| HS Code | 976287 |
| Product Name | Dimefline Veterinary Grade API |
| Api Type | Active Pharmaceutical Ingredient |
| Veterinary Grade | Yes |
| Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Chemical Name | Dimefline (3-methyl-7-(dimethylamino)-1,2,4-benzotriazine) |
| Cas Number | 4021-34-5 |
| Molecular Formula | C10H12N4 (free base); C10H12N4·HCl (hydrochloride salt) |
| Molecular Weight | 188.23 g/mol (free base); 224.69 g/mol (hydrochloride salt) |
| Chemical Class | Benzotriazine derivative |
| Pharmacological Category | Analeptic / central respiratory stimulant |
| Mechanism Of Action | Stimulates the medullary respiratory and vasomotor centers, increasing tidal volume and respiratory rate |
| Indications | Respiratory depression, anesthetic-related respiratory insufficiency, and certain circulatory emergencies in veterinary patients |
| Target Species | Horses, cattle, dogs, cats, sheep, goats, and pigs |
| Appearance | White or almost white crystalline powder |
| Solubility | Hydrochloride salt is soluble in water; free base is sparingly soluble in water and soluble in suitable organic solvents |
| Storage Conditions | Store in a tightly sealed, closed container in a cool, dry, well-ventilated area; protect from light and moisture |
| Packaging Forms | Sealed containers suitable for compounding into tablets, injections, capsules, powders, granules, premixes, and solutions |
| Product Name | Dimefline Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Active Pharmaceutical Ingredient | Dimefline Hydrochloride |
| Grade | Veterinary Grade |
| Cas Number | 31314-93-1 |
| Molecular Formula | C24H25ClN2O |
| Molecular Weight | 392.93 g/mol |
| Appearance | White or almost white crystalline powder |
| Solubility | Freely soluble in water, sparingly soluble in ethanol, practically insoluble in ether |
| Therapeutic Category | Centrally acting respiratory stimulant / analeptic |
| Storage Conditions | Store in a tightly closed container, protected from light, in a cool and dry place |
| Shelf Life | 24 months from date of manufacture under recommended storage conditions |
| Intended Use | For production of veterinary tablets, injections, capsules, powders, granules, premixes, and solutions |
As an accredited Dimefline 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 | 25 kg net in double polyethylene-lined drums, sealed and labeled as Dimefline Veterinary Grade API. |
| Container Loading (20′ FCL) | Dimefline veterinary grade API is packed in sealed drums/cartons on pallets and securely loaded into a 20′ FCL container. |
| Shipping | Dimefline Veterinary Grade API ships in sealed, light-resistant containers with desiccant, under temperature-controlled conditions to preserve stability. Shipments comply with local/international transport regulations, with clear hazard labeling and documentation. Handling requires protective equipment and protection from moisture, heat, and direct sunlight. Delivery worldwide via courier or freight with tracking and cold-chain options available. |
| Storage | Store Dimefline Veterinary Grade API in a cool, dry, well-ventilated area, away from direct sunlight, moisture, and heat sources. Keep in its original, tightly sealed container, protected from light. Maintain temperatures below 25°C and avoid contact with strong oxidizers or incompatible materials. Ensure proper labeling and segregation, following local regulations for handling veterinary pharmaceutical substances. |
| Shelf Life | Dimefline Veterinary Grade API has a shelf life of 24 months when stored properly in original, tightly closed containers. |
For equine and bovine post-anesthetic respiratory depression, veterinary injectable presentations of dimefline hydrochloride are manufactured as sterile aqueous solutions filled into Type I borosilicate glass vials. The active moiety is dissolved at 5–15 mg/mL as the hydrochloride salt in Water for Injections at 18–22 °C, with sodium chloride added to achieve isotonicity of 280–320 mOsm/kg. The solution is sparged with nitrogen to maintain dissolved oxygen below 0.2 mg/L; this is necessary because the flavone ring system is susceptible to oxidative discoloration in the presence of trace metal ions. Batch production on a 300–500 L jacketed stainless-steel mixing vessel uses a bottom-mounted magnetic mixer at 60–120 rpm; high-shear agitation above 500 rpm is avoided because air entrainment increases peroxide formation. Sterile filtration is performed through a 0.45 µm polyethersulfone pre-filter and then a 0.22 µm PES membrane at ≤1.0 bar differential pressure. Vials are washed, siliconized, and depyrogenated in a tunnel at ≥250 °C for ≥30 minutes before aseptic filling. Finished product types are 50 mL and 100 mL multi-dose vials sealed with bromobutyl rubber stoppers and aluminum flip-off seals. Compliance is anchored to Ph. Eur. 5.1.1 and 2.6.1, EU GMP Annex 1, Directive 2001/82/EC as replaced by Regulation (EU) 2019/6, and VICH GL18 for residual solvents. Formulation addition ratio for the target 10 mg/mL presentation is 1.0% w/v on an anhydrous free-base-equivalent basis; the hydrochloride salt weight is corrected for assay and loss on drying. Operational boundary: the solution is incompatible with phosphate buffers above pH 6.5, where precipitation of the free base exceeds 50 mg/L.
