| HS Code | 341898 |
| Product Name | Diamphenethide (Diamfenetide) Veterinary Grade API |
| Chemical Name | N,N'-[oxybis(4,1-phenylene)]bis(2,2-diethoxyacetamide) |
| Cas Number | 36141-82-9 |
| Molecular Formula | C24H32N2O7 |
| Molecular Weight | 460.52 g/mol |
| Appearance | White to almost white crystalline powder |
| Solubility | Practically insoluble in water; soluble in acetone; sparingly soluble in ethanol |
| Melting Point | 101-103 °C |
| Assay Purity | Minimum 99.0% (HPLC, on dried basis) |
| Storage Conditions | Store in tightly sealed, light-protected containers in a cool, dry place away from moisture |
| Shelf Life | 36 months from date of manufacture when stored under recommended conditions |
| Product Name | Diamphenethide (Diamfenetide) Veterinary Grade API |
| Cas Number | 36141-82-9 |
| Molecular Formula | C22H28N2O7 |
| Molecular Weight | 432.47 g/mol |
| Chemical Name | bis[2-(4-acetamido-2-methoxyphenoxy)ethyl] ether |
| Category | Anthelmintic / Fasciolicide |
| Appearance | White or almost white crystalline powder |
| Solubility | Practically insoluble in water; soluble in organic solvents such as ethanol, methanol, acetone, chloroform and dimethylformamide |
| Melting Point | approximately 145-148 degrees Celsius |
| Purity Assay | Veterinary grade with typical assay >= 98.0 percent on dried basis |
| Storage Conditions | Store in tightly closed containers in a cool, dry place; protect from light and moisture |
| Pharmaceutical Compatibility | Suitable for formulation into tablets, injections, capsules, powders, granules, premix and solutions |
| Target Species | Sheep and cattle |
| Therapeutic Indication | Treatment of fascioliasis caused by Fasciola hepatica; active against immature and adult liver flukes |
As an accredited Diamphenethide(Diamfenetide) 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 25 kg drums with double polythene liners, protected from moisture, labeled for veterinary use. |
| Container Loading (20′ FCL) | 20′ FCL loading: Diamphenethide veterinary-grade API, thoroughly packed in sealed drums/cartons for tablets, injections, powders, and other dosage forms. |
| Shipping | Diamphenethide (Diamfenetide) veterinary-grade API is shipped in sealed, light-protected, moisture-resistant containers under controlled ambient temperature. Dispatched with full compliance documentation, including safety data sheets, certificate of analysis, and handling protocols. Suitable for global transport with secure, tamper-evident packaging designed to preserve purity and stability. |
| Storage | Store Diamphenethide (Diamfenetide) Veterinary Grade API in a cool, dry, well-ventilated area, ideally below 25°C. Keep the container tightly closed and protected from light, moisture, and heat. Avoid contact with incompatible substances. Use clean, dry handling equipment. Under these conditions, the material retains its quality for pharmaceutical formulation into tablets, injections, capsules, powders, granules, premixes, or solutions. |
| Shelf Life | Shelf Life: 24 months from manufacture when stored tightly sealed, protected from moisture and light, below 30°C. |
The oral drench solution for sheep is formulated to deliver diamphenethide at a target dose of 100 mg/kg bodyweight against juvenile Fasciola hepatica during the 6–8 week post-infestation period. A registered sheep drench containing 5.0% w/v diamphenethide corresponds to 50 mg/mL, requiring 2.0 mL/10 kg live weight. The manufacturing formula is not a simple aqueous solution; diamphenethide is poorly water-soluble, so the carrier system typically contains 10.0–18.0% w/v propylene glycol or ethanol, 0.2–0.5% w/v polysorbate 80, 0.10–0.30% w/v simethicone emulsion, and citric acid monohydrate quantity sufficient to hold the continuous phase at pH 5.5–6.5. Production begins with air-jet milling of the API to D90 ≤ 40 µm before dispersion into the co-solvent under a high-shear rotor-stator mixer at 3,000–3,500 rpm for 12–15 min. The coarse dispersion is transferred to a jacketed vessel and passed through a high-pressure homogenizer at 250–300 bar for two passes; batch temperature is maintained at 20–25 °C throughout to limit crystal habit change. Filling into HDPE drench packs of 1 L, 2.5 L, and 5 L is performed with in-line 180 µm stainless steel sieves conforming to ISO 565 to reject agglomerates that would obstruct drench-gun nozzles. Release testing follows Ph. Eur. 2.9.40 for uniformity of dosage units, Ph. Eur. 2.9.10 for viscosity, and ICH Q3C for residual ethanol. On production lines, the dominant failure mode is nozzle clogging in automatic sheep race drench guns when sieve bypass occurs; batch-to-batch particle-size drift above D90 75 µm has been associated with delivered-dose variation exceeding ±10%.
