| HS Code | 427789 |
| Chemical Name | 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile |
| Cas Number | 120068-37-3 |
| Molecular Formula | C12H4Cl2F6N4OS |
| Molecular Weight | 437.15 g/mol |
| Purity | ≥99% (Veterinary Grade API) |
| Appearance | White to pale yellow crystalline powder |
| Solubility | Practically insoluble in water; soluble in organic solvents such as acetone, methanol, ethanol, and ethyl acetate |
| Melting Point | 200–201°C |
| Storage Conditions | Store in a cool, dry, well-ventilated place; keep container tightly closed; protect from light and moisture |
| Shelf Life | 24 months when stored under recommended conditions |
| Mechanism Of Action | Blocks GABA- and glutamate-gated chloride channels in target insects, causing neuronal hyperexcitation, paralysis, and death |
| Target Parasites | Fleas, ticks, lice, and mites affecting dogs, cats, and other animals |
| Available Dosage Forms | Tablets, injections, capsules, powders, granules, premix, and solutions (including spot-on formulations) |
| Pharmacological Classification | Phenylpyrazole insecticide/acaricide |
| Bioavailability | Systemic absorption depends on formulation; topical spot-on provides prolonged dermal reservoir with slow transdermal absorption |
| Excretion Route | Eliminated primarily via feces; metabolic degradation in liver with some accumulation in adipose tissue |
As an accredited Fipronil Spot On 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 | Sealed double polythene bags inside HDPE drum, 25 kg net weight, with certificate of analysis for veterinary grade Fipronil API. |
| Container Loading (20′ FCL) | One 20′ FCL container safely loaded with Fipronil veterinary grade API, packaged for tablets, injections, capsules, powders, granules, premix, and solutions. |
| Shipping | Fipronil Veterinary Grade API ships as a regulated hazardous substance, complying with IATA, IMDG, and ADR. Packed in sealed, moisture-proof drums with tamper-evident liners. Transported under temperature-controlled conditions with complete safety documentation, including MSDS and certificates of analysis. Suitable for air, sea, or road freight, respecting destination import regulations. |
| Storage | Store Fipronil veterinary grade API in a cool, dry, well-ventilated area, away from heat, sparks, and direct sunlight. Keep container tightly closed and protected from moisture. Store at controlled room temperature, ideally 15–30°C. Maintain segregation from oxidizing agents, food, and animal feed. Avoid dust accumulation to preserve stability and quality. |
| Shelf Life | Shelf life: 36 months from manufacture when stored in original unopened container below 30°C, protected from light and moisture. |
A practical constraint in direct compression of fipronil tablets is the API’s low aqueous solubility (1.9 mg/L at 20 °C) and plate-like crystalline morphology, which reduces bulk powder flow. To produce investigational oral solid dosage forms, fipronil is first micronized in a spiral jet mill with nitrogen gas at a feed pressure of 7–10 bar and grinding pressure of 5–8 bar; the target particle size measured by laser diffraction per ISO 13320-1:2020 is D50 < 15 µm and D90 < 40 µm. The micronized API is blended with lactose monohydrate, microcrystalline cellulose, croscarmellose sodium 2.0% w/w, colloidal silicon dioxide 0.5% w/w, and magnesium stearate 0.5% w/w in a bin blender at 12 rpm for 20 min; the fipronil load for screening batches is 1.0–5.0% w/w, adjusted to the required dose. Compression is performed on a rotary tablet press with a turret speed of 20–40 rpm and a compression force of 8–15 kN; tablet hardness measured by a Schleuniger tester is maintained at 40–80 N to ensure disintegration below 15 min in 0.1 M HCl per Ph. Eur. 2.9.1. Content uniformity is verified according to Ph. Eur. 2.9.40; acceptance value must be ≤15. Because published oral bioavailability data for fipronil tablets in dogs and cats are limited, these batches are intended only for controlled pharmacokinetic evaluation and are not interchangeable with approved spot-on formulations.