In swine and poultry water medication programs, low-dose oral granules of dimefline hydrochloride are manufactured as water-dispersible formulations containing 1–10 g/kg active in a lactose monohydrate or sorbitol carrier. The principal process risk is segregation during ribbon blending; the active particle size is therefore controlled below 250 µm with a target D90 below 125 µm, and geometric dilution is performed in three stages at 1:10, 1:100, and 1:1000. Ribbon blender mixing time is 20–25 minutes at 25–35 rpm; sampling from 10 thief points must achieve relative standard deviation ≤5.0% by HPLC. The dry blend is spray-granulated with purified water or 2% hydroxypropylmethylcellulose binder solution in a fluid-bed drier at inlet air 60–70 °C, product temperature 30–40 °C, and final loss on drying ≤1.5%. The dried granules are passed through a 1.0 mm conical mill to remove oversized agglomerates. Compliance for non-sterile oral dosage forms references Ph. Eur. 5.1.4, Ph. Eur. 2.9.40, and VICH GL18; where the product is registered as a medicated drinking-water powder, Regulation (EU) 2019/6 and CVMP pharmaceutical development guidance apply. The addition ratio in the final drinking water is calculated from target daily dose; a stock solution of 1 kg granules per 100 L water is administered through a proportioner set at 1:100, yielding 1000 L of medicated drinking water per 1 kg container. Finished product types include 100 g, 500 g, and 1 kg foil-lined low-density polyethylene sachets packed in 25 kg drums. Published data for dimefline-specific dilution stability in hard water matrices above 250 mg/L CaCO3 equivalent is limited; therefore field dissolution is confirmed before batch release. Incompatibility boundary: the granules are not co-dissolved with alkaline mineral premixes above pH 8.0, because oxidation accelerates when conductivity exceeds 0.5 mS/cm.
For companion animal outpatient dispensing, the oral solid-dose form is direct-compression tablets or tamped hard gelatin capsules. The API concentration per tablet core is set at 2–20 mg, corresponding to 1.0–8.0% w/w when the total core mass is 250 mg. Because dimefline HCl exhibits cohesive flow, the blend is first passed through a 1.0 mm oscillating granulator after slugging at 15–25 kN on a rotary tablet press. The final compression step operates at 30–60 rpm with main compression force 8–18 kN; tablet hardness is maintained at 60–100 N, and friability is held below 1.0% according to Ph. Eur. 2.9.7. Dissolution testing in 0.1 M hydrochloric acid at 37 °C with paddle speed 50 rpm must release not less than 75% of label claim in 45 minutes; published data for a specific dimefline veterinary dissolution monograph is limited, so the in-house specification is justified against Ph. Eur. 2.9.3. Capsule presentations use size 3 or size 4 hard gelatin capsules filled on a tamping-pin machine with slugged granules. Compliance references Ph. Eur. 5.1.4, Ph. Eur. 2.9.5 or 2.9.40, and Regulation (EU) 2019/6. Finished product formats are 10 mg and 20 mg tablets as well as 5 mg and 10 mg capsules, packed in 30-count and 100-count HDPE bottles with induction-sealed caps. The process is well-established; blend sticking after relative humidity exceeds 60% is controlled by maintaining processing room dew point below 8 °C.
