| HS Code | 710486 |
| Product | Trimedoxime (TMB-4) Veterinary Grade API |
| Chemical Name | 1,1'-Trimethylenebis[4-(hydroxyiminomethyl)pyridinium] dibromide |
| Cas Registry Number | 56-97-3 |
| Molecular Formula | C15H18Br2N4O2 |
| Molecular Weight | 446.14 g/mol |
| Appearance | White to off-white crystalline powder |
| Odor | Odorless |
| Solubility | Soluble in water; slightly soluble in ethanol; practically insoluble in ether and chloroform |
| Melting Point | 225-227°C with decomposition |
| Assay Hplc | ≥99.0% on dried basis |
| Loss On Drying | ≤1.0% |
| Grade | Veterinary Grade |
| Storage Conditions | Store in tightly closed, light-resistant containers in a cool, dry place |
| Shelf Life | 24 months from date of manufacture under recommended storage |
| Mechanism Of Action | Reactivates organophosphate-inhibited acetylcholinesterase by nucleophilic displacement of the phosphate moiety |
| Formulation Compatibility | Suitable for tablets, injections, capsules, powders, granules, premix, and solutions |
As an accredited Trimedoxime (TMB-4) 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, light-resistant, tamper-evident packaging for veterinary-grade Trimedoxime (TMB-4) API; supplied as 25 kg net quantity in moisture-protective containers. |
| Container Loading (20′ FCL) | 20′ FCL loaded with Trimedoxime (TMB-4) veterinary API, in sealed containers, safely packed and secured for transport. |
| Shipping | Trimedoxime (TMB-4) Veterinary Grade API is shipped in sealed, light-resistant containers under controlled temperature, protected from moisture and extreme heat. Each parcel includes safety documentation and traceable labeling. Ensure compliance with regional veterinary pharmaceutical transport regulations upon delivery. |
| Storage | Store Trimedoxime (TMB-4) Veterinary Grade API in tightly sealed, light-resistant containers in a cool, dry, well-ventilated area. Protect from moisture, direct sunlight, and temperatures above 25°C. Keep away from oxidizing agents and incompatible materials. Ensure container is properly labeled, stored off the floor, and used within the manufacturer’s stated shelf life. |
| Shelf Life | Shelf life: 24 months from manufacture when stored in original container below 25°C, protected from light and moisture. |
Trimedoxime bromide is formulated as a sterile aqueous injectable in which the bis-pyridinium aldoxime content is held between 95.0% and 105.0% of label claim after aseptic filling. In production-scale compounding for acute organophosphate toxicosis in ruminants and companion animals, a working concentration of 20 mg/mL to 50 mg/mL is prepared by dissolving the API in Water for Injections at 20–25 °C under low-turbulence agitation. A 1.02 g/mL density-adjusted q.s. method is used because TMB-4 contributes measurable volume displacement. The solution is adjusted to pH 3.0–4.0 with dilute hydrochloric acid to suppress oxime ionization shifts and reduce chromophore-forming degradation. pH adjustment above 5.5 is avoided because the aldoxime group undergoes base-catalyzed hydrolysis to pyridine-4-carboxaldehyde and hydroxylamine, which lowers antidotal potency and increases particulate load. The addition ratio for a 50 mg/mL batch is 5.00 kg API per 100 L final volume, corrected by assay; an API assay of 98.5% requires 5.076 kg/100 L. An overage of 2.0% is accepted only where 24-month stability data support the added input. Terminal products include 10 mL single-dose vials, 20 mL multi-dose vials with benzyl alcohol at 1.0–1.5% v/v, and 5 mL prefilled syringes calibrated to deliver approximately 10 mg/kg in a 50 kg sheep.
