| HS Code | 114299 |
| Productname | 1-PHENYL-3-METHYL-5-PYRAZOLONE Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Chemicalname | 1-Phenyl-3-methyl-5-pyrazolone |
| Synonyms | Edaravone; 3-Methyl-1-phenyl-2-pyrazolin-5-one; MCI-186 |
| Casnumber | 89-25-8 |
| Molecularformula | C10H10N2O |
| Molecularweight | 174.20 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay | 99.0% to 101.0% (on dried basis) |
| Meltingpoint | 127 °C to 131 °C |
| Solubility | Slightly soluble in water; soluble in ethanol, methanol, and acetone |
| Relatedsubstances | Conforms to pharmacopoeial limits |
| Storageconditions | Store in a cool, dry place, protected from light |
| Shelflife | 24 months when stored as directed |
| Dosageforms | Tablet, capsule, granule, injection |
| Routeofadministration | Oral and injectable |
| Pharmacopoeialgrade | Pharma grade; complies with applicable JP, USP, or EP standards |
| Therapeuticcategory | Neuroprotective agent; free radical scavenger |
| Mechanismofaction | Scavenges hydroxyl radicals and inhibits lipid peroxidation |
| Indications | Acute ischemic stroke; amyotrophic lateral sclerosis |
| Packaging | 25 kg net in fiber drum with double polyethylene bags |
| Manufacturingstandard | GMP, ISO, ICH Q7 |
As an accredited 1-PHENYL-3-METHYL-5-PYRAZOLONE 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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In oral tablet manufacturing for pyrazolone-containing antipyretic formulations, the starting material with CAS 89-25-8 is rarely processed as a direct-compression crystal because the melting range of 127–131 °C, measured by Ph. Eur. 2.2.14, creates a narrow thermal window during any heated drying step. For tablet cores where the API fraction is held at 10–25% w/w, microcrystalline cellulose and lactose monohydrate form the diluent continuum at 65–80% w/w. Crospovidone is incorporated at 2.0–4.0% w/w as a disintegrant because its wicking action remains effective in the weakly acidic tablet microenvironment generated by the enolic pyrazolone moiety. Wet granulation is performed in a high-shear granulator fitted with a 10 L bowl, at an impeller speed of 300–500 rpm and chopper speed of 1500–2000 rpm. Purified water or a 3.0% w/w aqueous povidone K30 solution is sprayed at 10–15% w/w of dry powder mass; granulation endpoint is confirmed when impeller torque rises by 15–20% over the dry blend baseline, a parameter measured by the motor load cell. After wet massing for 120–180 s, the granules are dried in a fluid-bed dryer with inlet air temperature 50–60 °C until loss on drying is 1.0–1.5% w/w, determined by Ph. Eur. 2.2.32. Dried granules are calibrated through a 1.0 mm oscillating granulator, then lubricated with magnesium stearate at 0.5–1.0% w/w for 3–5 min in a bin blender. Tablets compressed on a rotary press must meet uniformity of dosage units per USP <905> or Ph. Eur. 2.9.40 and dissolution Q=80% at 30 min in 0.1 mol/L HCl using USP apparatus II at 50 rpm. The terminal product is a pyrazolone-containing antipyretic tablet, typically presented as a round biconvex core with a hypromellose-based film coat applied in a perforated pan coater at a 2–3% w/w weight gain.
| Test parameter | Method | Acceptance criterion |
|---|---|---|
| Assay by HPLC | Ph. Eur. 2.2.29 | 98.0–102.0% on dried basis |
| Water content | USP <921> | NMT 0.5% w/w |
| Residue on ignition | USP <281> | NMT 0.1% w/w |
| Residual ethanol | USP <467> | NMT 5000 ppm |
| Elemental impurities | ICH Q3D, USP <232>/<233> | Based on oral PDE |
Direct compression is constrained by the crystal habit and bulk-density instability of the unprocessed powder. The substance has a needle-like or plate-like crystal morphology; without particle-size reduction, the Carr index frequently exceeds 30%, and the Hausner ratio is commonly above 1.40. These powder-flow values fall outside the accepted range for high-speed rotary tablet presses operating above 60,000 tablets/h. On an instrumented rotary press fitted with 12 mm round punches, direct-compression blends containing 25% w/w API may require compression force above 18 kN to achieve a tensile strength of 1.5 MPa; at higher API fractions the compact tends to cap because of elastic recovery. A co-processed excipient based on lactose and cellulose, used at 50–70% w/w, improves compressibility but does not eliminate the need for particle sizing. Roller compaction or wet granulation is therefore preferred when the API content exceeds 15% w/w or when the target tablet mass is below 200 mg. Acceptance of direct compression must be based on a compaction simulator or instrumented press data, not on visual flowability. Published data for this specific pyrazolone crystal in direct compression is limited; development batches should confirm tensile strength and ejection force.
