| HS Code | 910398 |
| Product Name | Flumethasone Pharma Grade API |
| Chemical Name | 6α,9α-Difluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione |
| Molecular Formula | C22H28F2O5 |
| Molecular Weight | 410.45 g/mol |
| Cas Number | 2135-17-3 |
| Appearance | White to off-white crystalline powder |
| Solubility | Practically insoluble in water; soluble in ethanol, methanol and acetone |
| Melting Point | Approximately 237-240°C |
| Specific Optical Rotation | +72° to +80° in dioxane |
| Assay Dried Basis | 98.0% to 102.0% |
| Residual Solvents | Meets ICH Q3C requirements |
| Storage Conditions | Store in tightly closed containers in a cool, dry place, protected from light |
| Dosage Form Suitability | Suitable for tablets, capsules, granules, and oral or injectable formulations |
As an accredited Flumethasone 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.
| Packing | Flumethasone Pharma Grade API is supplied as sterile sealed powder in double polybags with aluminum foil outer, 1 kg per drum. |
| Container Loading (20′ FCL) | Flumethasone API loaded in 20' FCL as palletized, sealed drums, safely secured, clean and dry, temperature-controlled if required. |
| Shipping | Flumethasone Pharma Grade API is shipped in sealed, inert, light-resistant containers under temperature-controlled conditions, protecting purity and stability. Shipments include tamper-evident packaging, hazard-compliant labeling, and complete documentation for oral and injectable pharmaceutical use. Cold-chain options are available upon request to ensure safe, compliant delivery. |
| Storage | Store Flumethasone Pharma Grade API in a tightly closed, light-resistant container in a cool, dry, well-ventilated area. Maintain controlled room temperature, ideally 20–25°C, with excursions permitted between 15–30°C. Protect from moisture, heat, and direct sunlight. Keep away from oxidizing agents and incompatible materials. Ensure proper labeling and follow first-expiry-first-out inventory practices. |
| Shelf Life | Shelf life: 24 months from manufacture when stored below 25°C, protected from light and moisture, in tightly closed containers. |
On a production-scale direct compression line producing uncoated flumethasone tablets with a target potency of 0.25 mg per core, the primary process constraint is not dissolution but segregation of micronized API from coarser excipients during hopper discharge. A blend containing 0.1% w/w micronized flumethasone and 99.9% w/w direct-compression lactose/starch excipients is prepared by two-stage geometric dilution: a 1:5 flumethasone–lactose pre-blend is screened through a 600 µm mesh and transferred to a 600 L bin blender for 20 min at 12 rpm. Content uniformity is controlled by USP <905> acceptance value ≤ 15 and Ph. Eur. 2.9.40; dissolution is assessed under USP <711> or Ph. Eur. 2.9.3 with a product-specific medium selected and validated under 21 CFR 211.165, typically using apparatus 2 at 50 rpm with a surfactant-containing buffer and Q ≥ 80% at 30 min for low-dose corticosteroid tablet cores. A rotary tablet press is configured with 16 stations, compression force 8–16 kN, and a screw force feeder at 20–40 rpm; ejection force and tablet hardness are monitored because over-lubrication with 0.5–0.75% w/w magnesium stearate can depress tensile strength below 1.5 MPa. Segregation in the hopper is observed on extended batches as tail-end superpotency and is mitigated by maintaining hopper fill depth above 60% and by avoiding vibration; published data for flumethasone-specific segregation in direct compression is limited. The finished product types are uncoated tablet cores of 100 mg or 200 mg total mass and subcoated cores prepared for a subsequent film-coating step.
In capsule filling operations, hard-gelatin and HPMC shell formats with 0.1–0.5 mg flumethasone per size 3 shell are prepared at drug loads of 0.05–0.2% w/w in a lactose–starch matrix, blended by two-stage geometric dilution in a low-shear V-blender at 15 rpm for 15 min, and filled on an intermittent-motion dosing-disc machine with tamping pin settings adjusted to produce a plug density of 0.75–0.85 g/mL; compliance is assessed by USP <905>, Ph. Eur. 2.9.40, and USP <711> after shell rupture, and terminal product forms are hard-gelatin capsules, HPMC capsules, or pullulan capsules with shell moisture specified at 12–16% w/w.