The bulk solution is prefiltered through a 0.45 µm polyethersulfone membrane, then passed through two 0.22 µm PVDF membranes in series. This dual filtration is selected because quaternary ammonium cations adsorb to nylon and mixed cellulose ester membranes at low ionic strength, causing flux collapse when the TMB-4 concentration exceeds 20 mg/mL and the solution ionic strength is below 0.02 M. Fill lines operate inside ISO 14644-1 Class 5 zones with nitrogen overlay to reduce headspace oxygen below 2.0% v/v. Terminal autoclaving at 121 °C for 15 minutes is avoided unless photodiode array data confirm no loss above 0.5% area; the preferred route is aseptic filtration because thermal degradation accelerates above 80 °C in unbuffered aqueous systems. In-process checks include fill volume verification under 21 CFR 211.110, container closure integrity under USP <1207>, and particulate matter limits under USP <790>. Compliance for sterile compounding is governed by USP <797>; EU distribution requires a risk-based stability protocol aligned with VICH GL3 and residual solvent control under VICH GL18. The finished injectable should not be mixed with bicarbonate-containing fluids or alkaline Ringer’s because pH excursion above 6.0 accelerates oxime degradation and forms insoluble quaternary dimer species.
In feed-mill operations, antidote-grade TMB-4 powder presents segregation risk when blended into standard cereal carriers because the API crystal density is commonly 1.3–1.5 g/cm³, while ground maize carriers range from 0.55 g/cm³ to 0.65 g/cm³. The downstream premix process therefore begins with a matched particle size distribution: ≥90% through a 250 µm sieve and ≤10% retained on a 500 µm sieve. A pre-blend of TMB-4 with tricalcium phosphate at 1:1 to 1:3 w/w reduces electrostatic adhesion to stainless steel ribbon mixers and improves flow through a rotary feeder. Without this pre-blend, assay variability across 10 sample points has been observed to exceed ±15% RSD in high-speed paddle mixers after 10-minute mixing, whereas the same system with the pre-blend reaches ≤5.0% RSD at 15 minutes. The API addition ratio for a 0.5% final feed premix is 5.0 kg per 1,000 kg premix; for a 5% intermediate concentrate it is 50.0 kg per 1,000 kg. The pre-blend carrier fraction is held at 10–20% of total batch weight before geometric dilution into the remaining carrier.
Production sequence uses a twin-shaft paddle mixer at 25–30 rpm for 15–20 minutes; release samples are collected from 8 points per 500 kg lot and must meet 90.0–110.0% label claim with RSD ≤5.0%. Fluid-bed granulation for dust reduction uses a 3–5% w/w aqueous hydroxypropyl methylcellulose binder at 45 °C inlet air temperature; binder temperature is not permitted to exceed 60 °C because oxime degradation accelerates when residual moisture exceeds 1.5% water activity. Compliance falls under 21 CFR 225.1 and 225.202 for medicated feed records, FAMI-QS 6.0 for hazard control, and ISO 22000:2018 clause 8.5.1 for process control. Terminal product types include 0.5% micro-ingredient premixes, 5% intermediate concentrates, and 1 g/kg water-soluble granules for proportioning into drinking water at 100–200 g/1,000 L under emergency authorization. Published data for this specific feed configuration is limited; the above ratios derive from standard geometric dilution calculations rather than controlled efficacy studies.
| Control Parameter | Standard Designation | Release Specification |
|---|---|---|
| Premix blend uniformity | 21 CFR 225.1 | 90.0%–110.0% label claim |
| TMB-4 assay in final premix | 21 CFR 225.202 | ±10% label claim |
| Residual moisture after granulation | USP <731> | ≤1.5% w/w |
| Total aerobic microbial count | USP <61> | ≤10³ CFU/g |
| Salmonella | USP <62> | absent per 10 g |
Non-sterile oral solid dosage forms of TMB-4 are prepared by direct compression when the API content does not exceed 30% w/w and the median particle diameter is ≤100 µm. The quaternary ammonium bromide salt exhibits hygroscopicity at relative humidity above 60%; tablets exposed to 75% RH for 24 h show visible surface wetting and edge softening, so production areas are maintained at 35–45% RH and 18–22 °C. A precompression stage at 1.0 ton force improves densification without causing capping, while final compression at 8–12 kN on a 27-station rotary press yields tablets with hardness 5–7 kp and friability ≤0.8%. The addition ratio for oral tablets ranges from 25 mg to 150 mg API per 300 mg tablet, corresponding to 8.3–50.0% w/w. In dry blending, a 1:5 API-to-microcrystalline cellulose pre-blend passaged through a 600 µm screen reduces agglomerate survival and improves content uniformity. Capsules use a fill weight of 250 mg to 400 mg on a dosator capsule machine; direct compression blends are substituted with slugged granulations when the API level exceeds 30% to reduce flow variation.