| Dosage form | Critical parameter | Method | Typical release limit |
|---|---|---|---|
| Spot-on solution | Fipronil content | HPLC per USP <621> | 90.0–110.0% label claim |
| Tablet | Content uniformity | Ph. Eur. 2.9.40 | Acceptance value ≤ 15 |
| Capsule | Disintegration | USP <701> | ≤ 15 min |
| Granule | Blend homogeneity | USP <621> | RSD ≤ 5.0% |
When hard gelatin capsule filling is planned for fipronil-containing blends, the operation depends on maintaining a bulk density of 0.45–0.55 g/mL and a Carr index of 20–25 to avoid inconsistent dosing disc fill. The blend for capsule manufacture contains micronized fipronil at 2.5–10 mg per capsule, spray-dried lactose monohydrate, pregelatinized starch 10.0% w/w, crospovidone 3.0% w/w, and sodium stearyl fumarate 1.0% w/w; the final mix is passed through a 600 µm mesh screen and filled into size 3 hard gelatin capsules at a fill weight of 150–180 mg. Capsule fill weight uniformity is controlled by in-line net weight checkweighers, and the acceptance criteria follow Ph. Eur. 2.9.40 with an acceptance value ≤15. Moisture content of the blend is kept below 4.0% by Karl Fischer titration per USP <921>, because micronized fipronil powders exhibit surface moisture uptake that can hinder capsule filling and reduce blend flow. Disintegration of capsules is tested in 900 mL of 0.1 M HCl at 37 ± 2 °C using the basket apparatus of USP <701>; all units must disintegrate within 15 min. For capsule-specific stability, open-container storage at 25 °C/60% RH is avoided because gelatin cross-linking can occur in the presence of trace aldehydes; the primary packaging is aluminium/PVC cold-form blister to reduce moisture ingress below 0.5 mg/day per blister.
In cutaneous spot-on manufacturing, fipronil veterinary grade API is incorporated into finished solutions at a target concentration of 10.0% w/v for companion animal ectoparasiticide products. The manufacturing sequence begins with API dissolution in a co-solvent system composed of diethylene glycol monoethyl ether and ethanol under low-shear agitation at 15–25 °C; butylhydroxyanisole at 0.01–0.05% w/v and butylhydroxytoluene at 0.01–0.05% w/v are added as antioxidants, followed by benzyl alcohol at 0.5–1.0% w/v as preservative when the formulation is packaged in multi-dose containers. The bulk solution is filtered through a 0.45 µm polypropylene depth filter into a storage vessel and then filled into low-density polyethylene or fluoropolymer-laminated tubes at a fill volume of 0.5–4.0 mL; filling is typically performed on piston-based volumetric filling lines with in-line check weighing to reject units outside ±1.0% of target weight. Viscosity of the bulk solution measured at 25 °C using a Brookfield rotational viscometer per Ph. Eur. 2.9.5 is maintained below 50 mPa·s to prevent pump cavitation. Residual solvent and antioxidant degradation are controlled by gas chromatography per ICH Q3C and high-performance liquid chromatography per USP <621>; a typical release specification limits ethanol to 5.0% w/w and benzyl alcohol to 1.0% w/w. Stability of spot-on solutions is monitored under VICH GL3 conditions at 25 °C/60% RH and 40 °C/75% RH for 6 months; fipronil content must remain within 90.0–110.0% of label claim, and no individual impurity above 0.2% is acceptable.
