For immediate-release tablet manufacture, cenobamate pharma-grade API is handled as a low-solubility, low-dose active that requires particle-size bounding before dry blending. The API is delumped through a 0.710 mm sieve. A representative dry-blend framework uses microcrystalline cellulose NF as the main filler at 60%–80% w/w, croscarmellose sodium at 1%–3% w/w as disintegrant, colloidal silicon dioxide at 0.25%–1.0% w/w as glidant, and magnesium stearate at 0.5% w/w as lubricant. The cenobamate fraction can range from 5%–30% w/w depending on the dose-proportionate core mass between 12.5 mg and 200 mg. Particle-size distribution is monitored by laser diffraction per ISO 13320:2020. If the d90 exceeds 20 µm, dissolution rate may become unacceptable because the API has low aqueous solubility. Micronization can introduce amorphous surface domains. If amorphous content is not controlled, storage recrystallization may reduce dissolution rate. Published data for production-scale micronized cenobamate under controlled humidity is limited. Compression is carried out on a rotary tablet press with 9 mm round tooling. Main compression force is kept between 6 kN and 18 kN, and core breaking force is checked at 5–8 kp using USP <1217>. In-process weight and hardness sampling follows 21 CFR 211.110(b). Finished tablets are tested for content uniformity by USP <905> and dissolution by USP <711>. Film coating is applied in a perforated pan coater to a weight gain of 2%–4% w/w using a hypromellose-based system. The terminal product is a film-coated immediate-release tablet in 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg strengths. Tablet cores should not be stored above 60% RH without desiccant protection because moisture uptake can shift hardness and disintegration behavior.

What Happens to Blend Uniformity When Encapsulation Runs Exceed 30 Minutes at Low Fill Weight?

Capsule filling with cenobamate is most sensitive to blend segregation, electrostatic adhesion, and capsule shell moisture. Low-dose strengths of 12.5 mg, 25 mg, and 50 mg require ordered mixing rather than simple dilution. The API is first premixed with colloidal silicon dioxide at 0.25%–1.0% w/w to reduce cohesive adhesion to stainless steel surfaces. Microcrystalline cellulose and pregelatinized starch may be combined in a filler ratio of 70:30 to improve powder flow without excessive capsule plug weight. Croscarmellose sodium is added at 2%–4% w/w and magnesium stearate at 0.5% w/w. Blend uniformity is assessed using stratified sampling and HPLC with acceptance at ≤5.0% RSD. Capsule shell equilibrium moisture is held between 13%–16% w/w to prevent brittleness and embrittlement on the filling line. Filling is performed on a dosator or tamping-pin capsule filler at 20°C–25°C and 30%–40% RH. Fill weight is controlled between 75 mg and 400 mg depending on capsule size and strength. The filled capsules are tested for weight variation and content uniformity per USP <905> and disintegration per USP <701> where applicable. Dissolution is measured using USP <711> apparatus at controlled agitation. Because the API is low-solubility, capsule formulations are more vulnerable to delayed release if the powder bed is compressed inside the capsule and the disintegrant is poorly distributed. Terminal products are hard gelatin or HPMC capsules containing 25 mg or 50 mg cenobamate in a dry-blend matrix. Production batches should avoid encapsulation run times beyond 30 min without re-verification of hopper blend uniformity because vibration-induced segregation occurs with free-flowing direct-fill blends.