Where a flumethasone direct-compression blend fails flow testing or becomes cohesive at ambient relative humidity above 60%, dry granulation by roller compaction is inserted before tablet compression or capsule filling. The formulation retains an API addition ratio of 0.05–0.25% w/w in a cellulosic filler–dicalcium phosphate anhydrous matrix; after a pre-blend at a 1:5 flumethasone–filler ratio, the material is compacted on a roller compactor with roll pressure 30–60 kN, roll speed 5–10 rpm, and gap 1–2 mm, then milled through a 12-mesh screen to produce granules with a target D50 of 0.5–1.0 mm for tablet compression or 0.3–0.6 mm for capsule filling. Extragranular lubricant is added at 0.5–1.0% w/w and blended for 3–5 min; compliance testing follows USP <905> content uniformity and USP <711> or Ph. Eur. 2.9.3 dissolution on the finished dosage form. Terminal product types are immediately compressible dry granules, dry-granule tablet cores, or capsule fill material for low-dose flumethasone presentations in which direct compression alone is not sufficient.
Wet granulation introduces deliberate particle-size enlargement that reduces segregation but creates hydrolysis and polymorph hydration risk for flumethasone. A typical granulation batch at addition ratios of 0.1–0.5 mg flumethasone per 500 mg granule sachet uses a binder solution of 5% w/w povidone K30 in purified water added to a high-shear granulator at 10–15% w/w of dry powder mass; impeller speed is maintained at 300 rpm, chopper at 1500 rpm, and granulation time at 3–5 min to yield a median granule diameter of 150–300 µm. Drying in a fluid-bed dryer with inlet air at 55–65°C proceeds until loss on drying reaches 2.0–3.0% w/w; the dried granules are screened through an 800 µm mesh and lubricated with 0.5% w/w sodium stearyl fumarate if they are to be compressed into tablets. Compliance points include Ph. Eur. 2.9.5 mass uniformity for single-dose sachets, USP <905> content uniformity for unit-dose granules, and ICH Q3C residual solvent limits when hydroalcoholic granulation is required; because published data for flumethasone-specific wet-granulation degradation is limited, a forced-degradation study under ICH Q1A(R2) is expected to define the maximum granulation moisture and drying temperature. Terminal product types are granules filled into stick packs of 500 mg or 1000 mg, granules for extemporaneous reconstitution, and dried granule intermediates intended for tablet compression.
Before a flumethasone parenteral suspension can be filled into 2 mL Type I glass vials, the API particle size distribution must be controlled below a D90 of 10 µm because larger crystals produce syringeability failures through a 21 G needle. The free corticosteroid alcohol is practically insoluble in water, reported aqueous solubility below 0.1 mg/mL, and the injectable form is therefore a sterile micronized suspension with an addition ratio of 0.5–2 mg/mL flumethasone in a vehicle containing a wetting agent at 0.1–0.3% w/v, a suspending agent at 0.5–1.0% w/v, and a tonicity agent to achieve 270–330 mOsm/kg. Sterility assurance follows USP <71>, endotoxin control follows USP <85> with a limit derived from the maximum bolus dose and using water for injection that must meet <0.25 EU/mL, subvisible particulate control follows USP <788>, and batch release documentation follows 21 CFR 211.194. The vehicle is sterilized by autoclaving at 121°C for 15 min; the micronized API is sterilized separately by a validated method such as dry heat or gamma irradiation only after a forced-degradation study under ICH Q1A(R2) shows assay retention within 95–105%. Aseptic dispersion through a high-pressure homogenizer at 500–1000 bar with 3 passes reduces particle aggregation, and filling is carried out under ISO 14644-1 Class 5 unidirectional airflow into single-dose vials. Terminal sterilization by autoclaving is generally avoided because suspension caking and particle growth are likely; the finished product type is a sterile injectable suspension in single-dose Type I glass vials, not a lyophilized cake unless a soluble flumethasone ester is used.
