| HS Code | 698272 |
| Product Name | Atipamezole Veterinary Grade API |
| Active Ingredient | Atipamezole Hydrochloride |
| Cas Number | 104075-48-1 |
| Molecular Formula | C14H16N2·HCl |
| Molecular Weight | 248.75 g/mol |
| Appearance | White or almost white crystalline powder |
| Solubility | Soluble in water; sparingly soluble in ethanol |
| Ph 1 W V Aqueous Solution | 4.0 - 6.0 |
| Melting Point | Approximately 250°C with decomposition |
| Purity Assay | ≥ 99.0% w/w on dried basis |
| Loss On Drying | ≤ 0.5% w/w |
| Residue On Ignition | ≤ 0.1% w/w |
| Heavy Metals | ≤ 10 ppm |
| Veterinary Therapeutic Class | Alpha-2 adrenergic receptor antagonist |
| Storage | Store below 25°C in a tightly closed, light-protected, moisture-proof container |
| Shelf Life | 24 months under recommended storage conditions |
As an accredited Atipamezole 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, light-protected containers with tamper-evident closures. Available in 1 kg, 5 kg, and 25 kg quantities. |
| Container Loading (20′ FCL) | One 20′ FCL contains Atipamezole veterinary-grade API, securely packed in sealed drums/packaging for safe transport. |
| Shipping | Atipamezole Veterinary Grade API is shipped in sealed, inert, moisture-resistant containers with tamper-evident packaging. Shipments are temperature-controlled, protected from light, and transported via secure, traceable courier with full documentation, including MSDS and certificates of analysis, ensuring stability, purity, and regulatory compliance throughout transit. |
| Storage | Store Atipamezole Veterinary Grade API in its original, tightly closed container, protected from light, moisture, and excessive heat. Keep in a cool, dry, well-ventilated area at controlled room temperature (15–25°C) unless otherwise specified. For solutions and injections, avoid freezing. Ensure all final formulations follow approved storage guidelines. |
| Shelf Life | Shelf life: 24 months from manufacture date when stored airtight, protected from light, below 25°C, in original container. |
Atipamezole hydrochloride injection manufacturing is anchored by the reference parenteral formulation in which each millilitre contains 5.0 mg atipamezole hydrochloride, equivalent to 4.27 mg atipamezole free base, 1.0 mg methylparaben as preservative, and 8.5 mg sodium chloride as tonicity adjuster, with water for injection quantum satis and pH adjusted to 4.0–5.0 using sodium hydroxide and hydrochloric acid. The downstream production sequence for a sterile multi-dose injection begins with dissolution of methylparaben and sodium chloride in water for injection at 20–25 °C under low-shear impeller agitation at 200–500 rpm, followed by addition of atipamezole hydrochloride and mixing until a clear solution is obtained; dissolved oxygen is reduced by nitrogen sparging before sterilizing-grade filtration through a 0.22 μm PVDF or PES membrane. The filtered solution is aseptically filled into depyrogenated Type I borosilicate glass vials in an ISO Class 5 filling zone within an ISO Class 7 cleanroom; vials are depyrogenated at 250 °C for no less than 30 min and stoppered with chlorobutyl closures selected for low methylparaben partitioning. Terminal moist-heat sterilization at 121 °C for 15 min may replace aseptic filtration only if drug substance thermal stability and plastic or rubber closure compatibility are validated; otherwise aseptic processing remains the default. Release testing includes USP <71> sterility, USP <85> bacterial endotoxins, USP <788> subvisible particulates, USP <790> visible particulates, USP <791> pH, USP <1> deliverable volume, and HPLC assay under USP <621> with acceptance limits of 95.0%–105.0% of label claim; container and closure integrity is evaluated per USP <1207>, elastomeric closure testing per USP <381>, and glass container evaluation per USP <660>. Stability is assigned under ICH Q1A(R2) and VICH GL3, and antimicrobial effectiveness testing follows USP <51>. The reference veterinary product for dogs is authorized under FDA NADA 140-973, and terminal product configurations are 5 mg/mL injection in 10 mL and 20 mL multi-dose vials. Because the addition ratio is fixed to preserve antimicrobial effectiveness and isotonicity, dilution below 5 mg/mL is performed only at point of use, not during manufacturing.
