| HS Code | 806814 |
| Product Name | NITROXYNIL Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Api Name | Nitroxynil |
| Synonyms | 4-Cyano-2-iodo-6-nitrophenol; 4-Hydroxy-3-iodo-5-nitrobenzonitrile; Nitroxinil; Trodax |
| Cas Registry Number | 1689-89-0 |
| Molecular Formula | C7H3IN2O3 |
| Molecular Weight | 290.02 g/mol |
| Appearance | Yellow to yellow-brown crystalline powder |
| Odor | Odorless or practically odorless |
| Melting Point | Approximately 137–139 °C |
| Solubility | Practically insoluble in water; soluble in dimethylformamide and dimethyl sulfoxide; slightly soluble in methanol and ethanol |
| Purity Assay | Typically ≥98.0% on dried basis |
| Grade | Pharma Grade / API Grade |
| Pharmacopoeia Standard | In-house / Veterinary Pharmacopoeia (where applicable) |
| Therapeutic Category | Anthelmintic; Fasciolicide |
| Mechanism Of Action | Uncouples oxidative phosphorylation in susceptible parasites |
| Target Parasites | Liver fluke (Fasciola spp.), Haemonchus spp., and other susceptible helminths |
| Target Species | Cattle, sheep, and other livestock (veterinary use) |
| Dosage Forms | Tablet, capsule, granule, injection; oral and injectable |
| Route Of Administration | Oral; subcutaneous injection (veterinary use) |
| Storage Conditions | Store in a cool, dry place, protected from light, in tightly closed containers |
| Shelf Life | Typically 2–5 years when stored properly |
| Packaging | Foil-lined drums, polyethylene bags, or as per customer requirement |
| Quality Standards | GMP, ISO, or as per customer specification |
| Hs Code | 2926.90.00 |
As an accredited NITROXYNIL 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.
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Manufacture of a sterile injectable solution from nitroxynil API begins with the free acid, which has low intrinsic aqueous solubility; the downstream route therefore depends on in-situ salt formation with N-ethylglucamine in Water for Injections. In a 316L stainless-steel jacketed vessel equipped with a bottom-mounted magnetic drive mixer, the free acid is wetted with approximately 60% of the final water volume at 25–35 °C under nitrogen overlay, followed by stoichiometric addition of N-ethylglucamine. The resulting glucamine salt is held at pH 8.0–9.5; below this boundary the salt reverts to free acid and precipitates, while above it the solution becomes progressively susceptible to oxidative discolouration of the iodo-nitrophenol chromophore. Mixing speed above 150 rpm is avoided because air entrainment accelerates free-radical oxidation. Residual moisture in the API is controlled below 0.5% w/w because hygroscopic variability of the salt-forming acid shifts the acid-base equivalence point from batch to batch. The solution is cooled to 20–25 °C, then passed through a 0.45 µm polyethersulfone prefilter and a 0.22 µm PVDF final filter, with final filter integrity tested by bubble point according to ASTM F838-20. Terminal steam sterilisation at 121 °C is not assumed; published thermal stability data for nitroxynil glucamine salt under autoclave conditions is limited, so aseptic processing with Grade A filling is the default. Filling into amber Type I glass vials after depyrogenation at 250 °C minimises light-induced iodide release. The practical dose of 10 mg/kg in ruminants produces a measurable dose-volume advantage when the salt is formulated at 34% w/v, reducing subcutaneous injection volume to 2.94 mL/100 kg body weight.