Because capsule filling equipment meters by volume, the fill weight of a pyrazolone granulate depends on the stability of bulk density during hopper residence time. Tapped density is measured according to USP <616> or Ph. Eur. 2.9.34; a tapped density of 0.55–0.70 g/mL is typical for the milled granulate intended for size 1 or 0 hard gelatin capsules. In a dosator-type encapsulation machine, excessive interparticulate adhesion causes inconsistent slug formation when the Carr index exceeds 25%; the fill weight variation must be NMT 2.0% relative standard deviation across 20 consecutive capsules. The dry granulation route uses a roller compactor at roll speed 2–5 rpm, roll force 5–8 kN/cm, and screen size 0.8–1.4 mm, followed by blending with croscarmellose sodium at 2.0–4.0% w/w and magnesium stearate at 0.25–0.75% w/w. If magnesium stearate is mixed longer than 5 min or above 1.0% w/w, dissolution at Q=80% in 30 min may fail because of hydrophobic lubrication of the pyrazolone particles; dissolution is tested per USP <711> with 900 mL of 0.1 mol/L HCl. Finished capsules are checked for disintegration per Ph. Eur. 2.9.1 and for moisture ingress by Karl Fischer titration USP <921>. The terminal product is a hard gelatin capsule filled with pyrazolone granulate, suitable for immediate release when the disintegrant is well distributed.
The pyrazolone ring is converted to phenazone by selective N-2 methylation, a reaction in which 1-phenyl-3-methyl-5-pyrazolone is dissolved in aqueous sodium hydroxide. In a glass-lined stirred reactor, 1.00 mol of the pyrazolone is combined with 1.05–1.10 mol of sodium hydroxide in 2.5–3.5 L of purified water per mol, producing a clear solution at pH 10.0–10.5. Dimethyl sulfate, 1.05–1.10 mol, is added dropwise over 2–3 h while the temperature is maintained at 50–60 °C; the addition rate is controlled to avoid hot spots and to keep dimethyl sulfate residual below the ICH M7 default threshold of 1.5 µg/day for a mutagenic impurity. After a hold period of 1–2 h, the reaction mass is cooled to 10–15 °C; phenazone precipitates and is isolated by centrifuge, washed with cold purified water, and dried under vacuum at 50–60 °C to water content NMT 0.5% w/w. The dried phenazone is assayed by HPLC according to Ph. Eur. 2.2.29 and must show a chromatographic purity of NLT 99.0% area. Related substances, including unreacted starting material and the N-1 methylation isomer, are limited by the phenazone monograph. This conversion is the primary downstream route for tablet and capsule grade phenazone, which is then processed in oral solid-dosage lines as described in the preceding granulation systems. The terminal product of this segment is phenazone API, not the finished tablet; the API is then micronized or granulated according to the final dosage form.
Aqueous injectable processing of the pyrazolone acid is constrained by the solubility cliff at pH below 3.0 and by oxidative discoloration at pH above 8.0. For an aqueous injectable solution based on the pyrazolone structure, the free acid is converted to the sodium salt by adding 1.0–1.05 molar equivalents of sodium hydroxide in water for injection. The pH is then adjusted to 5.0–5.5 with 0.1 mol/L hydrochloric acid or sodium hydroxide solution, and tonicity is established with sodium chloride to an osmolality of 280–320 mOsmol/kg, measured by freezing-point depression per Ph. Eur. 2.2.35. The solution is blanketed with nitrogen throughout compounding because the pyrazolone ring is susceptible to auto-oxidation at the 4-position. Sterile filtration is performed through a 0.22 µm PVDF membrane filter validated according to ASTM F838-20; the filtrate is filled into 2 mL amber glass ampoules under Grade A unidirectional airflow. Terminal sterilisation at 121 °C for 15 min is evaluated but is often rejected if forced degradation studies show an increase in total related substances above 0.5% w/w. The finished injectable must pass sterility per Ph. Eur. 2.6.1 or USP <71> and bacterial endotoxin testing per Ph. Eur. 2.6.14 with a limit NMT 0.25 EU/mg. The terminal product is an aqueous injectable solution of the sodium salt, intended for immediate release and protected from light. Published data for this specific configuration is limited; the pH and oxygen-control strategy must be confirmed by forced degradation studies according to ICH Q1A.