| Quality Attribute | Test Method | Release Criterion |
|---|---|---|
| Sterility | USP <71>, EP 2.6.1 | No microbial growth after 14 days |
| Bacterial endotoxins | USP <85>, EP 2.6.14 | Limit derived from maximum intended dose |
| Subvisible particles | USP <788> | ≥ 10 μm: ≤ 6000/container; ≥ 25 μm: ≤ 600/container |
| pH | USP <791> | 4.0–5.0 |
| Deliverable volume | USP <1> | 10 mL and 20 mL vial fills meet deliverable volume |
Free-ranging wildlife immobilization protocols are constrained by the fill capacity of portable dart syringes, and a 5 mg/mL atipamezole hydrochloride stock keeps a 0.2 mg/kg intramuscular reversal dose for a 50 kg animal to 2.0 mL; a 1 mg/mL dilution would require 10.0 mL, exceeding the usable volume of standard 3.0 mL gas-powered Pneu-Dart or Dan-Inject dart syringes. Field kits therefore retain the 5 mg/mL stock in 20 mL multi-dose vials and prepare lower concentrations only for animals below 10 kg, typically by drawing 1 part stock with 4 parts sterile 0.9% sodium chloride injection to yield 1 mg/mL, or 1 part stock with 9 parts diluent to yield 0.5 mg/mL. The dilution is executed in a clean field station under a portable laminar flow hood or in an accredited veterinary hospital using a 0.22 μm syringe filter to protect sterility; kit assembly places vials in crush-resistant polymer transit cases with desiccant and temperature-excursion indicators, with storage and distribution governed by USP <659> for controlled room temperature. Compliance includes USDA Animal Welfare Act 9 CFR Parts 2 and 3 for transport and handling, CITES permits for transboundary movement of immobilization agents, and IACUC protocols under the Guide for the Care and Use of Laboratory Animals when data are collected. Terminal finished product types include 20 mL multi-dose vials of 5 mg/mL injection, point-of-use 1 mg/mL and 0.5 mg/mL syringes for small carnivores and juvenile ungulates, and ready-to-ship reversal kits labeled with species-specific dose tables. Published pharmacokinetic data for free-ranging bison and large carnivore reversal remain limited, so injection volumes must be cross-checked against institutional SOPs rather than extrapolated from the domestic dog label dose.
In barrier-housed rodent and lagomorph facilities, the 5 mg/mL reference injection is diluted immediately before use because the required intramuscular or subcutaneous doses are below the accurate volume deliverable with a tuberculin syringe for animals weighing 20 g to 2 kg. A 1:49 v/v dilution of 5 mg/mL atipamezole hydrochloride with sterile 0.9% sodium chloride injection produces a 0.1 mg/mL working solution; a 1:9 v/v dilution produces a 0.5 mg/mL solution; and a 1:4 v/v dilution produces a 1.0 mg/mL solution for larger lagomorphs when a lower injection volume is not required. The addition ratios are fixed by the stock concentration and the requested working concentration; the diluent is pre-sterilized and passed through a 0.22 μm PVDF syringe filter in an ISO Class 5 biological safety cabinet to reduce particulate and microbial risk. Production equipment includes single-use polypropylene syringes with low dead-space plungers, depyrogenated Type I glass serum vials, and positive-displacement pipettes with ±1.0% accuracy for volumes below 50 μL; filter adsorption of atipamezole at 0.1 mg/mL is assessed before batch release because low-concentration solutions can show potency loss on certain membrane polymers. Compliance is anchored to USP <797> for sterile compounding, USP <71> for sterility, USP <85> for bacterial endotoxin testing, and the Guide for the Care and Use of Laboratory Animals, 8th edition, with 21 CFR Part 58 when the procedure resides under Good Laboratory Practice. Terminal finished product types are 0.1 mg/mL, 0.5 mg/mL, and 1.0 mg/mL injectable solutions aliquoted into 2 mL single-use vials or pre-filled 1 mL tuberculin syringes; retention samples are held at 20–25 °C and rechecked for pH and visible particulate matter after the procedure to detect batch-to-batch variability from manual dilution.