| Quality Attribute | Method | Designation |
|---|---|---|
| Sterility | Membrane filtration | Ph. Eur. 2.6.1 |
| Bacterial endotoxins | Kinetic chromogenic LAL | Ph. Eur. 2.6.14 |
| Particulate matter | Light obscuration | Ph. Eur. 2.9.19 |
| Filter integrity | Bubble point | ASTM F838-20 |
| Extractable volume | Volumetric | Ph. Eur. 2.9.17 |
Direct compression of nitroxynil free acid into tablets is constrained by the API’s low aqueous solubility, possible cohesion failure, and the high dose required for ruminants. The anthelmintic dose of 10 mg/kg in a 600 kg bovine corresponds to 6 g of active, which cannot be delivered as a single conventional tablet without a very large swallowable mass; for a 50 kg sheep the single dose is 500 mg, still approaching the upper practical size for immediate-release veterinary tablets. When tablet development is attempted, wet granulation with 5–7% w/w povidone K30 as binder in an isopropanol-water granulating fluid is often screened because the API has poor flow and compactability. The wet mass is discharged through a 1.0 mm mesh screen, dried in a fluid-bed dryer with inlet air temperature not exceeding 45 °C, and milled to a target granule fraction of 125–850 µm. Compression on a rotary press with precompression 6–8 kN and main compression 12–18 kN may be evaluated; tablet hardness in the range 80–120 N is screened alongside friability according to USP <1216> and disintegration according to USP <701>. Dissolution testing in pH 6.8 phosphate buffer and 0.1 M hydrochloric acid according to USP <711> is required, but published dissolution profiles for nitroxynil tablets are limited. Because the free acid is weakly acidic, dissolution in gastric pH may be low, and salt formation inside the tablet matrix is not guaranteed; therefore, tablet formulations should include a disintegrant such as crospovidone at 2–5% w/w to facilitate rapid matrix break-up. The absence of a recognised commercial nitroxynil tablet product limits production-scale equipment failure data; process development must rely on factorial design with content uniformity measured per USP <905>.
In oral drench manufacturing, the glucamine salt solution route is reused, but the formulation solvent system and viscosity modifiers are adjusted for drench-gun delivery. At 34% w/v nitroxynil salt, a 10 mg/kg dose corresponds to 0.0294 mL/kg; a 600 kg bovine requires 17.6 mL and a 50 kg sheep requires 1.47 mL. The alkaline pH of the salt solution, typically pH 8.0–9.5, can cause oral mucosal irritation and poor palatability; lowering the pH with citrate or phosphate buffers risks protonating the free acid and producing a precipitate, so any palatability improvement must be validated by visual precipitation tests at 2–8 °C and 25 °C. Xanthan gum or hydroxyethylcellulose at 0.2–0.5% w/v may be included to reduce drench-gun dribble loss, but high shear mixing must be controlled because shear-thinning polymers can trap air and alter delivered volume. The production line should use positive-displacement pumps with volumetric calibration at ±1% and in-line 0.45 µm strainers to remove incidental particulate matter from the polymer. Published comparative oral bioavailability data for nitroxynil in ruminants is limited; therefore, the oral drench route should not be assumed bioequivalent to subcutaneous injection without a controlled pharmacokinetic study.
Granulation of the nitroxynil glucamine salt into oral paste or suspension intermediates introduces a water-soluble drug migration failure mode that is less pronounced with the free acid. The salt is dissolved in the binder solution or remains solubilised at the granule surface during evaporation, producing surface enrichment and potentially failing content uniformity when the dried granules are subdivided. In a top-spray fluid-bed granulator with a product bowl of 60 L, binder solution containing 5% w/w povidone K30 and the dissolved salt is sprayed at 20–25 g/min, with inlet air temperature 50–55 °C and dew point below −10 °C to slow surface crust formation. Drying curves are terminated at a loss-on-drying endpoint of 1.0–2.0% w/w; over-drying below 0.5% w/w increases friable fines and may shift drug distribution to the fines fraction. The dried granules are screened through a 1.4 mm sieve, and the fraction below 125 µm is monitored because it typically carries a higher drug load due to surface erosion; if the fines exceed 20% w/w, the blend should be remilled and re-granulated to avoid downstream segregation in sachet or bottle filling. Fluid-bed airflow is maintained above 1.5 m/s to prevent collapse of the wet bed, while filter bag shaking is set to 15 s every 60 s to limit static charge on the polyamide filter. Published nitroxynil-specific granule drying data is limited, so the above operating ranges should be treated as starting parameters requiring mass-balance and content uniformity confirmation per USP <905>.