Cattle drench manufacture differs from sheep drench processing primarily in total dose volume and suspension yield stress. When the same 100 mg/kg dose is delivered as a 5.0% w/v product, a 600 kg cow requires 1.2 L of drench, which is operationally invalid; consequently, cattle presentations are compounded at 10.0% w/v diamphenethide, reducing the dose to 1.0 mL/kg and permitting delivery through 30 mL backpack dose-gun systems. The suspending system contains 0.15–0.25% w/v xanthan gum, 0.5–1.0% w/v microcrystalline cellulose with sodium carboxymethylcellulose, 0.2% w/v polysorbate 80, 0.1% w/v sodium benzoate, and citric acid to pH 5.0–6.0. Gum hydration is conducted separately at 60 °C for 2 h, cooled to 25 °C, then combined with the API dispersion. The mixture is recirculated three times through a colloid mill with a 50 µm gap before transfer to 500 mL and 1 L HDPE bottles. Viscosity is controlled at 200–800 mPa·s using a Brookfield RVT spindle 3 at 20 rpm and 25 °C; below 200 mPa·s, sedimentation exceeds 5% in 24 h, and above 800 mPa·s, dose-gun trigger force rises beyond the 40 N ergonomic limit observed in extensive cattle yards. Release testing includes Ph. Eur. 2.9.36 for flowability of suspensions after storage at 30 °C/65% RH for 90 days, and Ph. Eur. 2.9.17 for delivered-dose uniformity from the final container. The terminal finished product types are 10.0% w/v oral suspension in 500 mL and 1 L HDPE bottles, fitted with tamper-evident caps compatible with automatic drenching equipment.
| Dosage form | Compliance standard or method | Critical control parameter |
|---|---|---|
| Sheep oral drench solution | Ph. Eur. 2.9.40, Ph. Eur. 2.9.10, ICH Q3C, EudraLex Vol. 4 Part II | Delivered dose uniformity; residual ethanol; particle size D90 ≤ 40 µm |
| Cattle oral suspension | Ph. Eur. 2.9.36, Ph. Eur. 2.9.17, Ph. Eur. 2.9.10 | Viscosity 200–800 mPa·s; suspension redispersibility after 24 h |
| Dry premix for extemporaneous suspension | Ph. Eur. 2.9.12, USP <795>, ICH Q3D | Sieve fraction 150–500 µm; moisture content below 5% |
| Oral granules | Ph. Eur. 2.9.1, Ph. Eur. 2.2.32, Ph. Eur. 2.9.12 | Loss on drying below 2.0%; granule size 150–500 µm |
| Tablets and capsules | Ph. Eur. 2.9.7, Ph. Eur. 2.9.5, Ph. Eur. 2.9.40, USP <711> | Friability below 1.0%; disintegration below 15 min; dissolution Q ≥ 80% |
| In-feed premix | Regulation (EU) 2019/4, Regulation (EC) No 183/2005, ISO 6496 | Mixer homogeneity RSD ≤ 5%; free moisture below 5.0% |
Where flock-level treatment is required without individual animal handling, a dry premix intended for extemporaneous reconstitution into an oral suspension is manufactured at 20.0% w/w diamphenethide. The diluent matrix consists of lactose monohydrate 72.0–74.0% w/w, microcrystalline cellulose 3.0–5.0% w/w, sodium starch glycolate 2.0% w/w, colloidal silicon dioxide 0.5% w/w, and magnesium stearate 0.5% w/w. The process requires geometric dilution in a 500 L double-cone blender operated at 8 rpm for 15 min at 55–60% fill volume; the first premix is prepared at a 1:6 API-to-diluent ratio, screened through a 500 µm sieve, and then blended with the remaining diluent to a 1:19 final ratio. Homogeneity is verified by high-performance liquid chromatography with ten sampling points per batch; the acceptance limit is RSD ≤ 3.5%. Moisture is controlled below 5.0% using ISO 6496-aligned loss-on-drying measurement because higher free moisture causes Lactose monohydrate to form non-flowable cakes in the dosing scoop. The terminal finished products are 20.0% w/w dry premix powders packed in 100 g, 500 g, and 1 kg LDPE jars; reconstitution directions state that 25 g of premix per 100 mL purified water yields a 5.0% w/v oral suspension for sheep drenching. This dry premix route reduces shipment weight and improves stability compared with ready-to-use drench because water is excluded from the package.
