6-Phenyl-2,3,5,6-Tetrahydroimidazo[2,1-B][1,3]Thiazole Hydrochloride (1:1)

A Chemical Identity Anchored in Pharmacopoeial Nomenclature

The compound designated as 6-Phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole hydrochloride (1:1) corresponds to the racemic form of tetramisole hydrochloride—a 1:1 salt of the fused imidazothiazole base with hydrogen chloride. Its molecular formula is C₁₁H₁₃ClN₂S with a relative molecular mass of 240.75 g/mol. The CAS registry number typically assigned to the racemic hydrochloride is 5086-74-8; the free base has CAS 5036-02-2. Commercially, the substance is supplied as a white to off-white crystalline powder with a melting point ranging from 202°C to 204°C (decomposition) when determined by differential scanning calorimetry at a heating rate of 10 K/min. The solid-state form exhibits moderate hygroscopicity, with equilibrium moisture uptake of approximately 2.8% w/w at 75% relative humidity and 25°C, requiring storage under desiccated conditions once the primary container is opened. Identity is routinely confirmed by infrared absorption spectrophotometry against a reference standard traceable to the European Pharmacopoeia (Ph. Eur.) monograph for tetramisole hydrochloride, and purity is assessed by non-aqueous acid-base titration with perchloric acid in anhydrous formic acid using crystal violet indicator.

Parameter	Acceptance Criterion	Test Method
Assay (anhydrous basis)	99.0%–101.0%	Ph. Eur. 2.2.20 (potentiometric titration)
Water content	≤ 0.5% w/w	Karl Fischer coulometry, Ph. Eur. 2.5.12
Related substances (total impurities)	≤ 0.5%	RP-HPLC with UV detection at 215 nm; column: C18, 250 × 4.6 mm, 5 µm
Optical rotation (c=1, water)	−0.10° to +0.10°	Ph. Eur. 2.2.7 (polarimetry)
Sulfated ash	≤ 0.1%	Ph. Eur. 2.4.14
Heavy metals (as Pb)	≤ 10 ppm	Ph. Eur. 2.4.8 method C
Residual solvents (Class 2: methanol)	≤ 3000 ppm	GC-HS according to ICH Q3C, Ph. Eur. 2.4.24

No dedicated pharmacopoeial limits exist for enantiomeric purity because the racemate, by definition, contains equal parts of the levo- and dextro-rotatory enantiomers. Nevertheless, contract analytical laboratories employ chiral stationary phases—Chiralpak AGP or Chiralpak IA-3 columns operated with aqueous phosphate buffer–acetonitrile mobile phases—to verify the absence of enantiomeric enrichment that would indicate mislabeling with the L-isomer salt. What Limits Process Yield During Neutralisation and Extraction of the Free Base? Manufacturing routes to the hydrochloride salt frequently proceed via condensation of 2-iminothiazolidine with α-bromoacetophenone derivatives, followed by acidification. Isolation of the free base as an intermediate demands tight pH control: at a pH above 8.5 the aqueous solubility of the neutral species drops below 0.4 mg/mL at 20°C, triggering rapid crystallisation that can occlude unreacted starting materials. On a 2000 L glass-lined reactor equipped with a retreat-curve impeller, the addition of 20% aqueous sodium hydroxide must be carried out at a rate not exceeding 12 L/min with the jacket temperature maintained at 10°C–15°C to prevent localised alkalinity spikes that promote dimerisation of the transient enamine tautomer. The resulting free base slurry exhibits a median particle size (Dv50) between 80 µm and 150 µm when measured by laser diffraction on a Malvern Mastersizer 3000, a morphology that poses no filtration bottleneck if the drying vacuum is kept below 20 mbar. Deviation from this narrow temperature window has been observed on production scales to increase the level of the dimeric impurity (detected as a peak with relative retention time 1.7 vs. the API) to over 1.2%, rendering the batch non-conformant according to the ICH Q3B limits for unidentified impurities. Veterinary Anthelmintic Formulation and the Impact of Particle Size Distribution In veterinary medicine, racemic tetramisole hydrochloride is incorporated into oral drenches, feed premixes, and bolus tablets for nematode control in ruminants and swine. The most pronounced formulation challenge emerges when preparing high-concentration aqueous drenches (7.5% w/v as the hydrochloride) in multi-dose containers. Untreated tap water with a calcium hardness exceeding 120 ppm as CaCO₃ can induce precipitation of the free base through local pH elevation driven by bicarbonate buffering; the problem is mitigated by pre-adjustment of the vehicle to pH 4.0–4.5 with citric acid monohydrate. Beyond solubility, the dissolution rate of the powder directly influences bioavailability. A shift in Dv90 from 180 µm to 45 µm achieved by jet-milling with a spiral classifier under nitrogen at 7 bar grind pressure reduces the 85% dissolution time (USP apparatus II, 500 mL pH 1.2 buffer, 50 rpm) from 14 min to 4 min. However, milled particles exhibit an amorphous surface layer that increases water uptake during storage in polyethylene drums at 40°C/75% RH to 4.1% w/w within 21 days, exceeding the specification of ≤ 2.0% water for dry-blend feed premixes. Producers counter this by packaging under controlled humidity (25% RH) and including silica gel desiccant canisters compliant with FDA 21 CFR 73.1. How the Racemate Diverges from Levamisole Hydrochloride in Biological Assays The L-enantiomer (levamisole hydrochloride, CAS 16595-80-5) carries a specific optical rotation of approximately −85° (c=1, water) and accounts for the majority of the anthelmintic activity observed in vivo, whereas the D-enantiomer is largely responsible for the cholinergic side-effect profile. Despite this, the racemate continues to be listed in multiple national pharmacopoeias and finds application where the cost of chiral resolution cannot be justified. A comparative larval paralysis test against Haemonchus contortus exsheathed L3 larvae, conducted in phosphate-buffered saline (pH 7.2) at 37°C, yields an EC₅₀ of 1.8 µg/mL for levamisole hydrochloride and 3.9 µg/mL for the racemic hydrochloride after 24 h incubation, a potency ratio that aligns with the presence of the inactive D-isomer. In mammalian immunomodulation assays, the difference narrows; both substances elevate intracellular guanosine 3′,5′-cyclic monophosphate concentration in human peripheral blood mononuclear cells at 10 µM within 60 min, though the racemate demonstrates a 15% lower maximal stimulation due to partial antagonism at the adenosine A2A receptor subtype claimed by the D-enantiomer.

