| HS Code | 878719 |
| Productname | Pyrazole Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Chemicalname | 1H-Pyrazole |
| Casnumber | 288-13-1 |
| Molecularformula | C3H4N2 |
| Molecularweight | 68.08 g/mol |
| Appearance | White to off-white crystalline powder or crystals |
| Assaypurity | ≥99.0% |
| Grade | Pharmaceutical Grade |
| Meltingpoint | 67-70 °C |
| Boilingpoint | 186-188 °C |
| Solubility | Soluble in water, ethanol, methanol, chloroform; slightly soluble in nonpolar solvents |
| Storageconditions | Store in a cool, dry, well-ventilated area away from light and moisture |
| Dosageforms | Tablet, Capsule, Granule, Injection |
| Routesofadministration | Oral, Injectable |
| Pharmaceuticalcategory | Pharmaceutical API / Intermediate |
| Packaging | 25 kg fiber drum with double polyethylene inner bags |
| Shelflife | 24 months in unopened original packaging |
As an accredited Pyrazole 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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Pyrazole Pharma Grade API is supplied as a white to off-white crystalline solid with assay ≥99.0% (HPLC, Ph. Eur. 2.2.29), water content ≤0.5% w/w (Karl Fischer), and sulfated ash ≤0.1% w/w. The material is controlled for residual solvents under USP <467> and ICH Q3C, and for elemental impurities under ICH Q3D. Storage is specified at 15–25°C in closed containers protected from light. Pyrazole Pharma Grade API functions as the heterocyclic core input for pyrazole-containing active pharmaceutical ingredients in oral and injectable finished dosage forms; the following application scenarios are limited to commercially relevant therapeutic classes for which tablet, capsule, granule, and injectable product lines are operated under 21 CFR 210 and 211.
During capsule manufacture of pyrazole-containing selective COX-2 inhibitor actives for chronic inflammatory indications, Pyrazole Pharma Grade API is introduced as the core heterocycle input, and the final active pharmaceutical ingredient is controlled for pyrazole-related impurities below the ICH Q3A reporting threshold of 0.05% by reversed-phase HPLC (Ph. Eur. 2.2.29; USP <621>). The final active content in the filled hard capsule is typically 50–200 mg per unit, corresponding to 10–30% w/w of the fill weight. Compliance for this oral capsule line is anchored to USP <711> and Ph. Eur. 2.9.3 for dissolution, USP <905> and Ph. Eur. 2.9.40 for content uniformity, and ICH Q3D for elemental impurities. Capsule filling is performed on a tamping-pin or dosator-type capsule filler in an area controlled to ≤40% RH; the fill blend consists of lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate after low-shear tumble blending. In production-scale batches, agglomeration of the active fraction above 250 μm is a recurring content-uniformity fault, and a comil fitted with a 0.8 mm screen is used before filling. The terminal product is an immediate-release hard capsule.
Direct compression of a low-dose pyrazolo[3,4-c]pyridine anticoagulant tablet places content uniformity as the primary release specification because the active ingredient is present at 2.5 mg or 5 mg per 100–150 mg tablet core, i.e. 2–5% w/w. Pyrazole Pharma Grade API is charged at 1.0–1.1 mol equivalents relative to the heterocyclic coupling partner in the active pharmaceutical ingredient synthesis, and residual pyrazole is controlled by HPLC before formulation. The compliance set includes USP <905> and Ph. Eur. 2.9.40 for dose uniformity, USP <701> and Ph. Eur. 2.9.1 for disintegration, USP <711> for dissolution, and ICH Q3D for elemental impurities. Process experience on production-scale tumble blenders shows that stratified sampling at 10 locations after 15 min blending can still produce acceptance value drift when active particles below 75 μm adhere to vessel walls; delumping and sequential geometric dilution are therefore used. The blend is compressed on a rotary tablet press with 6–8 mm round tooling at 8–20 kN, targeting hardness 60–100 N. Disintegration acceptance is ≤15 min in 0.1 N HCl at 37°C. The terminal product is a film-coated oral tablet.