Manufacturing sequence includes weighing, 10-minute V-blender mixing at 25 rpm, lubrication with 0.5% w/w magnesium stearate, and compression to a target weight of 300 mg ±5%. Compliance standards are USP <795> for nonsterile compounding, USP <1151> for tablet disintegration, and VICH GL1 for analytical method validation on blend uniformity samples. Terminal product types include scored 50 mg and 100 mg tablets, 25 mg and 75 mg hydroxypropyl methylcellulose capsules, and flavored equine oral boluses at a unit dose of 2–5 mg/kg body weight. Wet mass granulation is not recommended for TMB-4 unless a fluid-bed oscillator is used with inlet air below 50 °C; conventional tray drying at 60 °C produces hard agglomerates and a measurable shift in tablet dissolution after 6 months.
Above pH 5.0, the nucleophilic degradation rate of TMB-4 in aqueous vehicles rises sharply because the oxime anion concentration drives hydrolysis to pyridine-4-carboxaldehyde. Liquid oral formulations are therefore buffered in citrate-phosphate systems at pH 3.5–4.0. A 10 mg/mL oral solution prepared in deionized water with 0.1% w/w sodium metabisulfite and 0.2% w/w sodium citrate retains ≥95% potency after 12 months in amber polyethylene terephthalate bottles stored at 25 °C/60% RH only if headspace oxygen remains below 2.0% v/v. Addition of sucrose or sorbitol above 20% w/v decreases degradation but increases viscosity above 10 mPa·s, requiring pump-assisted proportioning rather than gravity-flow dosing pumps in poultry watering lines. The API addition ratio for a 250 mL bottle is 2.50 g TMB-4 per bottle; for a 1,000 L drinking water concentrate, the ratio is 10.0 kg API per 1,000 L of final water volume.
Downstream production uses a high-shear disperser at 1,200 rpm for 20 minutes to hydrate the quaternary ammonium salt, followed by 1.0 µm bag filtration and filling into moisture-barrier bottles. Clean-in-place regimes should avoid alkaline hypochlorite residues because residual chlorite above 0.5 ppm oxidizes the oxime group to a nitrile. Compliance references include USP <795> for nonsterile liquids, 21 CFR 211.110 for in-process fill weight checks, and VICH GL3 for photostability screening under ICH Q1B conditions. Terminal product types are 10 mg/mL multi-dose oral syringes, 25 mg/mL dropper bottles, and 100 mg/mL concentrate for emergency drinking water proportioning at 1–2 mL/L in swine and poultry barns.
Lyophilized TMB-4 powder for extemporaneous reconstitution is produced in a stoppering lyophilizer with a shelf ramp from −40 °C to −20 °C under 50–100 µbar vacuum, followed by secondary drying at 25 °C for 4–6 h. The freeze-dried cake contains 50 mg TMB-4 and 150 mg mannitol per 10 mL vial; the reconstitution addition ratio is 5.0% w/v when diluted with 10 mL sterile Water for Injections. This dosage form is used in emergency kits where atropine sulfate is administered at 0.05–0.2 mg/kg intramuscularly before intravenous TMB-4; the two agents must not be combined in a single syringe because atropine sulfate at pH 4.0–5.0 can drag the mixture below pH 3.0 and precipitate the bis-quaternary oxime. The lyophilization fill line operates in ISO 14644-1 Class 5; residual moisture is controlled to ≤1.0% by Karl Fischer titration under USP <921>, and cake collapse is prevented by holding the product below the mannitol glass transition of −30 °C during primary drying.