To produce fipronil granules for sachet filling or in-feed premix dilution, a conical fluid-bed dryer is operated with inlet air temperature of 50–65 °C and product temperature maintained at 30–38 °C. The binder solution is prepared by dissolving polyvinylpyrrolidone K30 at 5.0% w/w in purified water and sprayed at 15–30 g/min per kg of powder bed; the fipronil content is adjusted to 0.5–2.0% w/w in the granule formulation, with lactose monohydrate and maize starch as diluents. Granulation endpoint is determined by loss-on-drying measured on a moisture balance at 85 °C, with a target of 1.5–2.5% residual moisture; particle size after sieving through a 1.0 mm screen and a 180 µm screen should fall in the range D50 200–400 µm measured by sieve analysis per Ph. Eur. 2.9.38. The dried granules are lubricated with 0.5% w/w magnesium stearate and packed into aluminium-lined sachets under nitrogen to limit oxidative degradation of the sulfoxide group. Premix production for feed application is restricted in many jurisdictions; when prepared for non-food companion animal research or in-facility use, a fipronil premix at 100 mg/g is geometrically diluted with ground maize cob or lactose to produce intermediate concentrations of 10 mg/g and 1 mg/g before final feed mixing. Homogeneity of the premix is confirmed by quantitative HPLC per USP <621> on ten stratified samples; acceptance requires relative standard deviation ≤5.0%. Because fipronil is not authorized for food-producing species in the European Union and many other markets, medicated feed applications must be limited to non-food animals or controlled experimental protocols under national veterinary oversight.
Because injectable fipronil is not a common therapeutic form, published data for commercial injectable formulations are limited; however, when a non-aqueous suspension is prepared for investigational use, several boundaries apply. Fipronil is practically insoluble in water (1.9 mg/L), so solubilization in aqueous injection vehicles is not feasible without high concentrations of cosolvents; an oil-based vehicle such as medium-chain triglycerides or ethyl oleate is used, with 10–20% w/w benzyl alcohol as co-solvent and 0.01–0.05% w/w butylated hydroxytoluene as antioxidant. The API is dispersed under high-shear homogenization at 10,000–15,000 rpm for 15–20 min to achieve a particle size of D90 < 20 µm measured by laser diffraction per ISO 13320-1:2020. Terminal sterilization of the oily suspension is performed by dry heat at 160 °C for 2 h only if the vehicle and container tolerate the cycle; if not, sterile filtration is not applicable because the suspension phase would blind the membrane, and therefore aseptic processing with sterile API is required. Syringeability is evaluated by pulling the suspension through 21 G needles at 25 °C; the force required must be below 25 N to be acceptable for manual injection. Particle size stability is tested after 3 months at 25 °C/60% RH, where agglomeration above D90 30 µm signals inadequate wetting and requires reformulation with 0.1–0.5% w/w lecithin. Sterility testing follows Ph. Eur. 2.6.1 with membrane filtration, and bacterial endotoxins are controlled according to Ph. Eur. 2.6.14; the limit is set at <2.5 EU/mL for intramuscular administration. Because injection-site reactions and systemic safety margins have not been fully established for fipronil in companion animals, this route is reserved for controlled veterinary research under regulatory approval.
In solution and premix manufacturing, fipronil requires a solvent system capable of maintaining the active in solution during storage and after dilution. A clear oral or topical dilutable concentrate can be prepared with fipronil at 2.0–5.0% w/v in a vehicle of propylene glycol, ethanol, and polysorbate 80; the polysorbate 80 content is typically 5–10% w/v to prevent precipitation when the concentrate is diluted with water to a working concentration of 0.01% w/v. The sequence is: fipronil is dissolved in ethanol at 20–30 °C under continuous stirring, polysorbate 80 is added, propylene glycol is charged, and the solution is mixed for 30 min before filtration through a 5 µm polypropylene cartridge filter. Clarity of the diluted solution is inspected by visual comparison against a standard opalescence tube per Ph. Eur. 2.9.20; precipitation or turbidity greater than reference suspension II is a rejection criterion. Chemical stability of the diluted solution is limited by fipronil hydrolysis under alkaline conditions, so final pH is adjusted to 4.0–6.0 with citric acid. For solution packaging, amber glass bottles with child-resistant closures are used to reduce photodegradation; light-protection testing is performed according to ICH Q1B with an illumination of not less than 1.2 million lux·h and an ultraviolet exposure of 200 W·h/m². Content of fipronil in solution is determined by HPLC at 280 nm per USP <621>, and the acceptance range is 95.0–105.0% of label claim. Feed or drinking-water use of such concentrated solutions for food-producing animals is prohibited in the European Union under Regulation (EU) 2019/6 unless specifically authorized; therefore, industrial application is confined to companion animal topical or oral use where national approvals exist.