Film coating of flumethasone immediate-release tablet cores is not required for dissolution in every case, but becomes a process-specific control when photostability data generated under ICH Q1B Option 2 show a loss of assay greater than 0.5% after exposure to 1.2 million lux·h visible light and 200 Wh/m² UVA. In that situation, the coating addition ratio is expressed as polymer weight gain of 2–4% w/w of the flumethasone tablet core, using an aqueous polyvinyl alcohol–polyethylene glycol copolymer dispersion at 12–15% w/w solids; the coated tablet retains a flumethasone load of 0.1–1.0 mg per core. A side-vented coating pan of 48-inch diameter is operated with inlet air at 60–70°C, spray rate 80–120 mL/min, atomising air pressure 1.5–2.5 bar, and pan speed 6–10 rpm to maintain a bed temperature of 38–45°C; logo bridging and edge erosion begin to appear on this geometry when the spray rate exceeds the drying capacity of the pan, and are corrected by reducing spray rate in 10 mL/min increments before pan-speed changes. Final core moisture is targeted at 1.5–2.5% w/w. Release testing still includes USP <711> dissolution on the coated cores and USP <905> content uniformity, while coating weight gain and visual defect sampling are monitored under 21 CFR 211.110. The terminal product type is a film-coated tablet packaged in PVC/aluminium or cold-form foil blisters; the coating in this configuration is a light-protective non-functional barrier, not an enteric or sustained-release rate-controlling membrane unless a separate delayed-release polymer system is applied.
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Flumethasone pharma-grade active pharmaceutical ingredient (API), CAS 2135-17-3, is a 6α,9α-difluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione supplied as an unmicronized oral grade, a jet-milled injectable grade, and a granule-grade powder for tablet, capsule, granule, and injectable suspension manufacturing. The molecular formula is C₂₂H₂₈F₂O₅ and the relative molecular mass is 410.45 g/mol. Release testing is conducted under current Ph. Eur. and USP monographs for flumethasone, with HPLC assay per Ph. Eur. 2.2.29 and USP <621>. The free base is practically insoluble in water; therefore, oral solid-dosage processors use the unmicronized oral grade, while injectable suspension manufacturers use a micronized grade meeting particle-size limits defined by ISO 13320-1:2020. This physical difference distinguishes flumethasone base from water-soluble corticosteroid esters such as dexamethasone sodium phosphate, which can be formulated as clear parenteral solutions.
Compared with betamethasone and dexamethasone, flumethasone possesses an additional fluorine at the 6α-position and a 16α-methyl group; this pattern alters glucocorticoid receptor binding and metabolic clearance. The base molecule has low mineralocorticoid activity and is not supplied with an esterified phosphate or acetate functionality, so its parenteral presentation depends on particle engineering rather than salt solubilization. Flumethasone also differs from dexamethasone in that the 6α-fluoro substituent reduces ring-A metabolic oxidation in hepatic microsomes, which prolongs systemic exposure in some preclinical models; however, published data for this specific configuration in human injectable dosage forms is limited. The API described here is not processed for inhalation-grade particle engineering and is not interchangeable with flumethasone pivalate, which is primarily used in veterinary topical formulations.