Downstream production includes aseptic filling of 2.0 mL bulk solution per vial, pre-stoppering with split-flange closures, and unloading under positive nitrogen pressure. In-process checks include container closure integrity, dose weight variation under 21 CFR 211.110, and visible particulate inspection. Compliance standards include 21 CFR 211.166 for stability commitments, USP <790> for particulate matter in injections, and VICH GL18 for residual solvent control in the mannitol excipient. Published data for the TMB-4–atropine co-administration compatibility in syringes is limited; the prohibition on mixing derives from pH-solubility calculations rather than controlled clinical studies. Terminal product types are 50 mg and 100 mg lyophilized vials, co-packed with 1 mL atropine sulfate prefilled syringes and 10 mL diluent ampoules.
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Trimedoxime bromide (TMB-4), CAS 56-97-3, is a bis-pyridinium aldoxime supplied as a veterinary-grade active pharmaceutical ingredient for processing into tablets, injections, capsules, powders, granules, premixes, and solutions. The accepted systematic name is 1,1′-(propane-1,3-diyl)bis{4-[(E)-(hydroxyimino)methyl]pyridinium} dibromide. The molecular formula is C15H18Br2N4O2, and the molar mass is 446.14 g/mol. The molecule contains two quaternised pyridine rings linked by a three-carbon alkylene spacer, with an aldoxime substituent at the 4-position of each ring. This structural arrangement distinguishes TMB-4 from monoquaternary oximes such as pralidoxime chloride and from bis-quaternary oximes with different linkers such as obidoxime chloride.
The veterinary-grade powder is presented as a white to off-white crystalline solid. It is freely soluble in water and poorly soluble in non-polar organic solvents. The permanent positive charge on both pyridine nitrogen atoms restricts passive diffusion across lipid membranes and is the principal basis for limited blood-brain barrier penetration after systemic administration. The bromide salt is hygroscopic and should be protected from moisture. Open handling above 60% relative humidity may require vacuum pre-drying at 40–50 °C before dry blending or filling. Double polyethylene liners, desiccant sachets, and sealed fibre drums are standard packaging for the unmicronised powder.
A certificate of analysis aligned with veterinary API expectations includes assay, related substances, water content, residue on ignition, residual solvents, elemental impurities, and particle-size distribution. Assay and related substances are determined by reversed-phase HPLC with UV detection; a release target of 98.0–102.0% w/w on the dried basis is applied, with total impurities not more than 1.0% and any single unspecified impurity not more than 0.10%. Water is measured by Karl Fischer titration according to Ph. Eur. 2.5.12 or USP <921>; the target is not more than 1.0% for dry solid dosage forms. Residue on ignition is controlled to not more than 0.1% by Ph. Eur. 2.4.14 or USP <281>. Residual solvents are analysed by headspace GC according to USP <467> and VICH GL18; Class 3 solvents are controlled at the limits specified in ICH Q3C. Elemental impurities are controlled by ICP-MS according to USP <232> and <233>, with limits selected using the target animal species and exposure duration. For injection-grade material, bacterial endotoxins are specified at not more than 0.10 EU/mg, and bioburden is monitored before sterilising filtration.
Because published monograph data for TMB-4 veterinary grade are limited, the limits above follow the general quality framework for quaternary ammonium APIs rather than a species-specific monograph. Batch-to-batch variability in residual water and particle-size distribution is the main reason downstream formulators require tight vendor specifications.