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Fipronil Spot On Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is a purified phenylpyrazole derivative supplied as a white to off-white crystalline powder. The substance is identified by CAS 120068-37-3, molecular formula C12H4Cl2F6N4OS, and relative molecular mass 437.15 g/mol. The product designation does not describe a finished spot-on formulation; it defines an API grade controlled for downstream formulation into topical spot-on vehicles and non-topical veterinary preparations. The model designation covers a single chemical entity with formulator-selected physical grades rather than chemically distinct variants. The sulfoxide-containing molecule is practically insoluble in water, with reported solubility below 2 mg/L at ambient temperature, and has a measured log P of 4.0, consistent with high lipid partitioning. Melting behaviour is reported in the range 200–201 °C; uncontrolled heating can generate hazardous decomposition products from the halogenated aromatic structure, so drying and melt-based processing require inert atmosphere and controlled temperature. This physical profile creates distinct constraints for each dosage form: spot-on solutions require fully miscible non-aqueous solvents, oral solids require wetting or carrier systems, injectables require non-aqueous vehicles with low moisture content, and premix or powder operations require segregation control. The API is therefore not a universal direct-use powder; each downstream route selects a particle size, residual solvent, and endotoxin specification appropriate to the finished product.
Veterinary-grade fipronil is differentiated by impurity profile, residual solvent control, and manufacturing oversight. Technical-grade material used in crop protection or urban pest control may contain related substances, colored impurities, and process solvents that are not controlled to the limits expected for parenteral, oral, or repeated-dose topical veterinary products. The veterinary API is manufactured under veterinary GMP conditions aligned with PIC/S GMP or regional equivalents; batch records and change control are maintained so that a formulation sponsor can trace every lot to a release decision. Residual solvent levels are aligned with ICH Q3C and VICH GL18 for Class 1 and Class 2 solvents; Class 1 solvents such as benzene and carbon tetrachloride are controlled at or below the specified limits or excluded from the process. Related substances are controlled by HPLC integration with a specification that typically includes total impurities ≤1.0% and unspecified single impurities ≤0.10%. The veterinary grade is also characterized for crystalline habit and particle size distribution; needle-shaped or plate-like crystals, if present, can generate poor flow, poor capsule fill weight, and non-uniform premix distribution. The particle size distribution is not merely a physical convenience; for spot-on solutions, a coarse fraction may settle in the holding tank and cause fill weight drift during high-speed ampoule or tube filling. The same CAS number does not imply interchangeability between grades, and replacement of a veterinary API with technical-grade material without full impurity and dissolution comparison is not acceptable under GMP change control. Compared with finished spot-on products from other ectoparasiticides, this API is not directly comparable on the basis of chemical identity alone; formulation-specific distribution, residual activity, and solvent matrix must be established separately.
Fipronil acts as a non-competitive blocker of arthropod GABA-gated chloride channels. Binding at the chloride channel complex reduces inhibitory neurotransmission, producing hyperexcitation and death in fleas, ticks, and chewing lice. Mammalian safety margins arise from receptor subtype differences; however, the API is not intrinsically nontoxic, and formulation personnel should handle it with engineering controls because liver and thyroid effects have been reported in rodent toxicology studies at elevated exposures. After topical spot-on application in dogs and cats, the lipophilic compound spreads across the lipid film of the skin and localizes in sebaceous glands, providing residual ectoparasiticidal activity. The primary metabolite fipronil sulfone retains activity and is formed slowly by oxidative pathways; this has relevance for oral or injectable dosage forms because clearance and accumulation can differ from topical kinetics. Published data for fipronil tablets and injections in veterinary species are limited, and bioavailability from oral solid dosage forms is not assumed to be equivalent to spot-on distribution. Any development program for a non-topical route should therefore establish pharmacokinetic bridging rather than rely on topical efficacy as a surrogate for systemic exposure. For ectoparasiticide indicators, the API is not a repellent; it requires parasite contact and sufficient contact time on the host surface or systemic availability. Co-formulation with other actives such as pyrethroids or amitraz requires separate compatibility data and justification for the target species and regulatory claim.
