity of the micronized grade. Residual solvents are controlled under ICH Q3C and VICH GL18. Class 3 solvents are limited to a combined concentration of 0.5%; Class 2 solvents are individually limited according to the option used in the registration dossier. Elemental impurities are calculated on a dose-based basis under ICH Q3D Option 1, which means the same API lot may pass for low-dose capsules but require additional control for large-volume intrauterine infusion if the daily dose is high.
| Dosage form | Primary API-related failure mode | Representative control method |
|---|---|---|
| Tablets and capsules | Segregation and content uniformity failure | Ph. Eur. 2.9.40 / USP <905> |
| Injections and intrauterine infusion | Endotoxin, non-sterility, particulate matter | Ph. Eur. 2.6.14, 2.6.1, 2.9.19 / USP <85>, <71>, <788> |
| Powders, granules, premix | Flow variance and blend inhomogeneity | Ph. Eur. 2.9.34, 2.9.36, 2.9.40 |
| Solutions | Oxidative and alkaline hydrolytic degradation | ICH Q1B; Ph. Eur. 2.2.46 |
Rifaximin is practically insoluble in water, which makes a true aqueous solution impossible without high concentrations of co-solvents. In tablet manufacture, dry particle size and excipient compatibility control the process; in a suspension, the dominant problems become wetting, flocculation, caking, and particle growth after temperature cycling. The API is therefore dispersed with a wetting agent such as polysorbate 80 and a structuring suspending agent, typically microcrystalline cellulose/sodium carboxymethylcellulose or xanthan gum. Particle-size distribution must be linked to syringeability and re-dispersibility, not merely to dissolution. The acceptable D90 is dossier-specific; it is derived from Ph. Eur. 2.9.31 syringeability, Ph. Eur. 2.9.40 uniformity, and sedimentation volume over 24 h. Because rifaximin is hydrophobic, micronized material may float or form aggregates if not pre-wetted; the manufacturing order of addition is therefore as important as the particle size.
Solution-based dosage forms use non-aqueous vehicles such as ethanol, propylene glycol, medium-chain triglycerides, or buffered co-solvent systems. Aqueous alkaline pH is not a reliable solubility-enhancement route because the macrocyclic lactone ring is vulnerable to base-catalyzed hydrolysis. Published stability data for specific veterinary uterine infusion vehicles are limited; therefore, each finished formulation requires forced-degradation studies under ICH Q1A and ICH Q1B before assigning a shelf life.
Premix and granule formulations containing rifaximin require stricter homogeneity controls than high-dose tablet blends because the API is often present at 0.5–5.0 wt% in a feed carrier. Mixing is performed in a V-blender, double-cone blender, or bin blender; the end-point is validated by sampling at least 10 locations and assaying rifaximin by HPLC. Acceptance criteria are aligned to Ph. Eur. 2.9.40 or USP <905>, with acceptance value not greater than 15.0. The fine crystalline powder does not exhibit free-flowing character; Hausner ratio and Carr index are reported by Ph. Eur. 2.9.36. Addition of colloidal silicon dioxide at 0.5–1.5 wt% or pre-blending with a portion of coarse carrier improves flow. If wet granulation is used, the granulating fluid must be limited because over-wetting can retard dissolution from granules by creating a hydrophobic barrier. Dry granulation or direct compression is preferred for moisture-sensitive premix carriers.
For tablet and capsule manufacture, the API is usually micronized and pre-blended with a low-dose carrier before main blending. Tablet compression parameters such as pre-compression force, main compression force, and ejection force are established by Heckel analysis and are not universal across tooling sizes. The compressed tablets are controlled for hardness, friability, disintegration, and dissolution where the finished product monograph includes a dissolution procedure. Hardness and friability data are release tests, but they do not substitute for blend uniformity when the dose is low per tablet.