| Release parameter | Control target | Test reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual / Ph. Eur. 2.2.1 |
| Identification | IR spectrum and HPLC retention time consistent with reference | Ph. Eur. 2.2.24; USP <621> |
| Assay on dried basis | 98.0–102.0% w/w | HPLC / Ph. Eur. 2.2.29 |
| Total impurities | ≤ 1.0% | HPLC area normalisation |
| Water content | ≤ 1.0% for dry forms; ≤ 3.0% if corrected in lyophilisation input | Ph. Eur. 2.5.12 / USP <921> |
| Residue on ignition | ≤ 0.1% | Ph. Eur. 2.4.14 / USP <281> |
| Residual solvents | Class 3 solvents per ICH Q3C; Class 2 solvents per VICH GL18 | USP <467>; headspace GC |
| Elemental impurities | Risk-based limits for oral or parenteral use | USP <232> / <233>; ICP-MS |
| Bacterial endotoxins, injection grade | ≤ 0.10 EU/mg | Ph. Eur. 2.6.14 / USP <85> |
| Particle-size distribution, direct compression | D90 ≤ 150 µm | Ph. Eur. 2.9.31 laser diffraction |
For tablet and capsule manufacture, the crystalline powder is rarely used without pre-processing because the material can exhibit poor flow and high static charge. Direct compression is practical only when the particle-size distribution is controlled to D90 ≤ 150 µm by laser diffraction according to Ph. Eur. 2.9.31, and powder flowability is not less than 10 mm by Ph. Eur. 2.9.36. When the as-received material fails this target, slugging or dry granulation is preferred over wet granulation because quaternary oxime bromides are sensitive to strongly alkaline binders and prolonged exposure to water at elevated temperatures. If wet granulation is unavoidable, an aqueous binder solution should be maintained below pH 6.0 and dried at product temperature not exceeding 50 °C.
Dry blending of low-dose TMB-4 formulations is performed by geometric dilution in a V-blender or bin blender equipped with an intensifier bar. Blend uniformity is confirmed by stratified sampling according to USP <905>; acceptance is typically a relative standard deviation not more than 5.0% for the active assay across at least 10 sampling points. Magnesium stearate is avoided above 1.0% w/w because hydrophobic lubrication can retard dissolution of this water-soluble API; sodium stearyl fumarate at 0.5–1.0% w/w is a suitable alternative.
In premix and granule applications, the primary risk is segregation. The API is milled to D90 ≤ 75 µm and combined with a carrier such as lactose monohydrate or calcium carbonate in a ribbon mixer. Overfilling the mixer beyond 60% of working volume reduces shear and may produce poor distribution; a mixing time of 10–15 min at 20–30 rpm is typical for pilot-scale batches. Finished premix should be tested for content uniformity using at least 20 samples and should not be stored in open bins above 40% RH.
Particle-size reduction by air-jet milling at 0.5–1.0 kg/h lowers D90 but increases specific surface area and moisture uptake. The milled product should be discharged into double-lined drums under nitrogen because amorphous content above 2.0% may recrystallise at 40% RH and cause agglomeration. If agglomeration occurs, the API may fail flow testing and require re-milling, which further increases amorphous content. This processing conflict is the reason TMB-4 is specified with a target PSD rather than a simple fine-powder description.
Injectable TMB-4 solutions are prepared from a dedicated injection grade of the API. Beyond chemical purity, the critical quality attributes are bacterial endotoxins, bioburden, insoluble particulates, and solution clarity. The API is dissolved in Water for Injection and filtered through a 0.22 µm membrane. Terminal sterilisation by autoclaving at 121 °C for 15 min should not be assumed acceptable without forced-degradation data because bis-pyridinium aldoximes can degrade at high pH or after prolonged heat exposure. If thermal degradation exceeds 0.5% total impurities, aseptic filtration is preferred. The final solution is tested for subvisible particulates according to Ph. Eur. 2.9.19 or USP <788>; for small-volume parenterals, the limit is not more than 6000 particles per container at ≥ 10 µm and not more than 600 at ≥ 25 µm.
Aqueous TMB-4 solutions are typically slightly acidic. The pH should be maintained below 7.0 to slow oxime degradation; amber glass or opaque packaging is required because photo-induced discoloration has been observed for quaternary oximes. Chelating agents are not required unless the solution contacts metal ions; transition-metal contamination above 1 ppm can catalyse oxidative degradation and should be excluded by the elemental impurity specification.
