| HS Code | 999427 |
| Productname | Closantel Base |
| Inn | Closantel |
| Pharmacopoeialgrade | IH/INN |
| Api Grade | Pharma Grade |
| Productcategory | Active Pharmaceutical Ingredient |
| Chemicalname | (RS)-N-[5-chloro-4-[(4-chlorophenyl)cyanomethyl]-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide |
| Casnumber | 57808-65-8 |
| Molecularformula | C22H14Cl2I2N2O2 |
| Molecularweight | 663.07 g/mol |
| Appearance | Off-white to pale yellow crystalline powder |
| Solubility | Practically insoluble in water; soluble in methanol, ethanol, acetone, and chloroform |
| Assay | 98.0% to 102.0% (on dried basis) |
| Purity | ≥98.0% (HPLC) |
| Lossondrying | ≤0.5% |
| Sulphatedash | ≤0.1% |
| Heavymetals | ≤20 ppm |
| Meltingpoint | 217°C to 220°C |
| Identification | IR and UV absorption |
| Therapeuticcategory | Anthelmintic |
| Mechanismofaction | Uncoupler of oxidative phosphorylation in parasites |
| Dosageforms | Tablet, Capsule, Granule, Injection |
| Routesofadministration | Oral, Injectable |
| Storage | Store in a tightly closed container, protected from light, in a dry place at controlled room temperature |
As an accredited Closantel Base IH/INN Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
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Closantel Base IH/INN is supplied as a free-acid anthelmintic active pharmaceutical ingredient for veterinary finished-product manufacture. The material is controlled for assay, loss on drying, residue on ignition, residual solvents under VICH GL18, and elemental impurities under ICH Q3D; particle-size distribution is agreed in the API specification because it governs downstream content uniformity in low-moisture blends and aqueous dispersions. The following application scenarios are restricted to registered or published downstream routes: oral aqueous drench suspension, medicated feed premix/granule, injectable solution, compressed tablet/intraruminal bolus, and hard gelatin capsule pilot formulations. Process descriptions refer to production-scale equipment behaviour; no unregistered companion-animal or human indications are included.
| Application route | Closantel base addition basis | Critical production control | Primary compliance anchors |
|---|---|---|---|
| Oral aqueous drench suspension | 50 g/L for 50 mg/mL label claim | D90 ≤15 µm; viscosity 80–150 mPa·s at 20°C | Ph. Eur. 2.9.5, 5.1.4; VICH GL18 |
| Medicated feed premix / granule | 1.0% w/w at 10 mg/g; 25.0% w/w at 250 mg/g | Roller compaction 8–12 MPa; granule 1.0–1.5 mm | Regulation (EU) 2019/4; Ph. Eur. 2.9.40; VICH GL11 |
| Injectable solution | 50 g/L closantel base as sodium salt equivalent | 0.22 µm filtration; sterility and endotoxin control | Ph. Eur. 5.1.1, 2.6.1, 2.6.14, 2.9.19 |
| Compressed tablet / bolus | 45.0% w/w in dry granule | Wet granulation; loss on drying 1.5–2.5% w/w | Ph. Eur. 2.9.3, 2.9.5, 2.9.7; USP <905> |
| Hard gelatin capsule pilot batch | 20.0% w/w, 200 mg per size 0 shell | Relative humidity 40–50%; mixing 25 rpm for 15 min | Ph. Eur. 2.9.1, 2.9.5 |
Within aqueous oral drench suspension manufacture for ovine and bovine fluke exposure, closantel base is incorporated as a dispersed hydrophobic solid rather than a dissolved solute. The API is first screened through a 150 µm stainless-steel sieve and discharged into a high-shear disperser containing purified water, a wetting agent such as polysorbate 80 at 0.2% w/v, and a suspending agent such as xanthan gum at 0.3% w/v; this pre-mix is recirculated through a colloid mill with a rotor-stator gap set between 100 µm and 300 µm until laser diffraction under ISO 13320:2020 indicates D90 ≤15 µm. The target oral dose of 10 mg/kg bodyweight is delivered by a 50 mg/mL suspension, corresponding to an API addition ratio of 50.0 g closantel base per litre of finished vehicle before any approved overage. Regulatory compliance for this scenario is anchored to Ph. Eur. 2.9.5 for uniformity of mass of single-dose preparations and Ph. Eur. 5.1.4 for the microbiological quality of non-sterile oral liquids, with residual solvents assessed under VICH GL18. Terminal finished product is a viscous oral drench in HDPE bottles or PET drench-gun packs. The main production-scale failure observed is nozzle blockage in pneumatic drench guns caused by particle agglomeration above 30 µm; this is controlled by maintaining viscosity between 80 mPa·s and 150 mPa·s at 20°C and by avoiding storage below 4°C, which accelerates crystal bridging on prolonged cycles.