Aseptic manufacturing of a methanol and ethylene glycol antidote injection based on 4-methylpyrazole hydrochloride begins with Pyrazole Pharma Grade API that is controlled for palladium, nickel, and boron by ICP-MS according to USP <233> and ICH Q3D. Pyrazole is charged at 1.0–1.1 mol equivalents relative to the C4 functionalization agent; the purified intermediate is then converted to the hydrochloride salt and formulated as an injectable solution containing 1 g/mL 4-methylpyrazole hydrochloride in an aqueous vehicle, filled into 1.5 mL Type I borosilicate glass vials. Sterility assurance follows 21 CFR 210 and 211, Ph. Eur. 5.1.1, and ISO 14644-1:2015 Class 5 cleanroom conditions. Terminal sterilization is not applied; the solution is filtered through a 0.22 μm sterilizing-grade membrane and aseptically filled. The solution is maintained at pH 6.5–8.5, and headspace oxygen is displaced with filtered nitrogen to limit oxidative color formation. Batch release includes visual inspection, vacuum-decay container closure integrity testing, bacterial endotoxin limit ≤0.5 EU/mg per USP <85> and Ph. Eur. 2.6.14, and subvisible particulate monitoring per USP <787>. The terminal unit is an injectable solution for intravenous administration.
For a Janus kinase inhibitor tablet containing a pyrazole core, Pyrazole Pharma Grade API is charged at 1.0–1.2 mol equivalents in the synthesis of the active moiety, and the final active ingredient is formulated at 5–25 mg per tablet, equivalent to 5–20% w/w of the tablet core. High-shear wet granulation is selected to densify the low-bulk-density active and to control particle size distribution. In production-scale equipment, the granulation endpoint is defined not by fixed time but by impeller torque, with a target 40–70% of equipment load at impeller speed 150–250 rpm and chopper speed 1500–2500 rpm. Purified water is sprayed at 0.5–1.5 kg/min until granulate moisture reaches 2.5–3.5% w/w. Wall adhesion and secondary granule growth above 2 mm are the two principal batch-to-batch variance sources; a wet mass mill with 2.0 mm screen is used before drying. The wet granulate is transferred to a fluid-bed dryer with inlet air temperature 50–70°C, dried to loss on drying ≤2.0% w/w, and milled through a 1.0 mm screen. Tablet compression uses 8–10 mm standard concave tooling at 12–20 kN, with target hardness 80–120 N and friability per USP <1216> of ≤1.0%. Dissolution is tested according to USP <711>; content uniformity follows USP <905> and Ph. Eur. 2.9.40; elemental impurity limits follow ICH Q3D. The finished form is an immediate-release film-coated tablet.