Batch release of the API is performed against a specification that combines identity, purity, physical form, and solvent control. Table 1 lists representative acceptance criteria common in veterinary GMP batch release; the binding values may be adjusted by a marketing authorization holder when a regional monograph or approved variation imposes tighter limits. Each criterion is linked to a pharmacopoeial general method where available.
| Parameter | Acceptance criterion | Method / standard |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual examination |
| Identification | IR spectrum corresponds to fipronil reference; HPLC retention time agrees with reference | Ph. Eur. 2.2.24, 2.2.29 |
| Assay | 98.0–102.0% on dried basis | HPLC, Ph. Eur. 2.2.29 |
| Related substances | Total ≤1.0%; unspecified single ≤0.10% | HPLC area normalization |
| Loss on drying | ≤0.5% | Ph. Eur. 2.2.32 |
| Sulfated ash | ≤0.1% | Ph. Eur. 2.2.14 |
| Residual solvents | Class 1 absent or at ≤ specified limits; Class 2 within ICH Q3C / VICH GL18 | Headspace gas chromatography |
| Particle size distribution | Formulation-specific; laser diffraction distribution must be agreed between manufacturer and formulator | Ph. Eur. 2.9.31 |
| Microbial limits | Total aerobic microbial count ≤10³ CFU/g; Escherichia coli absent in 1 g | Ph. Eur. 2.6.12, 2.6.13 |
| Bacterial endotoxins | ≤0.5 EU/mg when ordered for injectable development | Ph. Eur. 2.6.14 |
Direct compression of fipronil veterinary API is constrained by low aqueous solubility, high lipophilicity, and flow-related segregation. For tablet and capsule development, the compound is generally blended with a hydrophilic filler such as lactose monohydrate or microcrystalline cellulose and a disintegrant such as croscarmellose sodium; however, because fipronil is poorly wetted, granulation or surfactant addition is usually required to obtain acceptable dissolution. A wet granulation route using an aqueous binder may be unsuitable if the API degrades under prolonged moisture contact; organic granulation or dry granulation with roller compaction should be evaluated in parallel. Tablets produced without a wetting agent may show low drug release in dissolution apparatus II at 37 °C unless the medium includes sodium lauryl sulfate at a concentration justified by solubility data; a screening medium of water with 0.5% sodium lauryl sulfate is common for poorly soluble APIs, but sink conditions must be verified for each tablet strength. Dissolution testing follows Ph. Eur. 2.9.3. Capsule filling of micronized fipronil must account for static charge and cohesive flow; the powder should be qualified for angle of repose, bulk density, tapped density, and compressibility by Ph. Eur. 2.9.36 and 2.9.34. For low-dose tablets, geometric dilution is necessary because direct weighing of the active ingredient is not practical below 1 mg per unit. On rotary tablet presses, low-dose direct compression blends may show weight variability if the hopper level drops below the point where powder arching occurs; forced feeding or hopper inserts should be used when the formulation is prone to bridging. After aqueous wet granulation, the dried granule moisture content is typically controlled at 2.0–3.0% by Ph. Eur. 2.2.32; drying below this range can increase friability, while drying above this range can accelerate hydrolysis in the presence of residual water. Solubility screening should be performed before committing to a formulation route; a practical go/no-go for spot-on filling is that the selected solvent system dissolve the target dose with at least a 20% concentration margin for temperature fluctuations during filling.
