Compression behaviour of low-dose dexamethasone tablet blends

Companion-animal dexamethasone tablets are manufactured with dexamethasone base dispersed by geometric dilution into a lactose monohydrate and microcrystalline cellulose matrix. The addition ratio is typically 0.25% w/w for a 0.25 mg active core at 100 mg core mass, 0.3125% w/w for a 0.5 mg tablet at 160 mg core mass, and 0.30–0.50% w/w for 0.75 mg and 1.5 mg strengths depending on final core weight. Wet granulation with 5.0% w/w polyvinylpyrrolidone K30 in purified water is used when direct compression shows API segregation; granulate is dried in a fluid-bed dryer at inlet air 60–65 °C until loss on drying reaches 1.5–2.5% w/w, then milled through a 1.0 mm screen. Tableting is performed on a rotary press with 8–10 mm flat-faced bevel-edge punches at compression force 8–14 kN, target hardness 40–70 N, and friability not more than 0.8% per USP <1216>. Batch release includes content uniformity per USP <905> and dissolution per USP <711>; the product falls under FDA 21 CFR 520.540 where applicable, and residual solvent testing aligns with VICH GL18. Terminal finished product types are 0.25 mg, 0.5 mg, 0.75 mg, and 1.5 mg tablets in aluminium/PE blister packaging. Dexamethasone base is photosensitive and alkali-labile, so direct compression blends and finished tablets must be stored below 60% RH and protected from light; prolonged contact with strong mineral acids or alkalis is to be avoided.

What limits terminal sterilisation of dexamethasone sodium phosphate injection fluids?

In sterile injectable manufacture, dexamethasone sodium phosphate is selected over dexamethasone base because of its water solubility; the addition ratio is 2.0 mg/mL dexamethasone sodium phosphate, equivalent to approximately 1.52 mg/mL dexamethasone base, or 0.2% w/v as the phosphate ester. Tonicity is adjusted with 0.9% w/v sodium chloride, and pH is maintained between 7.0 and 8.5 using hydrochloric acid or sodium hydroxide. Multi-dose vials may contain 0.18% w/v methylparaben and 0.02% w/v propylparaben; single-dose vials omit preservatives to reduce incompatibility. The solution is prepared in nitrogen-sparged Water for Injection at 15–25 °C, then filtered through a 0.22 µm PVDF membrane and filled aseptically into Type I glass vials. Terminal steam sterilisation is generally avoided because the phosphate ester undergoes accelerated hydrolysis above 121 °C; if a validated 115 °C saturated-steam cycle is evaluated, published data for this specific configuration remains limited, and aseptic filtration is preferred. Release testing requires sterility per USP <71>, bacterial endotoxins per USP <85>, particulate matter per USP <788> and USP <790>, and residual solvents per VICH GL18. Terminal finished product types include 2 mg/mL dexamethasone sodium phosphate injection in 10 mL, 50 mL, and 100 mL vials. Strong oxidising agents and alkaline buffers above pH 8.5 must be avoided during compounding.

Capsule filling with dexamethasone base begins with a trituration step in which the API is ground with an equal portion of lactose monohydrate and passed through a 200-mesh screen before being geometrically diluted with the remaining capsule filler. The addition ratio for 0.5 mg strength is 0.357% w/w at a 140 mg fill weight, and for 1.0 mg strength is 0.5% w/w at a 200 mg fill weight. The blend is filled into size 3 or size 4 hard gelatin or hypromellose capsules on a dosator-type capsule filling machine operating at 60,000–100,000 capsules/h; relative humidity is held below 45% RH to prevent gelatin embrittlement and API moisture uptake. In-process controls include fill weight uniformity at ±3% and capsule disintegration per USP <701>; finished product release follows content uniformity per USP <905> and dissolution per USP <711>. Compliance is supported by VICH GL11 for impurity control and VICH GL18 for residual solvents under the veterinary medicinal product framework of Regulation (EU) 2019/6. Terminal finished product types are 0.5 mg and 1.0 mg capsules packed in HDPE jars with silica gel desiccant and induction-sealed caps. Dust generation during the trituration step must be controlled with closed transfer and local exhaust ventilation; wet granulation of this low-dose blend is not required because content uniformity is maintained by geometric dilution rather than intra-granule binding.

A water-soluble dexamethasone sodium phosphate granulate for poultry and swine drinking water is manufactured by top-spray fluidised-bed granulation, with the API dissolved in the binder solution before spraying to avoid separation during drying. The addition ratio is 0.10% w/w dexamethasone sodium phosphate, with 5.0% w/w polyvinylpyrrolidone K30 as binder, 0.5% w/w citric acid anhydrous and 0.2% w/w sodium citrate dihydrate as pH stabilisers, and lactose monohydrate q.s. to 100%. Granulation is conducted at inlet air temperature 60–70 °C, product temperature 30–40 °C, atomising air pressure 2.0–3.0 bar, and spray rate 10–30 g/min on a laboratory or pilot-scale fluid-bed. The dried granulate is sieved to 20–60 mesh and must have loss on drying not more than 2.0% w/w; moisture above 3.0% w/w accelerates dexamethasone sodium phosphate hydrolysis and causes caking in multi-dose packaging. Compliance for food-producing species requires adherence to residue limits under Commission Regulation (EU) No 37/2010, and the granulate is manufactured under Regulation (EU) 2019/6 with residual solvent testing per VICH GL18. Terminal finished product types include 1 kg foil sachets and 10 kg HDPE drums containing water-soluble powder or granulate intended for in-line drinking water proportioning; the final diluted solution must be used within 24 h after mixing. Contact with copper or iron dosing equipment should be avoided because transition metal ions can catalyse oxidative degradation of the corticosteroid side chain.