| Process segment | Standard designation | Test purpose |
|---|---|---|
| Oral capsule | USP <711>; Ph. Eur. 2.9.3; ICH Q3D | Dissolution and elemental impurities |
| Direct-compression tablet | USP <905>; Ph. Eur. 2.9.40; USP <701> | Dose uniformity and disintegration |
| Injectable solution | Ph. Eur. 5.1.1; USP <85>; Ph. Eur. 2.6.14; ISO 14644-1 | Aseptic processing, endotoxin, cleanroom classification |
| Wet-granulated tablet | USP <1216>; USP <905>; ICH Q3D | Friability, dose uniformity, elemental impurities |
| Roller-compacted tablet | USP <467>; ICH Q3C; USP <711> | Residual solvents and dissolution |
| Oral granules | ASTM F88/F88M-21; USP <905>; ICH Q3D | Seal strength, dose uniformity, elemental impurities |
When moisture-sensitive pyrazole-derived PDE5 inhibitor actives are processed, aqueous wet granulation is replaced by roller compaction to avoid hydrolysis potential and polymorphic conversion. Pyrazole Pharma Grade API is charged at 1.0–1.05 mol equivalents in the pyrazolo[3,4-d]pyrimidin-7-one scaffold construction; the final active ingredient represents 25–50 mg per tablet and 5–15% w/w of the core. The roller compaction process operates at roll pressure 4–8 MPa, gap 1–2 mm, and roll speed 5–12 rpm; compacted ribbons are milled to 0.8–1.5 mm granules. Ribbon density variation due to roll gap fluctuation above 0.2 mm is a critical processing fault that produces bimodal granule size distribution and subsequent tablet weight variation. To manage flow and lubricity, colloidal silicon dioxide is added at 0.25–0.50% w/w and magnesium stearate at 0.5–1.0% w/w, with stearate blending limited to 3–5 min to avoid tensile strength reduction. Tablets are compressed on 10–12 mm oval tooling at 12–25 kN; friability is controlled per USP <1216>, dose uniformity per USP <905> and Ph. Eur. 2.9.40, and residual solvents per USP <467> and ICH Q3C. Dissolution testing uses USP <711> Apparatus II at 50 rpm in 0.1 N HCl at 37°C. The terminal product is an immediate-release film-coated oral tablet.
Fluid-bed layering of a pyrazole-containing selective COX-2 inhibitor active onto microcrystalline cellulose starter seeds produces dose-divided oral granules for patients with swallowing difficulty and for pediatric dose adjustment. Pyrazole Pharma Grade API is introduced at 1.05–1.2 mol equivalents relative to the downstream derivation step; the final active content in the granule blend is 5–20 mg/g, corresponding to 0.5–2.0% w/w. The active suspension is prepared with hypromellose binder at 3–5% w/w and sprayed in a fluid-bed coater with inlet air temperature 45–70°C, atomizing air pressure 1.5–2.0 bar, and product temperature 30–40°C. Nozzle occlusion from binder precipitation is a known production bottleneck; atomizing air pressure and binder viscosity are monitored continuously to maintain droplet size. The dried granules are sieved to 0.5–1.25 mm and filled into single-dose sachets on a vertical form-fill-seal line; seal strength is tested according to ASTM F88/F88M-21 with acceptance ≥15 N/15 mm. Fill weight variation and active ingredient uniformity follow USP <905> and Ph. Eur. 2.9.40; dissolution uses USP <711>; residual solvents follow USP <467> and ICH Q3C; elemental impurities follow ICH Q3D. Published data for this exact fluid-bed top-spray configuration with pyrazole-derived actives are limited; cited ranges are derived from similar poorly water-soluble active ingredients and should be confirmed by design of experiments. The terminal product is a unit-dose sachet containing oral granules for reconstitution or direct administration.
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Pyrazole Pharma Grade API, assigned CAS registry number 288-13-1, is a crystalline heterocyclic active substance with molecular formula C₃H₄N₂ and molecular weight 68.08 g/mol. The product is supplied under model codes PYZ-API-PG-O for tablet, capsule, and granule operations and PYZ-API-PG-I for sterile injectable use. The base molecule exhibits a melting range of 66–68 °C by the capillary method described in Ph. Eur. 2.2.14, and the conjugate acid pKa is approximately 2.5. The powder is white to off-white, crystalline, and freely soluble in water and ethanol; quantitative aqueous solubility is typically reported above 100 mg/mL at 25 °C. No dedicated pharmacopoeial monograph exists for unsubstituted pyrazole as a finished API in major compendia. Consequently, the specifications documented here are vendor-defined release controls that must be qualified by the finished-product manufacturer under its pharmaceutical quality system. The most immediate formulation consequence is not dissolution-limited absorption but rather a processing boundary created by the low melting range, hygroscopicity, and residual impurity management. Bulk manufacture is performed under ICH Q7, and analytical procedures are validated according to ICH Q2(R1).