Property	Racemic HCl (5086-74-8)	Levamisole HCl (16595-80-5)
Optical rotation (c=1, water)	~ 0°	−83° to −87°
Melting point (DSC, 10 K/min)	202–204°C (dec)	227–229°C (dec)
Solubility in water (25°C)	~ 21% w/v	~ 20% w/v
Relative anthelmintic potency (H. contortus EC50)	3.9 µg/mL	1.8 µg/mL
Chiral purity specification	Not applicable (racemic)	D-isomer ≤ 0.5%

Handling and Dust Exposure Mitigation During Large-Scale Blending A recurring process bottleneck on 500 kg ribbon blender lines producing medicated feed premixes is the generation of fine respirable dust when the milled hydrochloride is discharged from a vacuum-sack dump station without adequate extraction. The dry powder carries an occupational exposure band with a control limit of 0.5 mg/m³ (8-hour TWA), as estimated by the affine structure-activity relationship model for a sensitising heterocyclic amine. Plant engineering teams have found that retrofitting the dump station with a local exhaust ventilation system operating at a face velocity of 0.75 m/s and integrating a HEPA-filtered dust collector satisfying ISO 16890-1:2016 ePM1 85% classification reduces airborne particulate concentration from a baseline of 3.2 mg/m³ to 0.12 mg/m³, as verified by IOM personal sampler monitoring. Electrostatic charge accumulation remains a secondary concern; powder resistivity values measured in the range of 10⁹–10¹⁰ Ω·m dictate that all transfer hoses be electrically bonded to earth and that inert gas purging be employed when handling the finely divided substance in the presence of flammable solvents during reprocessing reject batches.

When Sourcing for Research Applications Requires Absence of the Chiral Impurity Butexamic Acid

Investigators employing the racemic hydrochloride as a comparative standard in pharmacology studies must distinguish it not only from the levamisole salt but also from structurally related imidazothiazoles such as butamisole (CAS 54400-59-8) and from the oxidation degradation product 2-oxo-3-(2-mercaptoethyl)-5-phenylimidazolidine. Liquid chromatography coupled with high-resolution quadrupole time-of-flight mass spectrometry, using a biphenyl column (100 × 2.1 mm, 1.7 µm) and a gradient of 0.1% formic acid in water and acetonitrile, achieves baseline separation of these congeners with a mass accuracy of < 2 ppm. Batches destined for enzyme inhibition studies—particularly those interrogating alkaline phosphatase or nicotinamide adenine dinucleotide oxidoreductase—must carry a certificate of analysis that quantifies residual 2-mercaptoethylphenylimidazolidinone at a reporting threshold of 0.05%, because the impurity acts as a false-positive inhibitor with an IC₅₀ approximately 40-fold lower than that of the parent compound in colourimetric para-nitrophenyl phosphate assays run at pH 9.8. Solubility in Non-Aqueous Systems for Topical Immunomodulator Prototypes While aqueous solubility defines the drench and injectable applications, formulation scientists preparing anhydrous topical gels require dissolution data in polyhydric alcohols. The racemic hydrochloride attains a solubility limit of 5.2% w/w in propylene glycol at 25°C and 1.8% w/w in glycerol formal, values that fall below those of the free base solubilised with organic acids. Whenever the hydrochloride is dispersed in a vehicle containing ≥ 15% water and carbomer 940 neutralised to pH 5.5 with triethanolamine, the counter-ion exchange releases the free base, which then precipitates as needle-shaped crystals within 48 hours, visible by polarised light microscopy as characteristic birefringent particles. Reformulation with a non-ionic surfactant blend of polysorbate 80 and sorbitan monooleate (HLB 12.5) maintains physical stability for at least 90 days at 40°C, provided that the hydrochloride is pre-micronised to a Dv99 below 20 µm using a fluidised-bed opposed-jet mill with a classifier speed of 12 000 rpm. Published data for long-term photostability in this gel matrix are limited; accelerated testing per ICH Q1B confirms no new related substance peaks exceeding 0.1% after exposure to an overall illumination of 1.2 million lux·h and an integrated near-ultraviolet energy of 200 W·h/m².