Rumen-stable feed premix carrier systems and stepwise dilution

Medicated feed premixes containing dexamethasone base are confined to jurisdictions where therapeutic use in food-producing species is explicitly authorised and a valid veterinary prescription exists. The premix addition ratio is 1.0 g/kg dexamethasone base, equivalent to 0.1% w/w, on a carrier of wheat bran pre-dried to 10–12% moisture and protected with 0.5% w/w colloidal silicon dioxide as a flow and anti-dust agent. Stepwise dilution is performed in a horizontal ribbon mixer: the dexamethasone base is first blended 1:10 with colloidal silicon dioxide and a portion of ground limestone, then diluted 1:10 again with wheat bran, and finally incorporated into the full 1,000 kg batch at mixer speed 20–25 rpm for 12–15 min; blend uniformity must achieve a relative standard deviation of not more than 5.0% at 10 sampling points. Over-mixing beyond 25 min has been observed on production-scale ribbon mixers to increase fines and reduce carrier-flow consistency, so mixing time is controlled by batch record. Final feed inclusion rates are determined by species-specific prescribing and national residue-control programmes; the product is regulated under Regulation (EU) 2019/4 for medicated feed and Commission Regulation (EU) No 37/2010 for pharmacologically active substances in food-producing animals. Terminal finished product types include 25 kg multi-wall paper bags with a polyethylene liner and 1,000 kg bulk tote bags for integrated feed mills. Dexamethasone base should not be pre-mixed with strongly alkaline or acidic mineral carriers, and the finished premix must be stored below 25 °C in dry, light-protected conditions.

Oral solution batches for equine and small-animal dispensing are prepared by dissolving dexamethasone sodium phosphate in purified water with 20% w/v sorbitol solution 70% non-crystallising and 10% w/v glycerin to provide viscosity and sweetness without sucrose fermentation. The addition ratio is 0.1 mg/mL dexamethasone base equivalent, corresponding to 0.01% w/v, while a 0.5 mg/mL strength corresponds to 0.05% w/v. The pH is adjusted to 7.0–7.5 with a phosphate buffer, and antimicrobial preservation is achieved with 0.1% w/v potassium sorbate and 0.05% w/v sodium benzoate; the formulation is protected from photo-oxidation by nitrogen sparging before filling. Dissolution is performed in a stainless-steel jacketed vessel with overhead agitation at 300 rpm, the API being predissolved in 10% of the final volume before addition to the bulk solution. The bulk is filtered through a 5 µm polypropylene cartridge and filled into amber Type III glass bottles of 100 mL and 250 mL. Release testing includes pH, assay, antimicrobial preservation per Ph. Eur. 5.1.3, sterility per Ph. Eur. 2.6.1 where required, and residual solvents per VICH GL18. Terminal finished product types are preserved oral solutions of 0.1 mg/mL and 0.5 mg/mL dexamethasone base equivalent for syringe or bottle dosing. The product should not be frozen, and pH drift above 8.0 during storage increases hydrolytic degradation of the phosphate ester.

When a 0.1% ophthalmic suspension is compounded from micronized dexamethasone

Micronized dexamethasone base, rather than the sodium phosphate ester, is used in veterinary ophthalmic suspension because the base remains mostly undissolved and prolongs corneal contact time. The addition ratio is 0.1% w/v dexamethasone base, or 1.0 mg/mL, dispersed in a sterile aqueous vehicle containing 0.5% w/v hypromellose 2910 as suspending agent, 0.01% w/v benzalkonium chloride as preservative, 0.05% w/v disodium edetate as chelator, and sodium chloride to adjust osmolality to 290 mOsm/kg. The vehicle is heat-sterilised at 121 °C for 15 min, then the sterile micronized dexamethasone with particle size D90 not more than 10 µm is dispersed aseptically using a high-shear rotor-stator at 8,000 rpm for 20 min; the suspension is then filled into 5 mL low-density polyethylene dropper bottles. The API must not be autoclaved because dexamethasone base degrades at high temperature and the micronized particles may aggregate. Quality tests include sterility per USP <71>, particulate matter per USP <789>, ophthalmic product requirements per USP <771>, and preservative effectiveness per USP <51>. Terminal finished product type is a 0.1% veterinary ophthalmic suspension in a 5 mL dropper bottle, with storage between 15–25 °C and protection from light. Alkaline pH above 7.5 and contact with strong oxidising agents must be avoided during compounding to maintain the 1.0 mg/mL assay over shelf life.