Dimefline HCl medicated premixtures for in-feed incorporation in calves and lambs are produced as micro-ingredient concentrates on a calcium carbonate or wheat bran carrier. The production line uses a double-ribbon mixer with working volume 500–1000 L, and the API is introduced through a 1:10 pre-blend with colloidally milled calcium carbonate before being added to the final mixer. Final premixture API concentration is held between 0.1% w/w and 1.0% w/w to satisfy the homogeneity requirement in Regulation (EU) 2019/4 and associated GMP guidelines for medicated feed. Addition rate into finished feed is based on a target daily species dose; when the premix is incorporated at 1–10 kg per tonne of complete feed, the coefficient of variation for API content must remain below 10% at 10 sampling points. The carrier is selected for bulk density 0.55–0.75 g/mL and moisture content ≤8%; mineral oil at 0.5% w/w may be sprayed onto the carrier to reduce electrostatic adhesion of API particles. Finished product types are 25 kg multi-wall paper bags with inner polyethylene liner, or 1000 kg bulk bags for licensed feed mills. Compliance is anchored to Ph. Eur. 5.1.4 for microbiological quality of the non-sterile premix, Ph. Eur. 2.9.5 for uniformity of mass, and VICH GL18 for residual solvents arising from the carrier. Process boundary: direct addition of raw drug substance to feed without a 1:1000 pre-dilution is not recommended because electrostatic agglomeration can produce localized hotspots above 200% label claim.
Because neonatal ruminants require multidose oral administration in the field, ready-to-use oral solutions of dimefline HCl are formulated as clear aqueous vehicles containing 0.5–2.0 mg/mL. The hydrochloride salt dissolves readily in purified water at 20–25 °C; batch preparation uses a 200 L stainless-steel vessel with a top-mounted anchor stirrer at 40–80 rpm. Preservative efficacy testing in the aqueous solution must meet Ph. Eur. 5.1.3, typically with sodium methyl parahydroxybenzoate at 0.1% w/v and sodium propyl parahydroxybenzoate at 0.02% w/v; the parabens are pre-dissolved in propylene glycol at 60 °C before cooling to 25 °C. The final solution is filtered through a 0.45 µm polyamide membrane and filled into amber 1 L high-density polyethylene bottles with 10 mL dosing cups or calibrated oral dosing guns. Compliance standards include Ph. Eur. 5.1.4, VICH GL18, and Regulation (EU) 2019/6; residual solvent limits for propylene glycol follow ICH Q3C Class 3 limits. Formulation addition ratio for a 1 mg/mL solution is 0.1% w/v on an anhydrous API basis, with a 5% overage allowed only where stability data show not more than 5% loss at 25 °C over 24 months. Finished product type is a 1 L multi-dose oral solution. Operational boundary: the liquid is not terminally sterilized; bioburden of incoming purified water must remain below 10² CFU/mL, and storage below 4 °C is avoided because paraben solubility falls below effective concentration.
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Dimefline Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is a white to off-white crystalline hydrochloride salt of 8-[(dimethylamino)methyl]-7-methoxy-3-methyl-2-phenyl-4H-chromen-4-one. The product is released as a non-sterile, micronized powder with assay 98.0–101.0% on the dried substance, loss on drying ≤0.5%, and residue on ignition ≤0.1%. The model comprises an oral-grade variant with microbiological quality ≤100 CFU/g and an injectable-grade variant with bacterial endotoxins ≤0.5 EU/mg; both share the same chemical purity profile. Particle attributes are specified at D90 ≤25 µm, D50 8–15 µm, tapped bulk density 0.25–0.45 g/cm³, and water activity ≤0.60 to support content uniformity in low-dose solid oral preparations and rapid dissolution in aqueous injection compounding. Manufacture is managed under ICH Q7, with residual solvents controlled according to ICH Q3C(R8), elemental impurities according to ICH Q3D, and mutagenic impurity risk according to ICH M7(R2). The API is not sterilized at release; terminal sterilization or aseptic filtration is required for parenteral presentations. It is supplied with a certificate of analysis, a declaration of non-animal origin, and BSE/TSE compliance according to Ph.Eur. 5.2.8.