Release of the pharma grade is controlled by pharmacopoeial cross-references combined with ICH requirements. Assay acceptance is 99.0–101.0% on an anhydrous basis by HPLC with detection at 230 nm. Related substances are limited to total impurities ≤0.5% and any unspecified impurity ≤0.10%. Residual hydrazine, a potential genotoxic impurity arising from synthetic routes to the pyrazole ring, is controlled at ≤1 ppm by LC-MS/MS under the risk framework of ICH M7. Nitrosamine risk is assessed because secondary amine chemistry may be encountered in manufacture; limits are aligned with ICH M7 and current health authority guidance rather than assigned as a single generic value. Elemental impurities conform to ICH Q3D, with routine ICP-MS limits of ≤10 ppm lead, ≤5 ppm cadmium, ≤5 ppm nickel, and ≤5 ppm arsenic for oral and parenteral routes. Water content is limited to ≤0.5% by Karl Fischer because moisture accelerates caking and increases the risk of hydrolytic degradation in sealed bulk packaging. Sulfated ash is ≤0.1%. Residual solvents are managed under ICH Q3C; class 1 solvents are absent, and class 2 solvents are controlled below option 2 limits, including methanol ≤3000 ppm and dichloromethane ≤600 ppm. Identification by infrared absorption spectrophotometry is expected to match the reference spectrum acquired under USP <197>.
| Quality Attribute | Oral Grade PYZ-API-PG-O | Injectable Grade PYZ-API-PG-I | Method |
|---|---|---|---|
| Assay, anhydrous basis | 99.0–101.0% | 99.0–101.0% | HPLC USP <621> |
| Water content | ≤0.5% | ≤0.5% | Karl Fischer USP <921> |
| Melting range | 66–68 °C | 66–68 °C | Ph. Eur. 2.2.14 |
| Total related substances | ≤0.5% | ≤0.5% | HPLC area normalization |
| Residual hydrazine | ≤1 ppm | ≤1 ppm | LC-MS/MS |
| Bacterial endotoxins | Not routine | ≤0.25 EU/mg | USP <85> |
| Microbial enumeration | ≤10³ CFU/g | ≤10 CFU/g | USP <61> |
| Particle size distribution | D90 ≤ 250 μm | D90 ≤ 10 μm | Laser diffraction ISO 13320 |
| Residual solvents | ICH Q3C compliant | ICH Q3C compliant | GC-HS Ph. Eur. 2.4.24 |
Oral solid dosage development with pyrazole is governed by the low melting range and high aqueous solubility. Direct compression is preferred when formulation composition allows; however, production experience on high-speed rotary presses indicates that turret speeds above 30 rpm can generate sufficient frictional heat to soften the API and produce punch filming when pyrazole loading exceeds 20 wt%. To manage this boundary, the blend is pre-conditioned to 20–25 °C and 30–40% RH, and the press is operated with pre-compression 5–8 kN and main compression 8–15 kN. For capsules, a lactose monohydrate or dibasic calcium phosphate dihydrate diluent is used; direct-fill blends are screened through 40 mesh (425 μm) to break agglomerates. Particle size is controlled with laser diffraction: oral grade is specified at D90 ≤ 250 μm for direct compression and D90 ≤ 100 μm for wet granulation to reduce content uniformity risk. Lubrication with magnesium stearate at 0.5–1.0% w/w is standard; over-lubrication above 2.0% w/w slows tablet disintegration and is avoided in formulations with high binder content.
Wet granulation with pure water is generally avoided because the free aqueous solubility of pyrazole causes partial dissolution and non-uniform recrystallization during drying. A hydroalcoholic binder system containing 60:40 isopropanol:water is used instead; granulates are dried in a fluid-bed dryer with inlet air temperature not exceeding 50 °C and dew point below 5 °C. Drying endpoint is confirmed by loss on drying ≤1.0%. The dried granulate is milled through a 0.8 mm screen and lubricated. Granulation is necessary when high-dose tablets exceed 30 wt% pyrazole because direct-compression blends above this loading exhibit flow bias in forced feeders and increased segregation. In high-shear granulation, bowl fill volume is maintained between 50% and 70%, impeller speed is limited to 100–150 rpm, and chopper speed is set below 1500 rpm to limit frictional heat. If jacket temperature exceeds 35 °C, agglomeration shifts from controlled wet massing toward melt-assisted clumping, producing oversized granule fractions above 1.4 mm after milling.