For oral powders, the API is provided in low-moisture sachets or incorporated into flavoured carriers. The dose is usually presented as a reconstitutable powder because aqueous stock solutions have limited storage stability; published data for this specific configuration is limited. Dry powder losses during filling are controlled by maintaining room relative humidity below 40% and by using screw auger filling machines with inert gas purging. Hard capsules should be packed with desiccant and tested for dissolution according to Ph. Eur. 2.9.3 or USP <711> using water or 0.1 M hydrochloric acid as the medium. Because the API is freely soluble, dissolution is typically not the limiting factor unless lubricant or binder levels are excessive.
The defining difference between TMB-4 and pralidoxime chloride is the number and arrangement of cationic and oxime groups. TMB-4 has two aldoxime groups and two permanent positive charges; pralidoxime has one aldoxime and one pyridinium centre. This structural difference is relevant because acetylcholinesterase reactivation after organophosphate poisoning requires nucleophilic attack on the phosphorylated serine hydroxyl. In vitro, bis-quaternary oximes may bind more tightly to the enzyme active site, but they also cross the blood-brain barrier less readily. Published comparative reactivation data in food-producing species are limited; extrapolation from rodent or human in vitro models should be confirmed in the target species.
Compared with obidoxime chloride, TMB-4 has a less hydrophilic linker. Obidoxime uses a 2-oxapropane-1,3-diyl bridge, whereas TMB-4 uses a propane-1,3-diyl bridge. This difference modifies aqueous solubility, octanol-water partitioning, and possibly renal clearance. TMB-4 is regarded as freely soluble in water, while obidoxime is soluble but not identical in hydration behaviour. The molar mass of TMB-4 is 446.14 g/mol, compared with 172.61 g/mol for pralidoxime chloride and 359.21 g/mol for obidoxime chloride; therefore, milligram-per-milligram substitution among oximes is not valid.
| Parameter | Trimedoxime bromide | Pralidoxime chloride | Obidoxime chloride |
|---|---|---|---|
| CAS | 56-97-3 | 51-15-0 | 114-90-9 |
| Molecular formula | C15H18Br2N4O2 | C7H9ClN2O | C14H16Cl2N4O3 |
| Molar mass | 446.14 g/mol | 172.61 g/mol | 359.21 g/mol |
| Pyridinium centres | 2 | 1 | 2 |
| Aldoxime groups | 2 | 1 | 2 |
| Linker | Propane-1,3-diyl | N-methyl | 2-oxapropane-1,3-diyl |
| Aqueous solubility | Freely soluble | Freely soluble | Soluble |
| Primary formulation constraint | Hygroscopic; injection-grade endotoxin control | Lower molar mass; monoquaternary | Hydrophilic linker; similar oxime content |
For a veterinary formulation, the selection of TMB-4 over pralidoxime or obidoxime is made on the basis of the organophosphate agent, target species, dose volume, route of administration, and withdrawal-period data. TMB-4 is not a broad-spectrum replacement for all oximes; its reactivation efficacy against soman-inhibited acetylcholinesterase is limited in some species. The API must be used as part of a treatment protocol that includes atropine, decontamination, and supportive care, not as a monotherapy.
In tableting and encapsulation, the principal difference is not only molar potency but also counter-ion. TMB-4 is supplied as the dibromide, whereas pralidoxime is commonly the chloride. Bromide content contributes to overall mass and may influence hygroscopicity and compatibility with bromide-sensitive analytical methods. In aqueous solution, the pH of TMB-4 is typically mildly acidic; addition of sodium hydroxide beyond pH 7.5 accelerates oxime degradation, so buffering should be validated by forced-degradation studies at 40 °C/75% RH for solid forms and 60 °C for 7 days for solutions.
TMB-4 veterinary grade should be stored in a cool, dry place, protected from light, and segregated from strong oxidising agents, hypochlorite disinfectants, and alkaline excipients. The dry powder should not be exposed to open air above 60% RH without humidity-controlled handling. Aqueous solutions should be used within the stability window established by the finished-product manufacturer, and any colour change from colourless to yellow or brown indicates degradation and the batch should be rejected. The material is intended for veterinary use only and must not be used in human medicine.