Oral granule dosage forms based on this pyrazolone require a packaging barrier that maintains water content below 1.0% w/w during storage at 40 °C/75% RH for 6 months, as prescribed by ICH Q1A for Zone IVb. The granulation is produced by fluid-bed top-spray processing in a Glatt GPCG 3.1 with an inlet air temperature of 55–65 °C, atomizing air pressure of 1.5–2.5 bar, and a spray rate of 10–20 g/min for a 1000 g development batch. A binder solution of hypromellose E5 at 2.0% w/w in purified water is applied to achieve granule D50 of 150–250 µm, sieved according to Ph. Eur. 2.9.38. After drying to loss on drying NMT 1.0% w/w by Ph. Eur. 2.2.32, the granulate is filled into aluminium-aluminium laminated sachets with an integrated desiccant. The sachet seal integrity is tested by dye penetration according to ASTM F1929-15; oxygen transmission rate of the laminate should be below 0.5 cm³/m²·day·atm at 23 °C. This moisture-control strategy is not optional in packaging for tropical climates because the enolic form of the pyrazolone can sorb atmospheric water and lower the glass transition of the amorphous fraction of the granulate, leading to caking and loss of flow. The terminal product is an oral granule in sachet, reconstituted or swallowed directly, with a fill weight variance controlled per Ph. Eur. 2.9.5. Published data for this specific configuration is limited; the 6-month data point is the minimum long-term stability checkpoint under ICH Q1A, and additional time points must be generated for registration.
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The product model is designated as 1-PHENYL-3-METHYL-5-PYRAZOLONE Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable. This nomenclature combines chemical identity, pharmaceutical-grade control, and route-compatible processing. The chemical entity corresponds to CAS 89-25-8, molecular formula C10H10N2O, and molar mass 174.20 g/mol. The substance is supplied as a white to off-white crystalline powder with a nominal melting range of 129–131 °C. It is manufactured under ICH Q7 conditions, and release is controlled against specifications derived from ICH Q6A and ICH Q3D where no regional monograph is fully harmonized.
The C4-unsubstituted pyrazolone ring is responsible for pH-dependent tautomerization between the 2-pyrazolin-5-one and 5-pyrazolone forms. That equilibrium influences aqueous solubility, reversed-phase HPLC retention, dissolution, and oxidative degradation. The oral grade is intended for dry blending, wet or dry granulation, capsule filling, and compression. The injectable grade requires additional controls for bioburden, bacterial endotoxins, particulate matter, and oxygen exposure. Reagent-grade material is not interchangeable because it is not controlled for residual solvents, elemental impurities, microbial content, or endotoxins.
Dry blending of the oral grade is performed after passing the powder through a 250 µm sieve and equilibrating at 23 ± 2 °C and 40 ± 5% RH. For direct compression, a target D90 of ≤ 100 µm is applied. Powder flow is controlled to a Hausner ratio of 1.25–1.35 and an angle of repose of ≤ 35° per USP <1174>. Blend uniformity is evaluated by USP <905> with an acceptance RSD of ≤ 5.0%. Tablet hardness is generally maintained between 6 kp and 8 kp for a 250 mg core, while friability is kept below 1.0% per USP <1216>. Batch-scale processing in low-humidity dry powder lines has shown that blend moisture above 2.5% increases upper-punch sticking; the control strategy is to maintain blend moisture below 2.0% and to apply precompression force in the range of 4–6 kN on a rotary tablet press.
Capsule formulations use dry blending followed by encapsulation. A D90 of ≤ 150 µm is generally sufficient for weight variation control, but low-dose blends may require geometric dilution with lactose monohydrate before final mixing. Gelatin and hypromellose capsule runs are performed under controlled humidity; if the powder moisture exceeds 2.0%, desiccant usage and shorter hold times are applied. Magnesium stearate is added at 0.5–1.0% w/w and mixed for 3 min to reduce the risk of over-lubrication and delayed dissolution.