Oral granules are prepared when individual lamb dosing must be completed under field conditions where drench-gun volume errors exceed acceptable limits. The granule formulation contains 20.0% w/w diamphenethide, loaded onto a lactose-starch carrier with 3.0% w/w povidone K30 as binder, 2.0% w/w sodium starch glycolate as disintegrant, 0.5% w/w colloidal silicon dioxide, and 0.5% w/w magnesium stearate. Granulation is performed in a top-spray fluidized-bed granulator using purified water as the binder solvent; inlet air temperature is held at 55–65 °C, product temperature at 30–35 °C, and spray rate adjusted to maintain a bed moisture endpoint below 5.0%. After drying, the granules are sieved through 150 µm and 500 µm screens; over-size granules are milled with a low-shear cone mill at 1,200 rpm and recycled. Loss on drying is controlled by Ph. Eur. 2.2.32 at 105 °C for 15 min, with endpoint below 2.0%. Disintegration is measured by Ph. Eur. 2.9.1 using purified water at 37 °C; complete dispersibility within 3 min is required because the granules are poured directly into the oral cavity or top-dressed onto 0.5 kg concentrate. The 5 g sachet delivers 1,000 mg diamphenethide, equivalent to 100 mg/kg for a 10 kg lamb. Terminal finished product types are 1 g, 2.5 g, and 5 g sachets of 20.0% w/w oral granules in moisture-barrier foil laminate. The main processing hazard is electrostatic attraction of fines to the polyethylene packaging line; relative humidity must be maintained above 30% to prevent charge accumulation during filling.
Tablet and capsule presentations for diamphenethide are manufactured for individual treatment of registered zoological ruminants, small breeding rams, and animals where liquid drench aspiration risk is unacceptable. The tablet formula uses 250 mg or 500 mg diamphenethide per unit with 45.0–55.0% w/w API, 25.0–35.0% w/w microcrystalline cellulose, 10.0–20.0% w/w lactose monohydrate, 2.0–5.0% w/w croscarmellose sodium, 0.5–1.0% w/w colloidal silicon dioxide, and 0.5–1.0% w/w magnesium stearate. Compression is performed on a rotary tablet press at 8–15 kN compression force with a target hardness of 60–100 N, friability below 1.0% after 100 revolutions under Ph. Eur. 2.9.7, and disintegration below 15 min under Ph. Eur. 2.9.1. Capsules are filled with a similar dry blend into hard gelatin capsules size 0 or 00, with fill weight controlled at ±5% by automatic dosator systems. Dissolution testing follows USP <711> using 900 mL of 0.1 M hydrochloric acid with 1.0% sodium lauryl sulfate at 50 rpm and 37 °C; the acceptance criterion is Q ≥ 80% in 45 min. Uniformity of mass and content conforms to Ph. Eur. 2.9.5 and Ph. Eur. 2.9.40. Terminal finished products are 250 mg and 500 mg tablets in 10×10 blister packs, and 500 mg hard gelatin capsules in 100-count HDPE bottles. Injectable presentations are not a routine downstream route for diamphenethide; published data for a licensed parenteral formulation in ruminants is limited, and the API’s aqueous solubility profile imposes particle-size and sterilization constraints that have not been resolved in most major markets.
