Manufacturing an aqueous oral suspension of toltrazuril for piglet or calf drench administration begins with particle-size reduction of the crystalline API. Because toltrazuril is practically insoluble in water at neutral pH, the rate of redispersion and the uniformity of the withdrawn dose depend more on the specific surface area and wetting of the micronised solid than on dissolution kinetics. A typical liquid oral product is formulated at 50 mg/mL toltrazuril, using a wetting agent such as polysorbate 80 at 0.05–0.5% w/w, a hydrophilic suspending polymer, and a buffered vehicle held between pH 5.0 and pH 6.0 to minimise hydrolysis of the triazinetrione ring. On a production-scale high-shear mixer, the wetted API is incorporated into the aqueous phase under vacuum or low-speed sweep agitation to avoid air entrainment. The primary process conflict is transfer of the finished suspension through filling lines: if the milled particle size shifts from the validated D50 band, the suspension may become too viscous for the piston filler and may show caking in the neck of the multi-dose bottle. Laser diffraction data in accordance with ISO 13320:2020 are therefore maintained on every API lot, and any lot with a D90 above the validated upper limit is rejected for liquid suspension use. Batch records must also document the hydration temperature of the suspending polymer, because incomplete hydration at the beginning of mixing produces a yield stress that is not stable during the filling campaign.

The finished oral suspension is held in HDPE or amber glass multi-dose containers with a dosing pump or an oral syringe. In-use stability is a critical risk: repeated opening of the container under farm conditions can cause water evaporation in hot climates, raising the concentration per unit volume and destabilising the flocculated network. For this reason, the development programme includes an in-use stability study at 25 °C/60% RH and 30 °C/65% RH for 28 days after first opening, with sampling for toltrazuril content, pH, and redispersibility. The product is released only after passing uniformity of mass of delivered doses under Ph. Eur. 2.9.27 and uniformity of content under Ph. Eur. 2.9.40. The terminal finished product is a non-sterile oral suspension for drench administration in suckling piglets and calves, with the label instructing withdrawal periods in accordance with Commission Regulation (EU) No 37/2010 and the residue marker toltrazuril sulfone.

What Limits Blend Uniformity in Low-Dose Toltrazuril Premix Granules?

When toltrazuril is incorporated into a feed premix at a concentration of 0.5% w/w or lower, the first process bottleneck is pre-blending of a micronised API with a carrier such as lactose monohydrate or calcium carbonate. The API is cohesive and electrostatically charged after jet milling; simple ribbon blending without a binder can produce stratified zones if the blender is loaded above 70% of its working volume. Production-scale experience shows that batch-to-batch variation in blend uniformity is correlated less with total mixing time than with the order of addition: the API should first be triturated with an equal mass of carrier through a 500 µm sieve, then stepwise diluted to 1:10 before being added to the main blender. This geometric dilution sequence reduces the risk of agglomerates that pass the final sieve but are not representative of label content. Blend uniformity is assessed by sampling at least 10 locations with a thief sampler, and the finished premix should meet an RSD of 5.0% or less by HPLC. If the carrier has a moisture content above 2.0% w/w, the API can adhere to the blender walls and create dead zones that are not removed by extended mixing; therefore, carrier loss on drying is controlled before use.

For granulated premix, a fluid-bed spray granulator is preferred over a high-shear mixer when the formulation contains heat-labile carriers or vegetable oil. The binding liquid, typically purified water or a povidone K30 solution at 1–5% w/w, is sprayed at a rate that maintains the bed outlet temperature below 45 °C. The critical granule attribute is not size alone but the distribution of toltrazuril across sieve fractions: if the active substance migrates to the fine fraction, segregation in the final feed bin will cause underdosing in the first discharge and overdosing in the last. A sieve analysis in accordance with Ph. Eur. 2.9.12 is used, and the fraction between 150 µm and 850 µm is tested for content uniformity. The final diluted feed is prepared by the feed mill to deliver the approved mg/kg body weight daily dose; for poultry, this is commonly 7 mg/kg body weight per day for two consecutive days when specified by the licence. The terminal product is a non-sterile premix granule for incorporation into final feed, with batch records documenting the sequence and flushing of the mixer.

Fixed-dose tablets and capsules are not the most common toltrazuril presentations, but they are manufactured for small-animal or exotic species markets where a precision per-kilogram dose must be given without water logistics. Dry granulation is required because toltrazuril API is poorly flowing and low in bulk density; direct compression at a target tablet weight of 150–500 mg almost always fails weight control when the drug load is below 5% w/w due to segregation and feed shoe flooding. The API is first blended with a directly compressible filler, a disintegrant such as croscarmellose sodium at 2–4% w/w, and a glidant such as colloidal silicon dioxide at 0.2–0.5% w/w. The blend is then passed through a roller compactor with a roll gap of 2–3 mm and a roll surface pressure of 50–100 bar; the ribbons are milled through a 1.0 mm screen to yield granules with a target D50 of 250–500 µm. Lubrication with magnesium stearate at 0.25–0.75% w/w follows granulation rather than preceding it to avoid reduced tablet tensile strength. The final compression is run on a rotary tablet press with a turret speed of 20–40 rpm and a compression force of 8–15 kN; the tablets are checked for friability according to Ph. Eur. 2.9.7, with a maximum mean mass loss of 1.0% after 100 revolutions.

