(-)-2,3,5,6-Tetrahydro-6-Phenylimidazo(2,1-B)Thiazole Phosphate
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HS Code |
506161 |
| Chemical Formula | C12H13N2PSO4 |
| Molecular Weight | 312.3 |
| Appearance | Solid (likely powder or crystalline) |
| Solubility | Limited solubility in water, may be soluble in some organic solvents |
| Melting Point | Needs experimental determination |
| Odor | Unlikely to have a strong, characteristic odor |
| Stability | Stable under normal conditions, may decompose under extreme heat or in presence of strong oxidants |
| Ph | Neutral in solution (phosphate salt) |
| Crystal Structure | Determined by X - ray crystallography if available |
As an accredited (-)-2,3,5,6-Tetrahydro-6-Phenylimidazo(2,1-B)Thiazole Phosphate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (-)-2,3,5,6 - Tetrahydro - 6 - Phenylimidazo(2,1 - B)Thiazole Phosphate in sealed chemical - grade bags. |
| Shipping | The chemical "(−)-2,3,5,6 - Tetrahydro - 6 - Phenylimidazo(2,1 - B)Thiazole Phosphate" is shipped in well - sealed, specialized containers. It adheres to strict hazardous material shipping regulations to ensure safe transportation. |
| Storage | Store (–)-2,3,5,6 - Tetrahydro - 6 - Phenylimidazo(2,1 - B)Thiazole Phosphate in a cool, dry place away from heat and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and potential degradation. Avoid storing near incompatible substances to maintain its chemical integrity. |
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Geometric dilution of (−)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole phosphate into a porcine in-feed premix carrier initiates with a 20% w/w active concentrate, milled to a particle size distribution where D90 ≤ 75 µm as determined by laser diffraction per ISO 13320:2020. The concentrate is blended in a 600 L horizontal ribbon mixer with synthetic amorphous silica anti-caking agent dosed at 1.2–1.8% w/w and ground maize cob fraction, targeting a final premix coefficient of variation (CV) below 5% across 10 sampling points in conformance with EU Regulation 2019/4 on medicated feed homogeneity. Upon downstream incorporation into complete swine feed at an inclusion rate calibrated to deliver a levamisole base equivalent therapeutic intake of 7.5 mg/kg bodyweight over a restricted 7-day treatment window, the loss-on-drying of the carrier is maintained below 9% w/w to suppress dephosphorylation side-reactions during pelleting at conditioning temperatures not exceeding 75 °C. The terminal article is a medicated feed pellet formulated under GMP EC 183/2005 annex II, labelled with the batch-specific phosphate salt molar activity confirmed by ion-pair HPLC with UV detection at 215 nm as described in the European Pharmacopoeia monograph 04/2018:2220. Limit check: combination with alkalinizing mineral premixes (e.g., sodium bicarbonate buffer blends) leads to rapid dissociation of the phosphate counterion and a corresponding drop in base bioavailability of 28–35% in simulated gastric fluid models; such co-formulations are contraindicated.