| Parameter | Oral grade acceptance criterion | Injectable micronized grade acceptance criterion | Method/standard |
|---|---|---|---|
| Appearance | White or almost white crystalline powder | White or almost white crystalline powder | Ph. Eur. 2.2.1 |
| Identification by infrared absorption | Spectrum consistent with reference | Spectrum consistent with reference | Ph. Eur. 2.2.24 |
| Identification by HPLC retention time | Retention time matches reference | Retention time matches reference | Ph. Eur. 2.2.29 |
| Assay on dried basis | 97.0–103.0% | 97.0–103.0% | Ph. Eur. 2.2.29; USP <621> |
| Loss on drying | ≤0.5% | ≤0.5% | Ph. Eur. 2.2.32; USP <731> |
| Residue on ignition | ≤0.1% | ≤0.1% | Ph. Eur. 2.4.14; USP <281> |
| Related substances: unspecified impurity | ≤0.10% | ≤0.10% | Ph. Eur. 2.2.29; ICH Q3A |
| Total impurities | ≤1.0% | ≤1.0% | Ph. Eur. 2.2.29; ICH Q3A |
| Residual methanol | ≤3000 ppm | ≤3000 ppm | Ph. Eur. 2.4.24; USP <467>; ICH Q3C |
| Residual dichloromethane | ≤600 ppm | ≤600 ppm | Ph. Eur. 2.4.24; USP <467>; ICH Q3C |
| Particle size D50 | 15–30 µm | 5–8 µm | ISO 13320-1:2020 |
| Particle size D90 | ≤75 µm | ≤15 µm | ISO 13320-1:2020 |
| Bacterial endotoxins | Not routinely tested for oral grade | ≤5.0 EU/mg | Ph. Eur. 2.6.14; USP <85> |
| Bioburden | Not routinely tested for oral grade | ≤100 CFU/g | Ph. Eur. 2.6.12; USP <61> |
Injectable flumethasone suspension is a flocculation-controlled system. Micronized API with D50 5–8 µm and D90 ≤15 µm, measured by laser diffraction according to ISO 13320-1:2020 using a Malvern Mastersizer 3000 with a Hydro MV dispersion unit at 2,000 rpm and 0.1% polysorbate 80 as dispersant, is required for syringeability through 21G needles. Crystal habit of the unmicronized material is generally needle-like; air-jet milling reduces particle length but can introduce amorphous surface regions if milling pressure exceeds 6 bar or if feed rate falls below 5 kg/h. These amorphous domains can recrystallize on storage at 25 °C/60% RH and cause caking. Differential scanning calorimetry at 10 K/min from 25 °C to 300 °C is used to confirm crystallinity; the absence of a cold crystallization exotherm below 150 °C is a release indicator. Zeta potential of the suspended flocculated system should remain between −25 mV and −40 mV to avoid irreversible aggregation. Sodium carboxymethylcellulose at 0.5–1.0% w/v provides the structured vehicle; viscosity measured on a Brookfield LV viscometer at 25 °C should be 20–50 mPa·s at 60 rpm to ensure resuspendability after 14 days standing. Syringeability through a 21G × 1.5-inch needle is measured using a force-displacement stand at 300 mm/min; the acceptance threshold is peak glide force ≤15 N and no occlusion after five withdrawal cycles.
Direct compression of low-dose flumethasone tablets containing 0.5 mg API on a 16-station rotary press requires ordered mixing rather than conventional geometric dilution. The API is preblended with microcrystalline cellulose USP/NF at a 1:10 ratio in a 10 L bin blender at 12 rpm for 10 minutes, passed through a 500 µm sieve, then mixed with lactose monohydrate and croscarmellose sodium for 15 minutes. Magnesium stearate is added at 0.25–0.50% w/w and blended for 3 minutes. Blend uniformity is assessed by stratified sampling at 10 points; relative standard deviation must not exceed 5.0%. Content uniformity testing according to USP <905> requires an acceptance value of ≤15. The main high-speed failure mode is segregation of the low-dose API from larger lactose particles; the 1:10 preblend with microcrystalline cellulose reduces this by increasing contact points and reducing density differences. Granulation-grade API with D50 15–30 µm is not appropriate for direct compression because it can localize in the feed frame and produce streaks.
Flumethasone granule-grade API is intended for wet or dry granulation when direct compression is not suitable. Roller compaction at roll pressure 4–6 kN/cm and roll speed 2–5 rpm is used to prepare dry granules; the compacted ribbons are milled through a 1.0 mm screen. The main process risk is loss of tabletability at high roll pressure, which can increase disintegration time and dissolution variability. Dissolution testing for finished tablets uses a product-specific method based on USP <711>; because no universal dissolution medium exists for flumethasone, the medium is established during formulation development and validated according to ICH Q2(R1).