Capsule dosage forms for nitroxynil are limited by the same single-dose mass constraint as tablets; a 50 kg sheep would require 500 mg active, which is feasible as two 250 mg capsules, but a 600 kg bovine would require 6 g active and is not a practical capsule target. For smaller ruminants or subdivided dosing in veterinary practice, the granule blend is filled into hard gelatin or HPMC capsules using a dosator-type machine, where the critical operating variable is granule flow. A Hausner ratio below 1.25 and Carr index below 25% are typical targets to avoid weight variation; free-flowing granules reduce dosing pin compaction and cap-to-cap fill weight drift. Because the nitroxynil salt is hygroscopic, relative humidity during filling must be maintained below 40% RH to prevent granule softening and sticking to the dosator pin. Capsule shell selection should consider moisture exchange: gelatin shells become brittle below 35% RH and soften above 60% RH, while HPMC shells offer lower residual moisture but may require tighter pin lubrication settings. Dissolution from capsules should be tested with USP <711> Apparatus II at 75 rpm in pH 6.8 phosphate buffer; if the formulation contains a disintegrant and the granules are dry, mean release above 75% at 30 min is an initial screening threshold, but no nitroxynil-specific monograph dissolution limit is widely published. Published production-scale failure data for nitroxynil capsules is limited; machine settings should be verified by gravimetric checkweighing at 15-minute intervals during filling.
Published data for nitroxynil medicated-feed premix homogeneity, carryover thresholds, and species-specific feed intake variability remain limited; production-scale granule feed applications are therefore not established as a primary downstream route.
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NITROXYNIL Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a compendial-grade 4-hydroxy-3-iodo-5-nitrobenzonitrile supplied as a yellow crystalline powder. The chemical formula is C7H3IN2O3 and the relative molecular mass is 290.02 g/mol; the CAS registry number is 1689-89-0. The product is a manufacturing input for veterinary flukicide preparations used in cattle and sheep, not a finished therapeutic agent. In solid oral products the free acid form is blended, granulated, or filled into capsules; in aqueous injectable and oral drench products the meglumine salt is used because it provides water solubility. The physical form is therefore not a single universal grade; the free acid is specified for solid oral processing and the meglumine salt is specified for aqueous injectable preparation. Release and purity are aligned with the current European Pharmacopoeia (Ph. Eur.) monograph for nitroxynil for veterinary use and Ph. Eur. general chapter 2034. Unlike salicylanilide flukicides, nitroxynil contains both iodine and nitro substituents on a phenolic nitrile core, which changes its spectroscopic identity, chromatographic retention, and salt-forming behaviour.
The product model designation is the chemical entity rather than a device model. Available physical grades include the free acid and the meglumine salt, and particle-size grades are assigned by the API manufacturer according to the intended dosage form. Packaging is typically double polyethylene bags inside a fibre or HDPE drum. Each batch is released with a certificate of analysis that includes the tests stated in the pharmacopoeial monograph and any additional tests agreed for the specific finished product.
The free acid has low aqueous solubility and is handled as a practically water-insoluble solid in oral granulation. Tablet and capsule operations therefore depend on particle-size reduction, ordered mixing with lactose or mannitol, and binder addition that does not separate the hydrophobic API from the hydrophilic excipient phase. Injectable presentations are prepared from the meglumine salt dissolved in water for injection, clarified, and filled through a 0.22 µm sterilising-grade membrane. The change from free acid to salt is not a simple dilution step; it changes pH, solution viscosity, and filter compatibility.
In veterinary formulations, nitroxynil is administered by subcutaneous injection or oral drench for fascioliasis in cattle and sheep. Tablet and capsule presentations are used where discrete oral dose units are required; granule presentations may be filled into sachets or mixed with feed at the point of use. The API itself is not dispensed directly. The exact dose regimen is determined by the finished product, bodyweight, liver fluke burden, and local veterinary practice.
Oral grades are controlled by laser diffraction according to Ph. Eur. 2.9.31 and by loss on drying according to Ph. Eur. 2.2.32. Injectable grades are additionally controlled for clarity, colour, and bacterial endotoxins using Ph. Eur. 2.6.14. This route-specific control set is the technical basis for supplying separate physical grades rather than one universal powder.