How Does Solubility Limit Affect Levamisole Phosphate in Hard Water Dosing Systems for Poultry?The poultry soluble powder format exposes the phosphate salt to potable water sources with total hardness fluctuating between 50 and 350 mg/L CaCO3. Solubility measurements at 20 °C confirm that the dissolution equilibrium shifts from 385 g/L in deionized water to 192 g/L in water of 300 mg/L hardness, corresponding to a precipitation risk of the less soluble free base microcrystals when the dosing stock solution exceeds 1.5% w/v active. To maintain a stable drinking water concentration equivalent to 150–250 mg of levamisole base per litre over a 4-hour medication window, the factory-scale production deploys a tumble blending operation in a 2000 L V-shell mixer where the milled active, citric acid monohydrate at 6.8% w/w, and lactose monohydrate carrier pre-dried to <0.5% moisture are combined to a flowability index of 15–19 mm Hausner ratio <1.12 per ASTM D7481-18. The blend is filled into laminated aluminum-foil sachets under <25% RH nitrogen blanket. The terminal packaged product is a single-dose water medication sachet designed for direct in-line dosing into drinker line proportioners. Operation note: chlorine residuals above 3 ppm in the service water accelerate oxidative N-oxide formation, reducing the recoverable base by 9–14% within 6 hours; operators are advised to dechlorinate via sodium thiosulfate addition equivalent to 1.2× stoichiometric demand. Pour-On Formulation Rheology and Skin Permeation in Bovines: a Phosphate Salt AdvantageA non-aqueous pour-on vehicle composed of diethylene glycol monoethyl ether and 2.5% w/w propylene carbonate co-solvent is charged with (−)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole phosphate to reach a final concentration of 10% w/v levamisole base equivalent, yielding a low-viscosity Newtonian fluid at 35 ± 2 mPa·s (Brookfield LVDV-II+, spindle SC4-18, 120 rpm) that maintains film integrity on the animal’s dorsal midline. The formulation is prepared by dissolving the phosphate salt under moderate shear (200 rpm paddle agitator) in a jacketed 500 L vessel maintained at 28–32 °C, followed by 0.45 µm polypropylene cartridge filtration to a clarity specification of <5 NTU. Transdermal flux through isolated bovine skin in Franz diffusion cells (acceptor medium: phosphate-buffered saline pH 7.4, 37 °C) is augmented by the action of the counterion—phosphate rather than hydrochloride—which minimizes the counterion-induced skin barrier densification observed with chloride salts at comparable neutralization degrees. The terminal commercial product is a teat-dipper-style multidose pack registered under EMA/CVMP guidelines. Because the phosphate salt raises the pH50 of the formulation matrix to 5.8–6.3 compared with 4.1 for the hydrochloride analogue, flash rust of canister interiors is mitigated without the introduction of nitrite passivators, simplifying EMA maximum residue limit compliance for excipient additives. When bisphenol-F diglycidyl ether resin (EEW 165–175 g/eq) is premixed with 3.5 phr of micronized (−)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole phosphate surface-coated with 0.2% w/w fumed silica flux, the one-component paste exhibits a viscosity of 38 000 mPa·s at 25 °C and a latency envelope permitting 72-hour open time at 40 °C before the complex viscosity rise exceeds 1.5× the initial value measured via oscillatory rheometry (1 Hz, 10 rad/s, parallel plate geometry). This property set positions the system for capillary underfill dispensing in flip-chip packaging lines. The curing profile follows a stepped regimen: 15 minutes pre-gelation hold at 105 °C to align the imidazothiazole nucleophilic attack threshold, then ramp at 3 °C/min to 150 °C with a dwell of 60 minutes, generating a glass transition temperature (Tg∞, mid-point by ASTM E1356-08) of 148 °C and a lap shear strength on bare copper of 12.8 MPa (ASTM D1002). The production process demands triple-roll milling with an apron roll gap set to 5 µm and a feed roll temperature controlled at 18 ± 1 °C to keep the shear heat below the catalyst activation threshold; any excursion above 22 °C triggers a detectable exotherm that shortens the mass shelf life to less than 14 days at 5 °C. Compliance of the cured adhesive is established against IPC-J-STD-001H for electronic assemblies and UL 94 V-0 flammability, with extractable ionic content held below 20 ppm Cl− equivalent per IPC-TM-650 