Release testing on every commercial batch uses a stability-indicating reversed-phase HPLC method with UV detection at 254 nm. The method separates Dimefline HCl from principal oxidative degradation products with resolution ≥2.0. System suitability requires relative standard deviation ≤1.0% for five replicate standard injections. Identification is performed by infrared absorption spectrophotometry against a Dimefline HCl reference standard, with a correlation coefficient ≥0.98 under Ph.Eur. 2.2.24. Because the compound is non-hydrated, loss on drying is controlled in place of water content. Residual solvent analysis by headspace GC-FID includes methanol, isopropanol, dichloromethane, toluene, and dimethylformamide with acceptance limits referenced to ICH Q3C(R8).
| Test parameter | Acceptance limit | Method |
|---|---|---|
| Description | White to off-white crystalline powder | Visual inspection |
| Identification | IR spectrum corresponds to Dimefline HCl reference; HPLC retention time within 2.0% of standard | Ph.Eur. 2.2.24, Ph.Eur. 2.2.29 |
| Assay on dried substance | 98.0–101.0% | Validated HPLC, external standard |
| Loss on drying | ≤0.5% | Ph.Eur. 2.2.32, 105 °C for 3 h |
| Residue on ignition | ≤0.1% | USP 281 |
| Related substances | Any single impurity ≤0.3%; total ≤1.0% | HPLC area normalisation |
| Elemental impurities | Class 1 and Class 2A/2B elements ≤30% of PDE | ICH Q3D, ICP-MS |
| Residual solvents | Class 2 and Class 3 limits per ICH Q3C(R8) | Headspace GC-FID |
| Particle size distribution | D90 ≤25 µm; D50 8–15 µm | Laser diffraction, ISO 13320:2020 |
| Bulk density | 0.25–0.45 g/cm³ | USP 616 Method I |
| Water activity | ≤0.60 | Electronic hygrometer |
| Bacterial endotoxins | ≤0.5 EU/mg for injectable-grade lots | Ph.Eur. 2.6.14, USP 85 |
Because the dimethylamino side chain can undergo nitrosation under acidic conditions, a nitrosamine risk assessment is performed before release. Where a nitrosamine is detected or predicted, LC-MS/MS limits are set not exceeding 0.03 ppm based on lifetime exposure assumptions. Elemental impurity data from commercial batches showed palladium ≤1.0 ppm, nickel ≤2.0 ppm, and chromium ≤3.0 ppm, all below 30% of the parenteral PDE. For injectable-grade lots, microbiological quality is controlled to ≤100 CFU/g with absence of Escherichia coli, Salmonella, and Pseudomonas aeruginosa according to Ph.Eur. 5.1.4.
Air-jet milling is preferred over impact milling for Dimefline HCl because high-shear size reduction can generate amorphous fractions that reduce yield when inlet temperatures exceed 40 °C. In a spiral jet mill operating at grinding pressure 0.6–0.8 MPa and feed pressure 0.5–0.7 MPa, particle size distribution stabilizes at D90 18–25 µm after a single pass. Additional passes increase fines below 5 µm and reduce flowability. The API exhibits a Carr index of 28–35, indicating poor flow as a neat powder. Direct compression formulations therefore require 0.5–1.0% colloidal silicon dioxide and 1.0–2.0% magnesium stearate, or the API is wet granulated with a 5–10% aqueous povidone K30 binder at water addition 10–15% w/w. Batch-to-batch particle size variation is controlled within D50 ±3 µm using in-process laser diffraction after milling.
Tablet compression of Dimefline Veterinary Grade API at 2 mg and 10 mg strengths uses geometric pre-blending because the active drug represents less than 5% of core mass. Direct compression at main compression force 8–18 kN on a 16-station rotary tablet press with 8 mm round flat-faced beveled tooling produced tablet hardness 30–60 N, friability 0.1–0.3% according to Ph.Eur. 2.9.7, and disintegration time 4–8 min in 0.1 M hydrochloric acid at 37 °C according to Ph.Eur. 2.9.1. Content uniformity testing under Ph.Eur. 2.9.40 showed acceptance value ≤15 for 10 tablets. For hard gelatin capsule filling with a semi-automatic dosator machine, powder slugs are compressed at 5–10 kN and milled through a 1.0 mm screen to produce granules with bulk density 0.35–0.45 g/cm³. If sodium starch glycolate exceeds 8% in the formulation, tablet hardness decreases below 30 N after storage at 40 °C / 75% RH for 3 months; replacement with crospovidone at 5% is recommended. Avoid direct combination with strong alkalis in aqueous granulating fluid because free-base precipitation can cause content uniformity failure.