The incorporation of closantel base into medicated feed premixes and oral granules for ruminants is governed by segregation mechanics in low-moisture blends. Closantel base is added to a ribbon blender or double-cone blender at a ratio calculated to produce a 10 mg/g medicated premix, which is subsequently diluted into final feed at 1–5 kg/tonne according to the prescribed dose of 10 mg/kg bodyweight. The API addition ratio in a 10 mg/g premix is 1.0% w/w; in a 250 mg/g intermediate premix for granulation, the ratio rises to 25.0% w/w. Under Regulation (EU) 2019/4 on medicated feed, homogeneous incorporation and cross-contamination control are mandatory; release testing follows Ph. Eur. 2.9.40 for uniformity of dosage units, and residue safety data are assessed under VICH GL11. Production uses dry granulation by slugging or roller compaction at roll pressure 8–12 MPa, with screen milling to 1.0–1.5 mm granules; this densification reduces dusting and improves flow through a rotary sachet filler. The terminal finished product is a medicated feed premix or granular oral product packed in 5–25 kg laminated bags. Line audits show that free-flowing base powder with bulk density below 0.35 g/mL produces unacceptable content uniformity after vibratory conveying; granulation with an atomized water or starch paste binder at 3–5% w/w is required to stabilise the blend.
For subcutaneous injection in cattle and sheep, the oral flukicide dose is halved to 5 mg/kg, and closantel base is converted into the water-soluble sodium salt during vehicle preparation. A 50 mg/mL injectable solution requires 50.0 g closantel base per litre of Water for Injection, with one molar equivalent of sodium hydroxide or pre-formed closantel sodium used under nitrogen blanketing; the final solution is adjusted to target pH with dilute hydrochloric acid or sodium hydroxide and made isotonic with sodium chloride 8.5 g/L. Compliance for this route includes Ph. Eur. 5.1.1 for methods of preparation of sterile products, Ph. Eur. 2.6.1 for sterility, Ph. Eur. 2.6.14 for bacterial endotoxins, and Ph. Eur. 2.9.19 for sub-visible particulate matter. Downstream processing uses a 316L stainless-steel jacketed vessel at 40–50°C, a 0.22 µm PVDF sterilizing filter, and terminal autoclaving at 121°C for 15 minutes only where product-specific stability data support; otherwise aseptic filtration followed by filling in amber Type II glass vials under Grade A unidirectional airflow is used. The terminal finished product is an injectable solution of closantel sodium equivalent to 50 mg/mL closantel base in 50 mL, 100 mL, and 250 mL vials. The primary production bottleneck is post-filling precipitation caused by dissolved CO₂ ingress when vent filters are replaced without integrity testing; a 0.22 µm hydrophobic PTFE vent filter with water intrusion pressure above the filter manufacturer’s minimum and fill-line nitrogen purging prevents pH drift. Sterile filtration at 50 mg/mL requires product temperature above 30°C to prevent recrystallization in the filter housing; published data for this specific configuration are limited, so filter validation must be product-specific.