Rifaximin inhibits bacterial DNA-dependent RNA polymerase by binding the β subunit encoded by rpoB. This mechanism is distinct from the penicillin-binding protein target of β-lactams and the 30S ribosomal subunit target of tetracyclines; therefore, cross-resistance with oxytetracycline and ceftiofur is not pharmacologically automatic. The API is intended for veterinary preparations used locally in bacterial endometritis and retained fetal membrane metritis; however, the specific labelled indication belongs to the finished veterinary medicinal product and varies by jurisdiction. In-vitro coverage includes Gram-positive, Gram-negative, aerobic, and anaerobic bacteria. Published MIC90 data against Trueperella pyogenes and Escherichia coli isolated from bovine uterine secretions are not harmonized globally; therefore, susceptibility testing on local isolates is required before veterinary use under clinical protocols.
Pharmacokinetically, rifaximin is associated with oral systemic absorption below 0.4%. After intrauterine infusion, local retention is expected to be high, but systemic absorption across inflamed endometrium has not been fully characterized in all target species. This contrasts with ceftiofur and oxytetracycline, which are designed for measurable systemic exposure and tissue distribution. The clinical difference is that rifaximin uterine infusion is intended for lumen-localized infection when systemic inflammatory signs are absent; it is not a replacement for systemic antibiotic therapy in septic metritis or bacteremia.
The API is not a sterile raw material by default. For injection and intrauterine preparations, the finished dosage form must meet sterility according to Ph. Eur. 2.6.1 or USP <71>, bacterial endotoxin limits according to Ph. Eur. 2.6.14 or USP <85>, and subvisible particulate matter limits according to USP <788> or Ph. Eur. 2.9.19. The endotoxin limit is calculated by the K/M method, where K is 5 EU/kg for non-intrathecal routes and M is the maximum bolus dose per kilogram per hour. Because the larger dose volume of an intrauterine infusion can raise the total endotoxin load, the API used for this route must be selected from lots with sufficiently low endotoxin content, and the finished preparation may require depyrogenation of the vehicle. Terminal moist-heat sterilization is not universally applicable because rifaximin can undergo hydrolytic degradation under aggressive autoclave conditions; aseptic processing with pre-sterilized components is commonly used.
Compared with rifampicin, rifaximin contains a pyridoimidazole substituent that reduces systemic absorption and supports local mucosal administration. Compared with intrauterine oxytetracycline products, rifaximin does not chelate calcium to the same degree and is not expected to cause the same local irritation associated with some tetracycline formulations; however, published comparative uterine irritation studies are limited. The product is also distinct from florfenicol and ceftiofur intrauterine preparations because rifaximin is not established as a systemic antibacterial in food-producing animals and therefore requires route-specific residue evaluation when used in lactating or meat-producing cattle.
Rifaximin API differs from commonly used intrauterine antibiotics such as oxytetracycline dihydrate and ceftiofur hydrochloride in solubility and pH sensitivity. Oxytetracycline hydrochloride is water-soluble and can form acidic solutions; ceftiofur sodium is also soluble and suitable for reconstitution. Rifaximin requires a suspension or non-aqueous vehicle, which changes the manufacturing line configuration and the analytical release panel. The selection is not based on uniform potency advantage but on the reduced systemic exposure expected from a poorly absorbed rifamycin and the need to retain local antibacterial activity at the uterine mucosa.
Stability of the API in solid dosage forms is controlled by moisture-protective packaging. Rifaximin is prone to oxidative degradation under light and oxygen; bulk API should be stored in tight, light-resistant containers at controlled room temperature, and exposure to strong light should be minimized during manufacture. The finished product pack should include light-protective blisters or amber glass bottles unless photostability data show that a clear container is acceptable. The storage conditions assigned by the finished product dossier replace any generic API storage statement.
For extemporaneous compounding of intrauterine infusions, the API must be incorporated under conditions that preserve sterility or terminal sterility of the final product. Compounding is performed in a cleanroom environment with ISO 7 or better background and laminar-flow control. The final infusion is administered by veterinary personnel; the use of milk or meat from treated animals must follow local withdrawal-period guidance, which cannot be derived from the API certificate of analysis alone. Published data for specific withdrawal periods after rifaximin uterine infusion in cattle are limited; therefore, regulatory-approved withdrawal periods are mandatory where available, and extralabel use must follow veterinary oversight and applicable food-safety regulations.