A typical release specification for pharma-grade nitroxynil API includes appearance as a yellow crystalline powder; identification by infrared absorption spectrophotometry and by HPLC retention time; assay by liquid chromatography at 98.0–102.0% on the dried basis; related substances with total impurities not exceeding 1.0% and any single unspecified impurity not exceeding 0.3%; water by Karl Fischer titration at ≤1.0%; residue on ignition at ≤0.1%; and an elemental impurity profile consistent with ICH Q3D. Residual solvents are assessed under Ph. Eur. 5.4. For parenteral-grade material, bacterial endotoxins are commonly controlled at ≤0.25 EU/mg, although the finished product limit may be more stringent.
Assay uses an octadecylsilyl silica gel column with a phosphate-buffered mobile phase and ultraviolet detection. System suitability includes resolution from specified impurities, tailing factor ≤2.0, and injection repeatability with relative standard deviation ≤2.0%. The current Ph. Eur. monograph provides the specific column temperature and mobile-phase ratio; the method is stability-indicating after forced degradation. Related substances are reported by area percentage, and the specification may include specific impurities arising from synthetic intermediates or degradation products.
Residual solvents are limited according to ICH Q3C classes. If the synthesis uses methanol, acetonitrile, or dimethylformamide, their residual levels are verified by headspace gas chromatography against the solvent-specific limit. Elemental impurities are managed by ICH Q3D; because the molecule contains iodine, anion analysis is separate from metal screening and is not used as a substitute for assay.
Nitroxynil is a halogenated nitrile, not a salicylanilide. Closantel and rafoxanide are salicylanilides, and triclabendazole is a benzimidazole. This structural difference changes the ultraviolet spectrum, the HPLC retention time, and the pH range over which salt formation occurs. Nitroxynil is reported in veterinary parasitology literature as effective mainly against adult Fasciola hepatica, whereas triclabendazole is used where activity against early immature stages is required. Nitroxynil may therefore be selected when the clinical target is mature fluke and when an injectable or oral product with different tissue residue behaviour is required.
In formulation development, the main operational difference is that the nitroxynil free acid must be milled and ordered in a low-moisture blend, while the meglumine salt is directly soluble. Salicylanilide APIs also require salt formation for injection, but the absence of the nitro group changes the acid strength and the required counterion concentration. The nitroxynil molecule also carries iodine, which adds an elemental and mass spectral control burden not present for triclabendazole.
There is also a difference in analytical detection. Nitroxynil requires an HPLC method with UV detection at a wavelength specific to the nitro-aromatic chromophore. Closantel and rafoxanide have salicylanilide chromophores with different absorbance maxima and retention behaviour. A facility that runs multiple flukicide APIs must verify column selectivity after each product changeover because the nitroxynil peak is less polar than triclabendazole but more polar than closantel under common reversed-phase conditions. Published method transfer data for this exact separation is limited; laboratories establish retention times experimentally with the specific column lot.
Production-scale oral solid processing of nitroxynil free acid is performed in high-shear mixers or fluid-bed granulators. A pre-blend of the API with a portion of lactose or mannitol is prepared before aqueous binder is added, because the low aqueous solubility and hydrophobic surface of the free acid make it sensitive to non-uniform binder distribution. The wet mass is dried to a target moisture content compatible with capsule shells or film-coating processes, then dry-milled and screened before lubrication. Blend uniformity is verified by sampling across the compression run with acceptance criteria derived from Ph. Eur. 2.9.40. Tablet hardness and friability are assessed according to Ph. Eur. 2.9.8 and Ph. Eur. 2.9.7.
A process conflict arises in wet granulation because the free acid is hydrophobic and low-density; adding aqueous binder too quickly can produce a bimodal granule size distribution and slow drying. On high-shear mixers, the binder addition rate is therefore ramped and the chopper speed is adjusted to avoid lodgement on the bowl wall. Drying is monitored with in-process moisture analysis; the endpoint is not defined by time alone because bed depth and exhaust humidity vary between batches. Published data for the minimum drying endpoint of nitroxynil granulations is limited, so each site establishes a loss-on-drying specification through the process validation batches.