Capsule filling uses the same granulate but without final lubricant if a dosator-type machine is used; for tamping-pin machines, a small concentration of sodium stearyl fumarate may be selected as an alternative lubricant. The content uniformity risk is highest in capsules because the granule partition between body and cap during high-speed filling can be affected by granule electrostatic charge. The filled capsules are released on uniformity of content under Ph. Eur. 2.9.40 and disintegration under Ph. Eur. 2.9.1 with a limit of 15 minutes in water at 37 °C. Published product-specific dissolution data for toltrazuril capsules are limited; a validated dissolution method should therefore be developed using a discriminating medium such as 0.1 M hydrochloric acid with a surfactant, and the Q value must be justified by batch data rather than a compendial default.

Sterility Assurance and Particle Burden in Aqueous Injectable Presentations

When a parenteral toltrazuril preparation is manufactured for neonatal livestock, the central technical constraint is that toltrazuril is practically insoluble in water, so the product is a sterile suspension rather than a true solution. This has direct consequences for terminal sterilisation selection: the suspension cannot be sterile-filtered after milling, and moist-heat sterilisation at 121 °C for 15 minutes may alter the suspension flocculation state if the wetting agent is not selected for thermal stability. The formulation therefore uses a thermostable non-ionic surfactant, a buffer, sodium chloride for isotonicity, and a preservative-free vehicle because the product is single-dose. The API is wet-milled under aseptic conditions to a particle size compatible with syringeability through a 18–20 G needle, but not so fine that Ostwald ripening occurs in the vehicle. Sterility is evaluated by the membrane filtration method in Ph. Eur. 2.6.1 or USP <71>, and bacterial endotoxin is controlled by Ph. Eur. 2.6.14 with a limit tied to the maximum labelled dose per kilogram.

Manufacture may follow either aseptic processing of sterile API and vehicle or terminal sterilisation after filling; the aseptic route is chosen only when thermal degradation data show unacceptable assay loss above 100 °C. On a production filling line, the suspension must be continuously recirculated or stirred to prevent sedimentation during the filling campaign, but shear from the recirculation pump can cause particle attrition and a shift in the particle size distribution. The filling pump is validated at each campaign with in-process checks of fill volume every 15 minutes and a final check of deliverable volume under Ph. Eur. 2.9.17. Because injectable toltrazuril is less common than oral presentations, published product-specific stability data for this configuration are limited; the manufacturer should generate real-time and accelerated stability data at 25 °C/60% RH and 40 °C/75% RH for the intended market. The terminal product is a sterile suspension for subcutaneous or intramuscular administration in a single-dose glass vial sealed with a bromobutyl rubber stopper, protected from light.

When a Drinking Water Product is Diluted on Farm at 20 mg/kg Body Weight

For poultry and pig drinking water applications, toltrazuril is commonly supplied as a concentrated oral solution or suspension at 25–50 mg/mL, which is diluted into the drinking water system at a rate calculated to deliver 7 mg/kg body weight per day for poultry and 20 mg/kg as a single dose for piglets, depending on the licence. The highest field failure mode is precipitation in the water line when the concentrated product is mixed with hard water containing high levels of calcium and magnesium salts. Under such conditions, the cosolvent system can lose its solvency when the local water pH is above 8.5, resulting in deposited API on the nipple drinker and underdosing. The product is therefore formulated with a pH modifier or a chelating agent such as disodium EDTA at 0.1–0.5% w/w to buffer the diluted solution and to sequester multivalent cations. Farm-scale mixing studies should include a 2-hour standing test using water from the target region, with visual inspection and HPLC assay of the top and bottom of the tank; if the assay difference exceeds 5.0%, the dilution strategy must be changed to a continuous dosing pump rather than a batch tank.

The drinking water product is packaged in HDPE bottles with a measuring cap. The label and compliance documentation must carry the withdrawal period from Commission Regulation (EU) No 37/2010, the marker residue toltrazuril sulfone, and a warning against use in animals producing milk for human consumption unless the approved withdrawal is observed. The terminal product is a concentrated liquid that is used in the drinking water line for two consecutive days in poultry, and the bottle is designed for a single campaign on the farm. The chemical stability of the diluted product is short; once diluted, it should be consumed within 24 hours and the stock solution should not be stored in galvanised metal containers, which can react with the acidified vehicle. The production batch is released after testing according to Ph. Eur. 2.9.40 for delivered dose uniformity from the measuring device, Ph. Eur. 2.2.3 for pH, and HPLC assay, with a maximum assay range of 95.0–105.0% of label claim.

In-feed powder and granule systems for coccidiosis control in poultry and swine are manufactured by adsorption of the active substance onto a carrier. Toltrazuril is first blended with a high-surface-area carrier such as precipitated silica or corn cob granules; the carrier is selected to reduce the active substance’s contact with atmospheric moisture and to provide a free-flowing premix for the final feed mill. The process is not a simple dilution: when the API is adsorbed onto silica at a ratio of 1:1 to 1:3, the resulting powder may show a bulk density below 0.35 g/mL, causing bridging in the feed mill dosing hopper. To prevent bridging, the diluted premix is compacted to a bulk density of 0.55–0.70 g/mL using a roller compactor or a low-shear granulator with a small amount of vegetable oil as a dust suppressant. The powder is then passed through a 850 µm sieve before packing. The granule should be stable in a feed that contains organic acids and mineral premixes; storage studies at 25 °C/60% RH and 40 °C/75% RH in the intended final feed are required because the acidified matrix can accelerate degradation. No additional overage is permitted unless the regulatory file authorises it, because the carry-over of coccidiostats into non-target feed is restricted under Regulation (EU) 2019/4 Article 7 and, where applicable, 21 CFR 558.4(b). The terminal product is a non-sterile powder or granule for incorporation into final feed at the mill, with batch records documenting the sequence and flushing of the mixer.