When parenteral administration is not tolerated in captive small mammals, birds, or reptiles, compounding pharmacies may be asked to prepare oral capsules, powders, or tablets from atipamezole hydrochloride API; however, oral bioavailability and first-pass metabolism in these species are not systematically characterized, and published data for this specific configuration is limited, so all addition ratios must be derived from a veterinarian-specified dose rather than from an approved oral label. Nonsterile compounding is conducted under USP <795> and, if an internal risk assessment places the API on the hazardous drug list, under USP <800>; manufacturing of approved oral dosage forms would require FDA 21 CFR 211, but no approved oral atipamezole tablet or capsule exists in the United States or European Union at this time. Typical compounded dose units are prepared in the range of 0.5 mg to 5.0 mg atipamezole hydrochloride per capsule or tablet; the API-to-excipient addition ratio is calculated by dividing the requested dose by the target fill weight, such as a 5 mg dose in a size 3 capsule with fill weight 100 mg yielding 5.0% w/w API, followed by geometric dilution with microcrystalline cellulose and lactose monohydrate in 1:1 steps until homogeneity is reached. Dry blending is performed in a low-shear tumble blender at 20–30 rpm for 15 min after a pre-blend step; tablets are produced by direct compression on a rotary press at 10–20 kN to hardness 40–80 N, with disintegration testing per USP <701>; capsules are filled with a semi-automatic dosator or tamping-pin machine; and granules, if required, are produced by wet granulation using povidone K30 solution and dried at 40 °C until moisture content is below 2.0%. Terminal finished product types include oral capsules of 0.5 mg, 1 mg, and 5 mg strength, direct-compression tablets, oral powder sachets, and granules in amber glass vials.
Premix and feed-granule inquiries are confined to experimental oral administration in research settings and are not supported by a regulatory-approved medicated feed additive pathway; the U.S. Food and Drug Administration requires premarket approval under 21 CFR 558.4 and the European Union requires authorization under Regulation (EC) No 1831/2003 for feed additive or premix use, and no approval has been issued for atipamezole hydrochloride in any species. No validated inclusion rate or addition ratio can be assigned because pH-dependent solubility in feed matrices, first-pass metabolism, and oral bioavailability in target species have not been characterized in published peer-reviewed data; therefore, the downstream production process for a premix, extruded feed granule, or pelleted carrier is not established and no terminal finished product type can be specified for this application. Any request for a premix formulation should be redirected to an approved injectable dosage form or compounded nonsterile preparation under USP <795>, with the explicit operational boundary that atipamezole hydrochloride is not to be dry-blended into feed as a bulk powder without pre-approval from the relevant competent authority.
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Atipamezole Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is supplied as the hydrochloride salt of 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The free base carries CAS 104054-27-5 and molar mass 212.29 g/mol; the hydrochloride salt is CAS 104075-48-1. The material is a white to off-white crystalline powder intended exclusively for further manufacture into finished veterinary drugs, not for direct administration. In veterinary medicine the compound functions as a selective α2-adrenoceptor antagonist, reversing centrally mediated sedation, analgesia, and bradycardia induced by agonists such as medetomidine hydrochloride or dexmedetomidine hydrochloride. Finished forms produced from this API include conventional tablets, hard capsules, sterile injection solutions, powders, granules, oral solutions, and medicated premix carriers. The product is released under veterinary GMP documentation aligned with ICH Q7 and regional veterinary active-substance requirements; a certificate of analysis, batch production record summary, and retained sample are maintained for each batch.
Because no harmonized veterinary pharmacopoeial monograph for atipamezole hydrochloride is listed in the current USP–NF or Ph. Eur. index, release testing is driven by the applicant’s validation protocol, the active substance master file, and regional veterinary regulatory guidance. Common specifications require identification by HPLC retention time and infrared absorption, assay by HPLC on the anhydrous and solvent-free basis, related substances, residual solvents, water content, and particle-size distribution. The finished-dose manufacturer must define the API particle-size target according to the unit operation: direct compression blends frequently require a D90 below 250 µm, whereas low-dose premix and suspension systems tend to request D90 below 180 µm to avoid carrier segregation. The API is not interchangeable with yohimbine, tolazoline, or dexmedetomidine because each has different receptor activity and formulation constraints.