Compressed tablet and intraruminal bolus dosage forms for closantel base are produced by wet granulation because direct compression of the hydrophobic API yields unacceptable capping at tablet hardness above 8 kp and high ejection forces above 15 kN. A typical tablet batch is formulated with closantel base at 45.0% w/w, microcrystalline cellulose at 25.0% w/w, lactose monohydrate at 20.0% w/w, croscarmellose sodium at 4.0% w/w, and povidone K30 at 6.0% w/w in the granulating solution; this yields a 450 mg/g active blend that is compressed into 1.0 g tablets containing 450 mg closantel, suitable for dose-banding in sheep and young cattle. Process controls follow Ph. Eur. 2.9.5 for mass uniformity, Ph. Eur. 2.9.3 for dissolution, Ph. Eur. 2.9.7 for friability, and USP <905> for dosage unit uniformity. Granulation is conducted in a high-shear granulator at impeller 300 rpm and chopper 1500 rpm, followed by fluid-bed drying to a loss on drying target of 1.5–2.5% w/w and compression on a rotary tablet press with main compression force 16–20 kN and pre-compression force 4–6 kN. The terminal finished product is a non-sterile oral tablet or intraruminal bolus in aluminium-PVC blisters. Observed line failures include punch filming due to magnesium stearate over-lubrication beyond 1.0% w/w and tablet edge erosion when friability exceeds 0.8% after 100 rotations in the Ph. Eur. 2.9.7 friability apparatus. Below 1.0% w/w loss on drying the granules become static and adhere to the tablet press feeder, causing weight variation above 3.0% RSD.
Hard gelatin capsule presentation of closantel base is limited to pilot bioavailability and dose-linearity studies rather than commercial registration in most jurisdictions. The API is dry-blended with anhydrous lactose and sodium starch glycolate at 20.0% w/w closantel base, corresponding to 200 mg API per size 0 capsule shell, after pre-milling through a 150 µm screen. Capsule manufacturing uses an orbital motion mixer at 25 rpm for 15 minutes, then an intermittent-motion capsule filler with dosator or tamping pin configuration; the filled capsules are checked for weight variation under Ph. Eur. 2.9.5 and disintegration under Ph. Eur. 2.9.1. The terminal finished product is a size 0 hard gelatin capsule for single-dose oral administration to sheep or cattle in pharmacokinetic investigations. Published data for this specific configuration are limited; the disintegration time of the capsule shell is specified by the capsule vendor and must be confirmed in the finished product at 37°C in water. The main operational constraint is static charging of the micronized API on the gelatin shell when relative humidity exceeds 60%; pre-conditioning the capsules at 40–50% RH and adding 0.5% w/w colloidal silicon dioxide prevents flow stoppage in the dosator bowl. Batch reconciliation for capsule runs of 5,000–20,000 units must account for API loss to the dust collection system; extraction loss above 0.2% w/w invalidates content uniformity assumptions and requires revalidation of the containment cassette.
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Closantel Base IH/INN Pharma Grade API is the crystalline free-acid form of closantel, assigned CAS 57808-65-8 and the molecular formula C22H14Cl2I2N2O2 with a nominal molecular mass of 663.07 g·mol−1. The material is produced under an active pharmaceutical ingredient quality system aligned with ICH Q7 and is released with a certificate of analysis addressing appearance, infrared identification, assay by liquid chromatography, related substances, residual solvents, water content, residue on ignition, and particle-size distribution. The product is specified under the INN designation “closantel” and supplied as the base form for formulators requiring either direct incorporation into lipid-based oral vehicles or controlled in situ conversion to the sodium salt for aqueous injectable preparations. The distinction between the base and closantel sodium is a critical formulation boundary: the free base shows low aqueous solubility across the physiological pH range and therefore demands particle-size reduction, wetting agents, or conversion to the salt form to meet dissolution specifications in tablets, capsules, and granules.