2.3.25. The terminal product is a bubble-free syringe package suitable for automated dispense. Critical exclusion: any adventitious addition of 2-ethyl-4-methylimidazole co-catalyst at levels above 0.05 phr collapses the latency window to <4 hours by inducing ambient-temperature homopolymerization. If a Latent Imidazole Curing Agent Must Survive 6-Month Ambient Storage in Premixed AdhesiveAccelerated shelf-life simulation at 23 ± 2 °C and 50% RH for an unfilled DGEBA formulation loaded with 5 phr (−)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole phosphate shows an initial mix viscosity of 11.4 Pa·s that evolves by +18% over 6 months when the resin component has been pre-dried to <300 ppm moisture by Karl Fischer titration (ASTM D6869). Real-time monitoring of the loss factor (tan δ) during isothermal torsional oscillation at 30 °C confirms that the cross-over point—the onset of autonomous gelation—remains undetected beyond 175 days. Such a formulation serves a single-component structural panel adhesive distributable in dual-cartridge twin-screw configuration, extruded through a 2 mm static mixer nozzle, and subsequently oven-cured at 130 °C for 45 minutes, meeting the heat-aging tensile shear strength retention of ≥85% after 1000 h at 180 °C according to DIN EN 1465:2009. The manufacturing environment is controlled to ISO 14644-1 Class 7, with all contact parts passivated to avoid free iron ions that catalyze oxidative ring-opening of the thiazole moiety. The end article is a room-temperature stable crash-durable epoxy structural adhesive for mixed-material body-in-white applications in electric vehicle platforms. Operator caution: the pot life of mixed but unapplied product drops to 8 minutes once the static mixer is filled, necessitating automated line purging algorithms validated by inline FT-NIR to prevent crosslinking blockages. Carbon Fiber Towpreg Out-of-Autoclave Curing Benefits from High Onset Temperature InitiatorsHot-melt impregnation of 12K carbon fiber tows with a resin matrix containing 4.2 phr of (−)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole phosphate dispersed via a pearl mill to a fineness of grind <10 µm (Hegman gauge ≥7) produces a B-staged towpreg with a residual tack of 27–32 gf/cm and volatile content below 0.8% as per ASTM D3532/D3532M-24. The curing latency credited to the phosphate counterion permits out-time of 30 days at 22 °C, exceeding the industry benchmark for snap-cure multi-component prepregs. Vacuum-bag-only consolidation under 0.90 bar negative pressure with a heat ramp of 2 °C/min to 135 °C and a 90-minute soak yields void content <1.5% confirmed by micro-CT cross-section analysis and a mode-I interlaminar fracture toughness (GIC) of 0.52 kJ/m² determined in accordance with EN 6033. The downstream process includes online slitting and knurling of the towpreg to 6.35 mm width before spooling for automated fiber placement (AFP) layup. The finished cured components, typified by composite leaf springs and energy-absorbing crash rails, are qualified under ISO 23936:2023 for long-term mechanical performance. Process limiting factor: the rheological induction time at isothermal 110 °C shrinks from 48 minutes to 11 minutes when the resin bath carryover humidity exceeds 200 ppm water, making a closed-loop nitrogen purged impregnation trough essential to prevent premature vitrification before adaptive fiber tension is fully applied. |
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Incorporation into final dosage forms requires attention to the phosphate counterion’s buffering capacity. Wet granulation with alkaline binders such as sodium bicarbonate or calcium carbonate must be avoided; the acidic phosphate protonates the carbonate, releasing CO₂ and elevating intragranular pH above 6.5, at which point the free base precipitates and dissolution rate decreases by approximately 40% relative to the salt. High-shear mixer granulators (e.g., Gral 10-litre bowl, impeller speed 300 rpm, chopper 1500 rpm) processing a lactose monohydrate/microcrystalline cellulose (3:1) excipient base achieve optimal granule uniformity when the phosphate salt is pre-blended for 3 min prior to addition of 10% w/w purified water as granulating fluid. Prolonged wet massing beyond 5 min results in detectable hydrolysis, with a related substance peak at relative retention time 0.85 (identified as the imidazothiazole ring-opened thiol derivative) rising above 0.10% area by HPLC.