Assay variability across low-dosage tablets and premixes is controlled primarily by API particle-size distribution, bulk density, and surface adsorption tendency. In production-scale batches, the hydrochloride salt can agglomerate after vacuum drying at residual moisture below 0.5%; subsequent de-agglomeration through a conical screen mill with an aperture of 0.5 mm is used to restore flow. Bulk density values are typically requested between 0.25 g/mL and 0.45 g/mL to align with excipient matrices such as spray-dried lactose or mannitol. If the particle-size specification is not matched to the formulation process, the API segregates during transfer or final compression, producing content uniformity failures under USP <905> or Ph. Eur. method 2.9.40. The table below summarizes a representative release specification used in veterinary API supply agreements; actual limits may be narrowed by the finished-dose manufacturer based on process capability and stability data.
| Parameter | Typical acceptance criterion | Method or standard |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Identification | IR spectrum concordant; HPLC retention time concordant | FTIR; HPLC-UV |
| Assay as hydrochloride, anhydrous and solvent-free | 98.0%–102.0% | HPLC with reference standard |
| Water content | ≤0.5% | Karl Fischer titration |
| Residual solvents | Acetonitrile ≤410 ppm; isopropanol ≤5000 ppm | ICH Q3C via headspace GC |
| Related substances | Total ≤1.0%; any unspecified ≤0.10% | HPLC area normalization |
| Sulfated ash | ≤0.1% | Ph. Eur. 2.4.14 |
| Elemental impurities | As per ICH Q3D | ICP-MS |
| Particle size, solid oral | D90 ≤250 µm | Laser diffraction |
| Particle size, premix/suspension | D90 ≤180 µm | Laser diffraction |
The hydrochloride salt is the preferred input for sterile injection because it dissolves in water at levels sufficient for a 5 mg/mL atipamezole hydrochloride bulk solution. The solution is blanketed with nitrogen during compounding because the imidazole ring can oxidise under dissolved oxygen at elevated temperature. pH is adjusted to 4.5–5.5 with dilute hydrochloric acid or sodium hydroxide, and the bulk solution is passed through a 0.22 µm PVDF membrane. Terminal sterilisation is not universally applied; aseptic filtration is preferred when a low bioburden API and validated sterility assurance are required. Hold-time studies for the bulk solution should demonstrate chemical stability at 2–8 °C for the defined processing window; published data for this specific configuration is limited, so each applicant must generate solution stability data under ICH/VICH conditions. Glass vials are depyrogenated at 250 °C for 30 minutes, stoppers are washed and sterilised, and filling is qualified for 2 mL or 10 mL formats with headspace oxygen below 2%. The finished injection is inspected for particulate matter per Ph. Eur. 2.9.19, sterility per Ph. Eur. 2.6.1, and bacterial endotoxins per Ph. Eur. 2.6.14.
Atipamezole is a low-dose API in many solid oral formulations; finished tablets may contain as little as 0.05 mg to 1 mg of active per unit. The API is geometrically pre-dispersed with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide before final blending. Magnesium stearate is added at 0.5% to 1.0% w/w and blended for no more than 5 minutes at a V-shell speed of 15–20 rpm to minimize hydrophobic film formation. Compaction force is monitored during compression; tablet hardness typically falls between 40 N and 80 N for a 6 mm round tooling, but the exact target is set by dissolution testing. If wet granulation is used instead, the hydrochloride salt is pre-mixed with the binder solution, and the high-shear granulator endpoint is controlled by impeller power consumption at 200 rpm impeller speed and 1500 rpm chopper speed. Overgranulation shifts the granule size toward coarse agglomerates and can produce unacceptable dissolution at 30 minutes. Granules are dried in a fluid-bed dryer at inlet air temperature 60 °C or below until loss on drying is 1.0–2.0%; higher temperatures above 70 °C can increase the des-ethyl or hydroxylated impurity peaks visible by HPLC.