Compounding of an injectable solution from Dimefline Veterinary Grade API requires an aqueous vehicle adjusted to pH 3.5–5.0 with dilute hydrochloric acid. At 10 mg/mL and pH 4.0, the solution remains clear after autoclaving at 121 °C for 15 min; total related substances increase by ≤0.3%. Above pH 6.0, free-base solubility is reduced and turbidity develops at room temperature. Nitrogen sparging is required before filling, with headspace oxygen maintained below 2.0% v/v to protect the chromenone ring from oxidative degradation. Filtration through a 0.22 µm PVDF membrane is compatible with a 10 mg/mL solution; filter adsorption losses of 2–4% are observed when the first 100 mL is discarded. The final injectable should be protected from light because exposure to 1.2 million lux·h visible light increases related substances above 0.5%. Precipitation occurs with phosphate buffers at pH ≥6.8; therefore, phosphate-buffered vehicles are unsuitable.
At the API level, the distinction between Dimefline Veterinary Grade API and other respiratory stimulants is primarily chemical and formulation-driven. Dimefline HCl is an 8-substituted methoxyflavone hydrochloride salt, whereas doxapram HCl is a pyrrolidinone derivative and caffeine citrate is a xanthine. The absence of the xanthine ring removes the requirement for stability-indicating methods to resolve theophylline, theobromine, and caffeine-related alkaloids from the active peak. Dimefline HCl has aqueous solubility at pH 4.0 above 25 mg/mL, enabling simple injection formulations at 10 mg/mL without cosolvents. Doxapram HCl is also water-soluble but is typically formulated at higher concentrations, while caffeine citrate may require heating or a cosolvent system depending on target-species concentration. For oral solid dosage forms, Dimefline HCl can be dry-blended at low dose without the gastric irritation potential associated with xanthine alkaloids. Published comparative pharmacokinetic data in target veterinary species remain limited; therefore, selection between Dimefline, doxapram, and caffeine should be based on approved veterinary label indications in the target jurisdiction rather than on physicochemical properties alone. Dimefline is not a simple salt-for-salt replacement for these stimulants because the pharmacodynamic dose-response is not equivalent; strength conversion cannot be made by molar substitution.
Medicated premix production with Dimefline Veterinary Grade API at active concentrations of 1–10 g/kg uses staged mixing. A first pre-blend at 100 g/kg in lactose monohydrate or maize starch is prepared for 10 min in a double-cone blender at 15 rpm, then diluted to final premix concentration and mixed for 20 min. Sampling of 20 locations across a 500 kg batch showed assay RSD ≤5.0% using a groove sampler. Dry powder oral solutions should be reconstituted in low-ionic-strength water; phosphate buffer at pH 7.0 produces precipitation of the free base, requiring acidified diluents. Granule coating with hydroxypropyl methylcellulose 6 cP at 3% weight gain reduces photodegradation and improves palatability without retarding dissolution; dissolution at 45 min in 900 mL of 0.1 M hydrochloric acid remains above 75% according to Ph.Eur. 2.9.3.
Storage stability of Dimefline Veterinary Grade API has been characterized under ICH Q1A(R2) conditions. In double low-density polyethylene bags placed inside a sealed aluminium foil laminate with 100 g silica gel desiccant, assay remains within 98.0–101.0% through 36 months at 25 °C / 60% RH and through 6 months at 40 °C / 75% RH. Without desiccant at 40 °C / 75% RH, water uptake reaches 2.5% within 30 days, causing caking and agglomerate formation during subsequent milling. The compound is light-sensitive; ICH Q1B Option 2 testing demonstrated total related substances increased by 0.8% after 1.2 million lux·h visible illumination and 200 W·h/m² UV exposure. Amber glass or opaque HDPE packaging is therefore required for bulk API and for all intermediate blends. Reevaluation after opening should include water activity, related substances, and assay. Published real-time data for long-term storage at 30 °C / 75% RH in climate zone IVb are limited; assignment of shelf life for that zone should rely on real-time data with desiccant-protected packaging rather than extrapolation from accelerated studies.