Closantel base is not directly soluble in water at neutral pH; aqueous injectable solutions typically require the sodium salt, which is formed by reacting the free acid with sodium hydroxide under controlled pH. At production scale, this reaction is carried out in glass-lined or stainless-steel compounding vessels fitted with pH probes and conductivity cells. Incomplete neutralisation leaves undissolved base crystals that can produce filter-pressure excursions on 0.22 µm sterilising-grade polyethersulfone membrane filters. Over-neutralisation beyond the stoichiometric endpoint generates a strongly alkaline environment that stresses the salicylanilide amide linkage; manufacturing records therefore document the molar addition of alkali against a narrow alkaline endpoint defined during process development, with post-neutralisation hold times minimised to avoid prolonged exposure. The base form is more appropriate for non-aqueous injectable preparations where water content is controlled below the limit set by the finished-product specification and where the chosen carrier maintains the free acid in solution. Published data for this specific configuration of base-form parenteral solutions is limited; feasibility batches should therefore establish filter compatibility, sterility assurance, and chemical stability before routine manufacture.
For tablet and capsule manufacturing, the flow and compaction behaviour of the base form are influenced by the primary particle size and morphology generated during final purification. Air-jet milling is employed when a finer particle-size distribution is required for dissolution-rate control; pin milling under nitrogen is used for heat-sensitive batches. The resulting powder is typically blended in a bin blender with diluents such as microcrystalline cellulose and lactose monohydrate, followed by dry granulation in a roller compactor where roll gap, hydraulic pressure, and screen size are recorded as in-process controls. In direct compression trials on instrumented rotary tablet presses, force feeders are engaged to prevent bridging and to maintain die-fill uniformity. Weight variation and content uniformity are assessed according to the finished product specification; if the base is incorporated at high dose fraction, segregation risk increases with differences in particle density, and dry granulation is preferred over direct compression. Capsule filling on dosing-disc or tamping-pin machines requires strict control of powder bulk density because the free-flowing nature of the milled base can produce dose-weight variance if not preconditioned by granulation.
Wet granulation of closantel base requires a binder solution that does not introduce excessive moisture because the base has limited aqueous solubility but may be sensitive to high-shear thermal input during drying. A fluid-bed granulator equipped with inlet air dew-point control and a loss-on-drying checkpoint is used to achieve granule moisture below the limit set in the process validation protocol. Dry granulation is an alternative when the formulation contains moisture-labile excipients or when the API particle-size distribution is already fine enough to support dissolution; the roller-compacted ribbon is milled to a defined granule size, and the granule hardness is checked by sieve analysis and bulk density. The selection between wet and dry granulation is documented through manufacturability runs on the same equipment intended for commercial batches; more than one granulation route is not assumed to be interchangeable without equivalence data. Tablet hardness, friability, disintegration, and dissolution are then measured by USP methods ⟨711⟩ and ⟨701⟩, or the corresponding pharmacopoeial monographs of the target market.
In veterinary parenteral therapy, closantel injectable presentations are commonly formulated from the sodium salt because aqueous solutions facilitate high-volume administration in cattle and sheep. If the base is specified for an injectable product, the formulator must either generate the sodium salt during compounding or select a non-aqueous vehicle in which the free acid is chemically stable and filterable. Terminal sterilisation is favoured over aseptic processing when the formulation permits; steam sterilisation cycles are validated with biological indicators and heat penetration studies in the actual container-closure system. Container compatibility is tested under ICH Q1A(R2) conditions for photostability and thermal stress in glass vials or polymer bottles. The base form may also be used in oral drench concentrates that are subsequently diluted before administration; in such concentrates, the API may be dissolved in a non-aqueous solvent system with surfactants, and phase separation during storage is monitored by visual inspection and particle-size analysis. Because closantel is not approved for human use in most jurisdictions, veterinary maximum residue limits and withdrawal periods are part of the regulatory dossier; the relevant pharmacopoeial and VICH GL11 data govern impurity qualification.
Release testing for the base API includes identification by infrared absorption and HPLC retention time, assay by a stability-indicating reversed-phase HPLC method with UV detection at a wavelength appropriate for the salicylanilide chromophore, related substances by area-normalisation or external standard, residual solvents by headspace gas chromatography, residue on ignition by Ph. Eur. 2.4.14, and water content by Karl Fischer titration. The impurity profile of closantel base is influenced by the synthetic route and the final recrystallisation solvent; residual solvent limits are aligned with ICH Q3C classes. For oral and injectable dosage forms, the particle-size distribution is tested by laser diffraction and is reported as D10, D50, and D90. The base must be protected from direct sunlight and stored in a tightly closed container at controlled room temperature; long-term and accelerated stability protocols follow ICH Q1A(R2) and are evaluated for assay loss, related substance increases, and packaging leachables where relevant.