In-feed premix production for controlled trough feeding is limited to prescription-feed scenarios where the target dose is calibrated to measured concentrate intake. A 20.0% w/w diamphenethide premix is prepared by stepwise dilution on a corn-cob or maltodextrin carrier with 0.5% w/w colloidal silicon dioxide and 0.5% w/w vegetable oil to bind fine API particles. The first dilution is prepared at 1:6 API-to-carrier ratio in a 100 L ribbon blender at 20 rpm for 8 min; this pre-blend is then diluted to the final 1:19 concentration in a 1,000 L twin-ribbon mixer at 15 rpm for 12 min. Field inclusion of 5 kg of this 20.0% w/w premix per 1 tonne final concentrate yields 1,000 mg diamphenethide per 1 kg feed. For a 25 kg sheep consuming 2.5 kg concentrate daily, this delivers 2,500 mg, equivalent to 100 mg/kg bodyweight. Homogeneity is measured on 10 sampling points per batch by HPLC-UV; the acceptance limit is RSD ≤ 5.0%. Free moisture is controlled below 5.0% by ISO 6496-based loss-on-drying because moisture migration from hygroscopic trace-mineral premixes causes API aggregation on the ribbon blades. The terminal finished product types are 25 kg paper-lined multiwall bags of 20.0% w/w medicated premix and 5 kg LDPE pails for small-herd top dressing. This route is not suitable for free-choice pasture systems because diamphenethide intake becomes erratic when individual feed consumption cannot be verified.
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Diamphenethide (Diamfenetide), CAS 36141-82-9, is supplied as a veterinary-grade active pharmaceutical ingredient under the grade code DAP-VET-API. The product is N-[4-(2,2,2-trichloro-1-hydroxyethyl)phenyl]acetamide, with the empirical formula C10H10Cl3NO2 and a molar mass of 282.55 g mol⁻¹. The neat material is a white to off-white crystalline powder intended for incorporation into tablets, injections, capsules, powders, granules, premixes, and solutions. The chlorinated acetamide structure places it outside the benzimidazole, salicylanilide, and sulfonamide classes normally encountered in veterinary flukicide programmes.
Identity is verified by mid-infrared absorption spectrophotometry using Ph. Eur. 2.2.24 and by chromatographic retention-time agreement with a qualified reference standard. Assay is performed by a stability-indicating reversed-phase high-performance liquid chromatography method validated under ICH Q2(R1). Water content is determined by Karl Fischer titration under USP 921; residue on ignition follows USP 281; residual solvents are evaluated by headspace gas chromatography using the acceptance classes of ICH Q3C. The API is for veterinary use only and is not intended for human pharmaceuticals or for food-producing animal products without an approved residue file.
The release profile below describes the unformulated material. Acceptance limits are batch-specific but are representative for the grade used in solid, liquid, and feed-admix products.