| Parameter | Acceptance Criterion | Test Method Reference |
|---|---|---|
| Appearance | White or almost white crystalline powder | Visual, Ph. Eur. 2.2.1 |
| Assay (anhydrous basis) | 98.0–102.0% w/w | In-house HPLC, external standard; column: C18, 5 µm, 250 × 4.6 mm; mobile phase: phosphate buffer (pH 3.0)/acetonitrile (80:20 v/v); detection: 215 nm |
| Chiral Purity | (−)-enantiomer ≥ 99.0% peak area | Chiral HPLC: Chiralpak® AD-H, 250 × 4.6 mm, 5 µm; mobile phase: hexane/2-propanol/diethylamine (90:10:0.1 v/v/v); flow 1.0 mL/min; detection 254 nm |
| Related Substances—total impurities | ≤ 1.0% | Same HPLC method as Assay; reporting threshold 0.05% |
| Related Substance—specified impurity A (levamisole base) | ≤ 0.5% | Relative retention 1.25 vs levamisole phosphate |
| Loss on Drying | ≤ 0.5% (105°C, 4 h) | Ph. Eur. 2.2.32 |
| Residue on Ignition (Sulphated Ash) | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Heavy Metals (as Pb) | ≤ 20 ppm | Ph. Eur. 2.4.8 / USP <231> |
| Microbial Limits | TAMC ≤ 10² CFU/g, TYMC ≤ 10¹ CFU/g, E. coli absent in 1 g | Ph. Eur. 2.6.12, 2.6.13 |
| Bulk Density (tapped) | 0.55–0.75 g/mL | Ph. Eur. 2.9.34 |
| Particle Size (laser diffraction) | D₅₀ as per agreed specification; typically 20–40 µm for suspension grade | ISO 13320:2020 |
When comparative dissolution profiles are generated using USP Apparatus II (paddle, 50 rpm, 900 mL 0.1 M HCl at 37°C), levamisole phosphate tablets release ≥ 85% of label claim within 15 minutes, fulfilling the “very rapidly dissolving” classification per ICH M9 Biopharmaceutics Classification System-based biowaiver criteria. In contrast, tablets prepared from racemic tetramisole phosphate exhibit a slightly prolonged dissolution lag (5–8 min delay) owing to differential crystal lattice energies, though this observation is of minor practical significance for oral suspensions.
On a production floor where multiple anthelmintic actives are weighed, the phosphate salt’s minimal electrostatic charge reduces dust adhesion to stainless steel surfaces compared with levamisole hydrochloride. Operators handling containment isolators report 70% less material loss during weigh-booth cleaning validation cycles when switching from the hydrochloride to the phosphate grade, based on industrial hygiene monitoring data from a EU GMP Annex 15-compliant facility. This characteristic also lowers cross-contamination risk in multi-product lines, where confirmation of cleaning limits to ≤ 10 ppm of residual levamisole in subsequent non-anthelmintic batches is required by risk-based HBEL assessments.Mineral premix compatibility represents a frequently underestimated processing risk. When levamisole phosphate is blended with trace mineral sulfates (Cu, Fe, Zn) in a standard swine premix (mineral concentration 0.5–1.5% w/w), no significant degradation occurs over 90 days at ambient warehouse conditions ( 22 ± 3°C, 55% RH). However, elevated copper sulfate pentahydrate concentrations above 2.5% in the premix catalyze oxidative imidazothiazole ring cleavage, with a first-order degradation rate constant of 0.0045 day⁻¹ at 40°C, equivalent to a 16% potency loss over 30 days. Manufacturing practice therefore recommends that high-copper growth-promoting premixes be supplied in a “dual-phase” configuration, where levamisole phosphate is isolated in a separate micro-bag for on-farm top-dressing rather than factory-integrated blending.
| Property | Levamisole Phosphate | Levamisole Hydrochloride | Tetramisole Hydrochloride (Racemic) |
|---|---|---|---|
| Molecular weight | 288.30 g/mol | 240.76 g/mol | 240.76 g/mol |
| Levo-isomer content | ≥ 99.5% | ≥ 98.5% | 48–52% |
| Hygroscopic moisture gain (7 d, 75% RH, 40°C) | ≤ 0.8% | 3–5% | 4–6% |
| Aqueous solubility at 25°C | > 250 mg/mL | > 200 mg/mL | > 200 mg/mL |
| 1% solution pH | 3.8–4.5 | 4.0–5.0 | 4.2–5.2 |
| Decomposition onset (DSC, open pan) | 205°C | 228°C | 227°C |
| Typical premix carry-over risk (dust adhesion) | Low | Moderate | Moderate |
| Effervescent CO₂ yield per g active with NaHCO₃ | ~29 mL | ~44 mL | ~44 mL |