| Parameter | Method | Typical criterion |
|---|---|---|
| Appearance | Visual inspection | White to faintly cream crystalline powder |
| Identification | IR absorption / HPLC retention time | Conforms to reference standard |
| Assay | Stability-indicating HPLC | 98.0%–102.0% on dried basis |
| Related substances | HPLC area normalisation | Individual unknown ≤0.50%; total ≤1.00% |
| Water content | Karl Fischer titration | ≤0.5% w/w |
| Residue on ignition | Ph. Eur. 2.4.14 | ≤0.10% w/w |
| Residual solvents | Headspace GC | ICH Q3C limits |
| Particle size | Laser diffraction | As agreed for dosage form route |
Within the salicylanilide anthelmintic class, closantel base acts as a proton ionophore that uncouples oxidative phosphorylation in susceptible helminths. This mechanism differs fundamentally from that of benzimidazole anthelmintics such as albendazole and fenbendazole, which inhibit β-tubulin polymerisation, and from the macrocyclic lactones used widely in cattle and sheep, which potentiate glutamate-gated chloride channels. Within the salicylanilide group, closantel is distinguished from oxyclozanide and rafoxanide by its substitution pattern and resulting lipophilicity; the high lipophilicity supports plasma protein binding reported to exceed 98% in sheep and a prolonged plasma residence time after oral or parenteral administration. This persistence contributes to sustained activity against liver fluke (Fasciola hepatica), blood-sucking nematodes such as Haemonchus contortus, and certain larval arthropods including Oestrus ovis. The formulation and dosage form therefore influence systemic exposure and withdrawal period; oral suspensions and injectable solutions are not interchangeable on a simple milligram-per-kilogram basis without comparative pharmacokinetic data in the target species.
| Property | Closantel base | Closantel sodium |
|---|---|---|
| Aqueous solubility | Low; requires micronization or non-aqueous vehicle | Soluble in water to yield alkaline solution |
| Preferred dosage forms | Tablets, capsules, granules, non-aqueous injectables | Aqueous injectables, oral drench concentrates |
| Particle-size control | Critical for dissolution | Less critical for injectable solution if fully dissolved |
| pH dependence | Neutral species; low solubility at physiological pH | Ionized salt; solution pH alkaline |
| Sterile filtration | Requires complete dissolution or conversion | Filterable after salt formation |
In continuous solid-dosage lines, the base API may be fed from loss-in-weight feeders into a twin-screw granulator or continuous direct compression unit. Near-infrared spectroscopy is used to monitor blend uniformity and water content in real time; the calibration set must include the crystalline base form and the selected excipients across the planned concentration range. Raman spectroscopy can be deployed to confirm the absence of the sodium salt when the base is the intended chemical form, because the two forms differ in their salt-related vibrational bands. Residence time distribution is characterised for the continuous blender and dryer using tracer studies; feed-frame height and screw speed are recorded to link raw material lot changes to finished dosage form dissolution. The use of process analytical technology does not eliminate the need for end-product testing but allows real-time release under a validated control strategy. The equipment train should be qualified under ISO 14644-1 for open powder handling areas and should include metal-detection and magnetic separation stages to protect downstream tablet tooling from incidental metal contamination.
Bulk packaging of the base API typically uses double low-density polyethylene liners inside a fibre drum with a desiccant, and the label states the storage condition as controlled room temperature. The base is not classified as hygroscopic, but high-humidity processing environments above 60% RH may require pre-conditioning or moisture-barrier packaging if the final blend contains hygroscopic excipients. The product is incompatible with strong oxidising agents and with prolonged exposure to strong alkali at elevated temperature; such conditions are avoided in granulation, drying, and sterilisation steps. Stability data generated under ICH Q1A(R2) conditions support retest dating, and any change in the final salt form or particle-size specification triggers revalidation because the base and sodium salt are not bioequivalent without demonstration.