Granulation for oral suspension sachets is adopted when direct compression and dry capsule filling cannot deliver dose-proportionate content uniformity below 2% RSD at the 12.5 mg dose. The granulation vehicle is built by dissolving hypromellose or povidone K30 in purified water at 5%–10% w/w. Binder solution viscosity is held between 5 mPa·s and 50 mPa·s at 25°C. The API is dispersed in a pre-mix containing mannitol and microcrystalline cellulose. Granulation is performed in a top-spray fluid-bed granulator with a 1.2 mm two-fluid nozzle. Inlet air temperature is set at 40°C–60°C, and spray rate is adjusted to maintain product temperature below 35°C. Droplet size is controlled to D50 10–30 µm to avoid over-wetting. Drying continues until loss on drying reaches 1.0%–3.0% w/w, measured by a halogen moisture analyzer at 105°C. Dried granules are passed through a 0.850 mm screen. The retained fraction above 0.850 mm is remilled. Granule tap density is held between 0.45 g/mL and 0.65 g/mL. The terminal product is a powder blend filled into aluminum foil sachets at dose weights equivalent to 25 mg or 50 mg cenobamate per sachet. Reconstitution in 5 mL to 20 mL water gives an oral suspension for immediate administration. The granules are tested for moisture content, sieve distribution, and dose uniformity by USP <905>. Dissolution of the suspension powder uses USP <711> apparatus with pH-shifted media. Processing above 60% RH requires pre-drying of mannitol and microcrystalline cellulose because moisture-activated binder surface migration can create hard granule shells and slow release.

Fluid-Bed Granulation Endpoint, Inlet Dewpoint, and Moisture Transfer Limitations

The endpoint of cenobamate wet granulation is not determined by time alone. A fixed outlet air temperature and a fixed pressure drop across the product bed are required to produce reproducible granule porosity. The fluid-bed inlet dewpoint is maintained below 4°C when processing humidity-sensitive excipients. If the dewpoint exceeds this value during top-spray granulation, droplet drying capacity is reduced and localized over-wetting occurs. This creates dense agglomerates with low intragranular porosity. Such agglomerates may survive disintegration testing but delay API release. The granulation endpoint is defined by a target product moisture of 1.5%–2.5% w/w and a granule fraction between 0.150 mm and 0.850 mm of ≥85% w/w. Process analytical technology may use near-infrared moisture probes calibrated to loss-on-drying reference values. Granule friability is assessed by rotating 10 g of granules with glass balls in a 100 mL flask and measuring the increase in ≤0.150 mm fines. Terminal granules are filled into sachets under 35% RH or less. The sachet should include a desiccant unless the granule matrix has been designed to maintain stability up to 25°C/60% RH. These operational limits apply because moisture transfer into granule pores changes both flowability and dissolution rate over the product shelf life.

Injectable Presentations Are Constrained by pH-Solubility Behaviour and Terminal Sterilization Limits

Injectable cenobamate remains a preformulation route rather than an established commercial product. The API is practically insoluble in water, so a simple Water for Injection vehicle cannot supply therapeutic concentrations. Published data on the solubility and stability of cenobamate in parenteral cosolvent systems is limited. The first technical step is pH-solubility profiling under shake-flask conditions across pH 1.0–8.0 at 37°C. If pH adjustment alone cannot reach the target concentration, nonaqueous cosolvents such as PEG 300 or propylene glycol are added at 10%–40% w/v. Surfactant-based systems using polysorbate 80 are limited by hemolytic potential and should be evaluated below 1.0% w/v for parenteral use. Terminal autoclaving at 121°C for 15 min is acceptable only if forced degradation demonstrates no carbamate hydrolysis or ring-opening products. Otherwise, aseptic filtration through a 0.22 µm polyethersulfone filter is required. The fill environment is controlled to ISO Class 5 per ISO 14644-1:2015. Sterility assurance follows current pharmacopeial methods. Bacterial endotoxins are tested by USP <85>, with the limit calculated from route and dose using a bolus threshold of 5 EU/kg for parenteral products. Particulate matter is controlled by USP <788> and visible inspection by USP <790>. If the solution cannot meet the required chemical and physical stability at final concentration, a lyophilized powder for reconstitution in 10 mL to 20 mL diluent is the next technical option. Any injectable development must be supported by ICH Q3D elemental impurity data and pre-clinical toxicology bridging, because the current clinical safety database is established for oral administration, not injection.