Wet granulation is possible with a polyvinylpyrrolidone K30 binder solution, but granulation moisture is limited to 2.0–3.0% and drying is conducted at product temperature ≤ 45 °C. Roller compaction is preferred for moisture-sensitive campaigns. Ribbon density is maintained at 1.10–1.25 g/cm³, and milled granules are screened through an 850 µm screen before compression. Fluid-bed drying uses inlet air at 50–60 °C and final loss on drying of ≤ 2.0% to avoid melt bridging and oxidative degradation. Forced degradation under thermal and humid conditions is used to establish the acceptable granulation window for a given formulation.
Aqueous solubility is limited at neutral pH and improves under alkaline conditions above the enolic pKa. pH-solubility profiling in phosphate and acetate buffers from pH 2 to pH 8 is used to define dissolution media and injection vehicles. Published data for absolute aqueous solubility in compendial buffers is limited; therefore, formulation development should not extrapolate directly from methanol or ethanol solubility. Intrinsic dissolution in pH 1.2 and pH 6.8 media is pH-dependent because of tautomerization, and dissolution method development typically includes a surfactant evaluation under USP <1092>.
Parenteral use of this API imposes additional controls that are not applicable to the oral grade. The compound is dissolved under nitrogen overlay, adjusted to pH 3.5–4.5 with hydrochloric acid or sodium hydroxide, and sterile-filtered through a 0.22 µm polyethersulfone or polyvinylidene fluoride filter. Dissolved oxygen is maintained below 2 ppm. Sub-visible particulate matter is controlled per USP <788>, with not more than 6,000 particles of ≥ 10 µm and 600 particles of ≥ 25 µm per container. Visible particulate inspection is performed per USP <790>. Osmolality of the finished injection is adjusted with sodium chloride to 280–320 mOsm/kg per USP <785>. Sodium sulfite or sodium bisulfite may be used as an oxygen scavenger in some registered parenteral formulations, but compatibility must be confirmed because the API itself behaves as a free-radical scavenger.
Bacterial endotoxins in the injectable-grade API are limited to 0.25 EU/mg when the finished product is a small-volume parenteral, but the release limit should be derived from the maximum dose per kilogram using USP <85>. Terminal steam sterilization at 121 °C for 15 min is not automatically applicable; published data for this specific configuration is limited. Forced degradation under ICH Q1B is required to establish thermal and photolytic stability before terminal sterilization is introduced. Aseptic filtration remains the default sterile-processing route. Filter integrity testing is performed by bubble point, diffusion flow, or pressure hold using the filter manufacturer’s validated protocol. Type I borosilicate glass vials or non-PVC infusion bags are used, and extractables and leachables are assessed per USP <1663>/<1664>.
Release specifications are established according to ICH Q6A and are updated as regional monographs are adopted. The following table lists representative release parameters for the oral and injectable grades.
| Parameter | Method | Release limit |
|---|---|---|
| Appearance | Visual | White to off-white crystalline powder |
| Identification | FTIR reference spectrum and HPLC retention time | Concordant with reference standard |
| Assay, anhydrous basis | HPLC | 99.0–101.0% |
| Total related substances | HPLC area normalization | ≤ 0.5% |
| Single unspecified impurity | HPLC | ≤ 0.10% |
| Loss on drying | Drying oven or Karl Fischer | ≤ 0.5% |
| Residue on ignition | Sulfated ash | ≤ 0.1% |
| Melting range | Capillary | 129–131 °C |
| Residual solvents | Headspace GC, USP <467> | Class 1 excluded; Class 3 ≤ 5000 ppm |
| Elemental impurities | USP <232>/<233>, ICH Q3D | Pb ≤ 0.5 ppm; Cd ≤ 0.2 ppm; As ≤ 1.5 ppm; Hg ≤ 0.3 ppm |
| Microbial enumeration, oral | USP <61>/<62> | TAMC ≤ 100 CFU/g; TYMC ≤ 10 CFU/g; E. coli absent |
| Bacterial endotoxins, injectable | USP <85> | ≤ 0.25 EU/mg or derived from dose |
| Particle size, oral | Laser diffraction | D90 ≤ 100 µm |
| Particle size, injectable, if applicable | Laser diffraction | D90 ≤ 20 µm |
Residual solvent limits follow ICH Q3C; Class 1 solvents are excluded from the manufacturing process. Elemental impurity limits in the table reflect conservative oral permitted daily exposure assumptions. Parenteral grades may require lower values based on ICH Q3D route-specific permitted daily exposure. Process impurities may include phenylhydrazine-related residues and condensation by-products; genotoxic impurity assessment is performed under ICH M7(R1). A typical validated HPLC system uses a 250 × 4.6 mm stainless steel column packed with 5 µm octadecylsilane, a phosphoric acid/methanol mobile phase, and UV detection. System suitability requires resolution between tautomeric forms of not less than 2.0 and injection precision RSD not more than 2.0%, consistent with ICH Q2(R1).