For spot-on manufacturing, dissolution of the API in the solvent matrix is the primary critical operation. On filling lines using peristaltic pumps and sterilizing-grade capsule filters, undissolved fipronil or excipient precipitates can plug the membrane and drive line pressure excursions; pre-dissolution in a jacketed stainless-steel vessel with low-shear impeller at controlled temperature reduces that failure mode. The solvent matrix is generally non-aqueous and may include ethanol, diethylene glycol monoethyl ether, or other solvents with demonstrated skin tolerance in the target species. Solvent selection cannot be based solely on solubility; it must be tested for compatibility with pipette materials, closure elastomers, and barrier films because non-aqueous solvents can extract plasticizers or swell polymers. Injection development is even more constrained because fipronil is practically insoluble in water. Aqueous vehicles are not suitable without cosolvent or complexation, and any water-containing formulation risks precipitation upon injection or storage. Non-aqueous vehicles such as propylene glycol, glycofurol, or medium-chain triglycerides may dissolve the compound, but species tolerance and injection-site reactions must be evaluated; published data for this specific configuration is limited. Sterilization by autoclaving may generate thermal degradation products if moisture is present, so aseptic filtration through a 0.22 µm sterilizing membrane is preferred only after the non-aqueous solution passes filter compatibility testing. Powder, granule, and premix forms place the primary risk on homogeneity. High-density crystalline particles of fipronil may segregate from low-density carriers during transfer; carrier adsorption, wet massing, or granulation may reduce that risk, but residual solvent levels must be rechecked after drying because non-aqueous granulation fluids can remain trapped. Dry blending is usually performed in a bin blender or ribbon mixer, and mixing time should be established by blend uniformity sampling using pharmacopoeial content uniformity methods after serial dilution. For feed premix applications, the API should only be considered where the target species and regional residue requirements permit; use in food-producing animals is not automatically acceptable and may violate pesticide MRL or veterinary residue control rules.
Fipronil veterinary API is sensitive to prolonged ultraviolet exposure, and storage conditions should control light exposure according to VICH GL5 or regional stability guidance. Bulk powder should be stored in tightly closed containers at controlled room temperature; desiccant protection is indicated when the packaging is opened at relative humidity above 60% because moisture uptake can alter flow and accelerate hydrolysis at elevated temperature. The compound is incompatible with strong bases, strong oxidizing agents, and reducing agents; formulation with such excipients should be assessed by forced degradation studies before stability batches are manufactured. Oxidative degradation can produce the sulfone derivative, while reductive conditions may alter the sulfoxide group and change pharmacological activity. Stability protocols should include assay, related substances, water content, and a dissolution or dissolution surrogate where applicable. For tablets and capsules, accelerated stability at 40 °C / 75% RH is expected to be evaluated according to VICH GL3, but a retest period is assigned only after long-term data are available. Photostability testing should include a forced degradation arm under UV and visible light using a photostability chamber conforming to VICH GL5. The API should not be combined with amines or other nucleophiles in multicomponent premixes without compatibility data; such combinations may generate degradation products that are not captured by a standard HPLC impurity method. Because the molecule is highly lipophilic, pH adjustment alone is often insufficient to dissolve it, so stabilizing the API typically depends on water activity control and protection from oxygen rather than pH modification.
Selection of a manufacturing route for the API is summarized in Table 2. The entries are screening-level and do not replace product-specific development reports.
| Dosage form | Principal process risk | Governing technical control |
|---|---|---|
| Spot-on solution | Incomplete dissolution, filter plugging, pipette incompatibility | Solvent capacity screening; 0.22 µm filter compatibility; viscosity at filling temperature |
| Tablet | Poor wetting, dissolution failure, low-dose segregation | Granulation route; dissolution apparatus II at 37 °C per Ph. Eur. 2.9.3; surfactant level |
| Capsule | Micronized powder flow, static charge, fill weight variability | Ph. Eur. 2.9.36 flow; tapped density; fill weight RSD on capsule machine |
| Injection | Aqueous insolubility, precipitation, sterility | Non-aqueous vehicle; aseptic filtration; bacterial endotoxin limit per Ph. Eur. 2.6.14 |
| Powder / granule | Segregation, dusting, cross-contamination | Particle size by Ph. Eur. 2.9.31; bulk density; containment validation |
| Premix | Homogeneity after dilution, carrier incompatibility, residue control | Assay uniformity after serial dilution; stability in final feed matrix; regional residue compliance |
Each route requires a distinct specification for particle size, water content, and endotoxin burden; no single physical grade satisfies all routes without additional processing.