| Test parameter | Method or standard | Acceptance criterion |
|---|---|---|
| Appearance | Visual examination | White to off-white crystalline powder |
| Identification | FTIR / Ph. Eur. 2.2.24 | Spectrum concordant with reference standard |
| Assay by HPLC | ICH Q2(R1) validated HPLC | 98.0%–102.0% on dried basis |
| Water | USP 921 | ≤0.5% |
| Residue on ignition | USP 281 | ≤0.1% |
| Heavy metals | Ph. Eur. 2.4.8 limit test | ≤10 mg/kg |
| Related substances | HPLC / ICH Q2(R1) | Total ≤1.0%; any unspecified single ≤0.5% |
| Residual solvents | Headspace GC / ICH Q3C | Class 3 solvents ≤0.5% each; no Class 1 solvents |
| Particle size Dv90 | Laser diffraction / ISO 13320:2020 | ≤50 µm standard; ≤25 µm for oral-drench and parenteral suspension |
| Microbial limits | USP 61/62 | Total aerobic count ≤100 CFU/g; fungi ≤10 CFU/g |
Particle-size distribution is not treated as a single release limit because the optimum size depends on the finished dosage form. Dry blends and hard capsules can tolerate a Dv90 of ≤50 µm; suspension products require the tighter ≤25 µm endpoint to limit sedimentation and avoid needle occlusion in injectable presentations. The measurement uses laser diffraction with wet dispersion under ISO 13320:2020; ultrasonic dispersion time is fixed during method qualification to avoid irreversible particle breakage.
Because the neat API can enter aseptic filling lines, it is controlled for bioburden. Acceptance for nonsterile processing is ≤100 CFU/g total aerobic microbial count and ≤10 CFU/g fungi by USP 61 and 62. For injectable use, bacterial endotoxin content is tested under USP 85; the limit is derived from the maximum intended veterinary dose and is not assigned solely to the API.
Solubility screening in purified water, pH 4.0 acetate buffer, pH 6.8 phosphate buffer, methanol, and dimethyl sulfoxide is part of the method-development package. The compound exhibits low water solubility, which makes particle-size control and wetting-agent selection the primary factors for consistent oral absorption in suspension products. Dissolution testing is not a routine API release criterion; it is established for each tablet or capsule product with a validated medium and agitation speed. No universal dissolution limit is assigned to the neat API.
Diamphenethide has a stage-specific action profile. Published pharmacological literature places the principal activity against early immature Fasciola hepatica at 3–6 weeks post-infection in sheep; activity against adult flukes is comparatively reduced. This differentiates the product from triclabendazole, which is active from 2 days post-infection through adult stages, and from closantel and rafoxanide, which are used for late immature and adult stages. Oxyclozanide is classified as an adult flukicide, while clorsulon is used primarily against adult stages in cattle.
The structural separation is equally important for formulation and toxicology. Diamphenethide is a chlorinated acetamide; closantel, rafoxanide, and oxyclozanide are salicylanilides; albendazole and triclabendazole are benzimidazoles; clorsulon is a sulfonamide. Co-formulation with other anthelmintics should be supported by compatibility data generated under ICH Q1A(R2) or equivalent storage conditions. Residue-depletion profiles and withdrawal periods from other flukicide classes cannot be transferred to diamphenethide products.
| Compound | Chemical class | Principal activity window | Formulation consideration |
|---|---|---|---|
| Diamphenethide | Chlorinated acetamide | Early immature 3–6 weeks; reduced adult activity | Micronized suspension; strategic early intervention |
| Triclabendazole | Benzimidazole | 2 days post-infection through adult | Oral suspension; broad stage window |
| Closantel | Salicylanilide | Late immature and adult | Injection or oral; withdrawal periods vary |
| Oxyclozanide | Salicylanilide | Adult | Combination oral suspension |
| Clorsulon | Sulfonamide | Adult | Injection/co-product; cattle use |
Diamphenethide has no meaningful broad-spectrum nematode claim and is not a general-purpose anthelmintic. When mixed liver fluke and gastrointestinal nematode control is required, a companion compound must be selected on the basis of target parasite epidemiology and demonstrated compatibility. Published data for some fixed-dose combinations containing diamphenethide is limited; therefore, formulation development must include assay recovery, related-substances comparison, and dissolution-profile characterisation rather than assuming dose proportionality from mono-component products.
Low-water-solubility APIs in oral-drench and injectable suspensions require shear-rate profiling beyond simple visual inspection. Sedimentation volume is measured in 100 mL stoppered cylinders after 24 h at 25 °C; an acceptable development suspension should retain a sediment-volume ratio ≥0.90 and should redisperse after 5 manual inversions. Brookfield viscosity measurements at 10 rpm and 25 °C are recorded because the same product can fail by caking even when the initial viscosity appears acceptable.