Solid-state characterization includes X-ray powder diffraction and differential scanning calorimetry. The anhydrous material shows a single endothermic event associated with the melting transition at 129–131 °C; no dehydration event is observed under standard storage. Polymorph consistency is controlled by XRPD, and any new crystalline form is evaluated for changes in dissolution and powder flow. The API is packaged in double low-density polyethylene bags inside an aluminum-laminate outer bag with desiccant. Storage is recommended at ≤ 25 °C in tight, light-resistant containers under nitrogen per USP <659>. A retest period of 24 months is commonly assigned with ongoing stability evaluation under ICH Q1A(R2).
Replacement of 1-phenyl-3-methyl-5-pyrazolone with antipyrine, 4-aminoantipyrine, or phenylbutazone is not chemically neutral. The C4 position in this entity is unsubstituted, preserving the enolizable hydrogen and pH-dependent tautomerism that governs lipophilicity, HPLC retention, and dissolution. Antipyrine carries an additional methyl at N2, which reduces the degree of tautomerization and changes the oxidative degradation profile. 4-Aminoantipyrine introduces a primary amine that can react with aldehyde-bearing excipients and is normally limited to analytical derivatization rather than pharmaceutical dosage forms. Phenylbutazone has a 3,5-dione oxidation state and a butyl substituent at C4, yielding a much higher molecular weight and a different toxicological profile.
These structural differences translate into different processing boundaries. The unsubstituted C4 compound requires nitrogen overlays and low-moisture blending because its antioxidant activity is coupled to reversible oxidation. Antipyrine is generally less sensitive to oxygen and may allow direct compression without particle-size reduction. The particle size and compaction behavior of the unsubstituted compound after micronization are closer to those of a brittle crystalline powder, while antipyrine’s larger crystal habit may provide better initial flow. Published data for direct compression comparisons across all these pyrazolones is limited; therefore, formulation-specific forced degradation and processability studies are necessary before any substitution.
| Compound | CAS No. | Molecular weight | Notable structural difference | Processing relevance |
|---|---|---|---|---|
| 1-Phenyl-3-methyl-5-pyrazolone, edaravone form | 89-25-8 | 174.20 g/mol | C4-H; pH-dependent tautomer | Oxygen-sensitive; nitrogen overlay; aseptic filtration preferred |
| Antipyrine, phenazone | 60-80-0 | 188.23 g/mol | N2-methyl; less enolization | Less oxygen-sensitive; oral solid dosage forms common |
| 4-Aminoantipyrine | 83-07-8 | 203.24 g/mol | C4-amino group | Reactive with aldehyde/ketone excipients; analytical reagent |
| Phenylbutazone | 50-33-9 | 308.37 g/mol | 3,5-dione; C4-butyl; two phenyl groups | Higher molar mass; different toxicity profile; not interchangeable |
In reversed-phase HPLC under acidic mobile phase, the unsubstituted compound elutes earlier than phenylbutazone because of lower molecular weight and lower lipophilicity. This retention difference is used in system suitability and forced degradation studies. The oral and injectable grades share the same chemical identity but differ in bioburden, endotoxin, particulate matter, and packaging controls. The oral grade is processed under low-humidity dry conditions but is not sterile. The injectable grade is filtered under aseptic conditions and filled in a controlled environment meeting ISO Class 5 conditions. Finished drug product manufacture is conducted under 21 CFR 210/211, and analytical control follows 21 CFR Part 11 where electronic records are used.