For capsules, the milled API is blended with direct-fill excipients and filled into size 3 hard gelatin or HPMC capsules using an intermittent-motion dosator or tamping-pin machine. Fill weight variation is evaluated with Ph. Eur. method 2.9.5 or USP <905>. At relative humidity above 60%, the hydrochloride salt may absorb surface moisture and adhere to machine contact surfaces; therefore the manufacturing suite is maintained at 40–50% RH and 20–25 °C. Powder and granule intermediates intended for reconstitution or direct oral administration are commonly size-reduced through a 0.5 mm sieve and packed in foil-lined polyethylene bags with desiccant. Oral solution formulations use a buffered vehicle composed of purified water, a preservative, and a pH buffer; the target pH is maintained between 4.0 and 5.0 to maximize chemical stability. The hydrochloride salt is dissolved under slow stirring at 100–300 rpm to avoid foaming. For feline oral solutions, the preservative benzyl alcohol is avoided because of known species-specific toxicity; potassium sorbate at 0.1% or sodium benzoate at 0.1% is evaluated as an alternative. The solution should be protected from light in amber PET or glass bottles, and accelerated stability studies should be conducted at 40 °C / 25% RH and 30 °C / 65% RH per VICH GL3.
Atipamezole differs from older α2-adrenoceptor antagonists by its higher α2/α1 selectivity and its more predictable reversal time in dogs, cats, and certain non-domestic species. In radioligand binding experiments, the α2/α1 affinity ratio for atipamezole has been reported in the range of 100:1 to 200:1 depending on tissue preparation, whereas yohimbine and tolazoline show lower selectivity and greater α1-adrenergic and serotonergic interactions at therapeutic concentrations. This selectivity is relevant to manufacturing because dosage form performance claims cannot be extrapolated from yohimbine or tolazoline formulations. Dexmedetomidine hydrochloride is an α2-adrenoceptor agonist and is not a substitute for the antagonist API; the two are used sequentially in veterinary protocols but are chemically and pharmacologically distinct. The comparative table summarises the main differences that affect formulation and clinical use.
| Compound | Receptor activity | Key formulation consideration | Key clinical or toxicological limitation |
|---|---|---|---|
| Atipamezole hydrochloride | Selective α2 antagonist | HCl salt preferred for aqueous and solid forms; low-dose content uniformity controlled by particle size | Not active against opioid, benzodiazepine, or dissociative sedation |
| Yohimbine hydrochloride | α2 antagonist with lower selectivity | May require higher dose and more frequent administration | Central excitation and tachycardia at therapeutic doses |
| Tolazoline hydrochloride | α2 antagonist with broader α-adrenergic activity | Less selective; formulation choice is driven by species-specific protocols | Gastrointestinal and cardiovascular side effects may limit use |
| Dexmedetomidine hydrochloride | α2 agonist | Supplied as sedative; pH and oxidative stability differ | Cannot be used as an antagonist; overdose requires separate reversal agent |
The hydrochloride salt is hygroscopic at high relative humidity and should be protected from light. Forced degradation data indicate that the compound is susceptible to oxidation; the main control strategy for liquid formulations is the addition of a nitrogen overlay and, where appropriate, a metal chelator such as disodium edetate at 0.1% w/v. The API is incompatible with strong bases, strong oxidizing agents, and reducing sugars in aqueous granulation at elevated temperature due to the potential for imidazole ring degradation or Maillard-type adduct formation. Dry formulations should avoid unbuffered amino acid carriers unless compatibility has been demonstrated by HPLC purity after storage at 40 °C / 75% RH for 6 months. The veterinary grade differs from research-grade material because serialized manufacturing, full traceability, and regulatory documentation are required. Each batch is accompanied by a certificate of analysis, safety data sheet, and a batch production record summary. The vendor quality agreement normally defines the number of retained samples, reserve sample retention time of 1 year after expiry, and change notification period of 90 days; research-grade material is not released under veterinary GMP and may contain unidentified process impurities that are not controlled.
Atipamezole added to a premix carrier must be passaged through a ribbon or paddle blender at low shear to avoid API loss to dust. A typical carrier system uses lactose monohydrate or corn starch at a drug load not exceeding 2% w/w. The blend is monitored for homogeneity using a thief probe with 10 sampling points, and acceptance is set at 90–110% of label claim with relative standard deviation below 5%. Moisture ingress during premix storage reduces blend homogeneity because the hydrochloride salt adheres to the carrier surface and forms agglomerates; foil-lined woven polypropylene bags with heat-sealed closures are required at room temperature. If the premix is combined with molasses or liquid binders, the API should be pre-dispersed in a non-aqueous vehicle because direct contact with alkaline molasses can degrade the imidazole ring. The concentration in final feed must be verified by extraction and HPLC because medicated feed matrices can adsorb the API onto fibrous components, leading to incomplete recovery if the method is not fully validated.