The suspending system is typically built from microcrystalline cellulose/sodium carboxymethylcellulose at 1.0–2.0% w/v and a non-ionic wetting agent at 0.1–0.5% w/v. The wetting agent is added to the vehicle before the API to reduce agglomeration. High-shear mixing is used for the vehicle; the micronized API is then incorporated under low shear to prevent air entrapment. After final mixing, the batch is passed through a 0.300 mm screen or colloidal mill if agglomerates persist. pH is adjusted to 4.0–6.0 with a suitable buffer, and the batch is de-aerated under vacuum.
For injectable suspensions, the vehicle is autoclaved at 121 °C for 15 min; the sterile micronized API is added aseptically. Filtration through a 0.22 µm membrane is not suitable for suspensions, so all raw materials and process equipment must meet stringent bioburden and endotoxin controls. Terminal autoclaving of the finished suspension is evaluated only after confirming that the particle-size distribution and related-substance profile remain unchanged under the selected thermal cycle.
Direct compression of tablets is restricted to formulations in which the active fraction is high enough to avoid segregation; below 5% w/w, wet or dry granulation is preferred. In a dry-granulation route, the API is blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate in a bin blender at 60–70% fill volume. The blend is compacted in a roller compactor and milled through a 1.0 mm screen. The API is passed through a 0.500 mm mesh before use to disrupt loose agglomerates. Stratified blend samples are taken from 10 locations and tested by HPLC; acceptance is calculated using USP 905 for the finished dosage form.
Capsule filling and powder sachet operations use the same blend with flow-conditioning agents if Carr index or angle of repose indicates marginal flow. Loss-on-drying after wet granulation is maintained at ≤2.0% to minimise picking and sticking during tabletting. Granules for oral use are dried in a fluid-bed dryer at 45–50 °C until the target moisture is reached; the drying curve is terminated before the product temperature rises above the assigned limit for the crystalline form.
For feed premixes, the API is diluted stepwise onto a carrier such as lactose monohydrate, calcium carbonate, or ground corncob. Mixing is performed in a ribbon mixer at 70–80% fill volume. Acceptance for low-inclusion premix is usually a relative standard deviation ≤5.0% in HPLC assay across 10 sampling points. Cross-contamination control requires dedicated vacuum transfer lines and validated washdown because the compound is active at low inclusion rates.
Stability protocols for the API and finished product follow ICH Q1A(R2) where applicable. Long-term conditions are 25 °C/60% RH; accelerated conditions are 40 °C/75% RH. Open-container studies at 40 °C/75% RH for 3 months are used to evaluate moisture sensitivity. If water uptake exceeds 0.5% or total related substances increase by more than 0.3%, the packaging configuration is revised. Published data for this specific molecule under all finished-dose configurations is limited; site-specific protocols are required before a shelf life is assigned.
Packaging for the neat API uses double low-density polyethylene liners sealed inside high-density polyethylene drums. Storage in unopened original packaging is specified at ≤25 °C and ≤60% RH. The initial retest interval is assigned from site stability data; a typical starting value is 24 months from the date of manufacture. In-use period after first opening is not derived from the closed-container retest interval and must be evaluated separately in the compounding site’s quality system.
Each batch is assigned a certificate of analysis with actual batch-specific results. The analytical laboratory operates under ISO 17025 for the assay and related-substance procedures, or under an equivalent pharmaceutical quality-control system. Batch-to-batch consistency is monitored by control charts for assay, total impurities, water content, and Dv90; any result outside the release boundary triggers a formal out-of-specification investigation under the manufacturer’s quality system.
Handling should follow a risk assessment under local chemical-safety regulations. The API is a fine powder; local exhaust ventilation and dust-control measures are required during weighing, milling, and sampling. Work areas should be cleaned with a detergent solution; dry sweeping should be avoided to prevent airborne dust. Personal protective equipment selection is based on the safety data sheet and relevant national hygiene standards. No occupational exposure limit is published for this API in most jurisdictions.