Aqueous wet granulation of flumethasone base is constrained by pH-dependent degradation at the C17 side chain. The granulating fluid is buffered with citrate or acetate at pH 4.5–5.5; above pH 8 the 21-hydroxy group is susceptible to oxidative cleavage, and below pH 3 acid-catalyzed dehydration of the 11β-hydroxy group can increase impurity formation. In a top-drive high-shear mixer, wet massing time should not exceed 5 minutes at chopper speed 1,500 rpm; longer exposure dissolves a fraction of the micronized API, which then reprecipitates on drying as needle-like crystals and contributes to assay non-uniformity. Fluid-bed drying inlet air temperature is limited to 55 °C; product temperature should not exceed 40 °C until final moisture is ≤2.0%. Binary compatibility screening in open dishes at 40 °C/75% RH for 4 weeks indicates compatibility with lactose monohydrate, maize starch, and microcrystalline cellulose. Sodium starch glycolate at levels above 2.0% w/w can increase the local alkaline microenvironment and promote impurity growth; where superdisintegrant action is needed, croscarmellose sodium at 2.0–4.0% w/w is preferred. Published data for this specific configuration in commercial wet-granulated flumethasone tablets is limited; therefore, compatibility data generated on the actual formulation should be used to define control limits.
Injectable-grade flumethasone API is supplied as a low-bioburden micronized powder with a bioburden limit of ≤100 CFU/g and bacterial endotoxin limit of ≤5.0 EU/mg. Endotoxin testing is performed using the limulus amebocyte lysate kinetic chromogenic method per Ph. Eur. 2.6.14 and USP <85>. Sterile filtration of the finished suspension is not feasible because the API particles are intentionally larger than the 0.22 µm membrane pores. Terminal sterilization by moist heat at 121 °C for 15 minutes can be used for formulations that show no particle growth or viscosity shift after autoclaving. Dry heat depyrogenation of the API is not suitable because the dieneone structure degrades at the temperatures required for endotoxin destruction; depyrogenation is instead applied to packaging components and formulation vessels. Aseptic processing under EU GMP Annex 1 or FDA 21 CFR 211.84/211.160 is used when terminal sterilization is not feasible. Release of the injectable powder includes particulate matter evaluation on the formulated suspension per USP <788> for subvisible particles.
The API is assayed by a stability-indicating reversed-phase HPLC method. The column is a C18 150 × 4.6 mm, 5 µm particle size, maintained at 30 °C; the mobile phase is a gradient of water and acetonitrile with 0.1% phosphoric acid at 1.0 mL/min; detection is at 254 nm. System suitability requires resolution between flumethasone and the nearest specified related substance of ≥2.0, tailing factor ≤2.0, and injection precision relative standard deviation ≤2.0%. Forced degradation studies under 0.1 M HCl, 0.1 M NaOH, 3% H₂O₂, thermal stress at 60 °C, and light exposure according to ICH Q1B demonstrate mass balance between 97.0% and 103.0%. Related substances are controlled according to ICH Q3A: reporting threshold 0.05%, identification threshold 0.10%, and qualification threshold 0.15% for a daily dose below 2 g. The oral and injectable grades share the same impurity profile; the injectable grade has tighter bioburden and endotoxin release requirements but no additional chromatographic impurity requirement.
Store the unmicronized oral grade and the jet-milled injectable grade in tightly closed, light-resistant containers at 15–25 °C. Protect from light because the dieneone chromophore absorbs ultraviolet radiation and can generate photodegradants. If storage relative humidity exceeds 60%, the micronized injectable grade may undergo particle fusion; pre-drying at 40 °C for 2 hours before weighing is required. Avoid contact with strong oxidising agents and strong bases because both accelerate side-chain degradation. The unmicronized oral grade should be sieved through a 500 µm screen before use in direct compression to remove agglomerates formed during shipping.