Because published quantitative data on the relationship between nitroxynil particle size and tablet dissolution is limited, the particle-size specification is normally established from finished-product dissolution testing using Ph. Eur. 2.9.3 or USP <711>. A micronized grade may be targeted to a D90 below 50 µm for direct compression or dry granulation, but this value is a product-specific target rather than a compendial limit.
Injectable production starts from the meglumine salt or from the free acid neutralised in situ. The solution is prepared in water for injection, passed through a clarifying filter, and then through a sterilising-grade 0.22 µm membrane. Aseptic filling follows EU GMP Annex 1 requirements in Grade A with Grade B background. Where the formulation is heat-stable, terminal sterilisation may be validated at 121 °C for 15 min or an equivalent F₀ ≥8 min. Sterile filtration is confirmed by bubble point or diffusion flow integrity testing; the filtered solution is held for no longer than the validated holding time before filling. Sterility testing follows Ph. Eur. 2.6.1, and sub-visible particulate matter is controlled according to Ph. Eur. 2.9.19.
The meglumine salt solution is typically filtered at room temperature; solution viscosity is low enough for membrane filtration, but formulation variations such as added preservative or cosolvent can require a filter compatibility study. The solution pH is maintained in the region that keeps nitroxynil in solution without causing tissue irritation, and precipitation at low pH is a known failure mode. Filtration validation includes chemical compatibility, extractables, and integrity after processing. Published viscosity curves for all commercial formulations are not public; manufacturers confirm them during development.
| Presentation | API form | Typical critical controls | Primary compendial references |
| Tablet | Free acid, dry-milled or micronized | Particle size distribution, loss on drying, assay, dissolution | Ph. Eur. 2.9.31; Ph. Eur. 2.9.3; USP <711> |
| Capsule | Free acid, dry-milled | Bulk density, flow, dust containment, content uniformity | Ph. Eur. 2.9.34; Ph. Eur. 2.9.40 |
| Granule | Free acid in granulated intermediate | Moisture content, granule size distribution, compressibility | Ph. Eur. 2.9.38; Ph. Eur. 2.2.32 |
| Injection | Meglumine salt | Clarity, pH, bacterial endotoxins, sterility, particulate matter | Ph. Eur. 2.6.14; Ph. Eur. 2.6.1; Ph. Eur. 2.9.19 |
This matrix is a compliance reference rather than a formulation guide. In each row, the API manufacturer and finished-dose manufacturer define a mutually agreed specification. The assay result for the meglumine salt is expressed as the free acid content, and the excipient used for injection is separately designated because the salt form is not part of the free acid monograph. Table limits are not clinical dose recommendations.
During dry handling in high-humidity regions, pre-drying of the free acid may be required if the water content exceeds 1.0%. The material is stored in well-closed containers protected from light. Prolonged direct sunlight should be avoided; published photostability data for nitroxynil under ICH Q1B conditions is limited, so light protection is retained during scale-up until forced-degradation data are available.
The API is incompatible with strong oxidisers, strong acids, and nitrating conditions. Uncontrolled decomposition can release nitrogen oxides and iodine-containing vapours, so local exhaust ventilation is required during weighing and milling. Dust concentration and equipment grounding are assessed under ATEX and relevant combustible-dust standards. The safety data sheet should be consulted for current hazard classification and personal protective equipment. Nitroxynil should not be stored with strong acids, strong bases, or oxidisers. The API is considered stable under normal warehouse conditions, but it is protected from moisture and light to maintain the release specification over the assigned retest period.
For personnel protection, the API is treated as a potential respiratory and skin irritant. Weighing and milling are conducted in a downflow booth or isolator with dust extraction. Airborne exposure is controlled to a site-specific occupational exposure level because published health-based exposure data for nitroxynil is limited. Wash-down procedures after campaign handling prevent cross-contamination with other flukicides on shared equipment. No interchangeability claim is made; substitution of nitroxynil for another flukicide is a veterinary clinical decision made with the finished-product labelling.