Granule-grade material for oral sachets or dry syrups is typically densified by slugging or roller compaction prior to blending with mannitol, citric acid, and sodium bicarbonate if an effervescent vehicle is selected. Roller compaction pressure is maintained between 20–40 kN on a roll press with 200 mm roll diameter and 0.8–1.0 mm gap; ribbons are milled through a 1.0 mm screen. Because pyrazole dissolves rapidly, granule dissolution is less likely to be rate-limiting than granule disintegration; effervescent pairs should be separately granulated and blended to prevent premature reaction in moist air. Loss on drying of finished granules is held ≤1.0% before filling into aluminum-laminated sachets with desiccant at ≤25 °C and ≤60% RH.
For injectable presentations, pyrazole is dissolved in Water for Injection at concentrations up to 100 mg/mL. Because the conjugate acid pKa is approximately 2.5, the free base remains almost fully unprotonated at physiological pH and does not require pH-dependent salt selection. Solution pH is adjusted to 6.0–7.5 with dilute hydrochloric acid or sodium hydroxide under aseptic conditions. The solution is made isotonic with sodium chloride 0.9% w/v or mannitol 5% w/v. Terminal steam sterilization at 121 °C for 15 min is the default cycle; however, forced degradation data should confirm that solution color remains below the acceptance threshold and that assay remains within 95.0–105.0% of label claim. Aseptic filtration through a 0.22 μm polyethersulfone membrane is applied prior to filling when terminal sterilization is not selected. Injectable-grade material is specified with bacterial endotoxins ≤0.25 EU/mg and microbial enumeration limits ≤10 CFU/g. The most significant difference from oral grade is not chemical identity but bioburden, endotoxin, and submicron particle control; sterile API is milled to D90 ≤ 10 μm under nitrogen to avoid oxidative discoloration and is filled into siliconized glass vials. Particulate matter in the finished injection must meet USP <788> for subvisible particles. Aseptic subdivision occurs under ISO 14644-1 Class 5 conditions.
Differences between pyrazole pharma grade and technical-grade heterocycles are not limited to assay. Technical pyrazole is often supplied with purity 98% but lacks release controls for endotoxin, residual hydrazine, elemental impurities classed under ICH Q3D, and microbial limits. Technical material also does not carry an ICH Q3C residual solvent statement and is often packaged in paper or non-dedicated containers with higher moisture ingress, making it unsuitable for aseptic processing. Compared with substituted pyrazole-containing APIs such as celecoxib or sildenafil, the unsubstituted pyrazole core has much lower molecular weight and higher water solubility; the processing challenges therefore differ: substituted pyrazoles may require micronization and dissolution enhancement, while unsubstituted pyrazole requires agglomeration control and thermal protection. Compared with pyrazoline or pyrazolone intermediates, the aromatic pyrazole ring is resistant to reducing agents that would open pyrazoline ring systems, and it does not carry the labile ketone functionality of pyrazolones. These distinctions mean that a technical-grade material cannot be qualified for tablet, capsule, granule, or injectable use simply by retesting assay and water; the entire contaminant profile, particle size distribution, and packaging history must be upgraded.
| Parameter | Technical-Grade Pyrazole | PYZ-API-PG-I |
|---|---|---|
| Assay | ≥98% | 99.0–101.0% |
| Bacterial endotoxins | Not controlled | ≤0.25 EU/mg |
| Microbial enumeration | Not controlled | ≤10 CFU/g |
| Particle size distribution | Not specified | D90 ≤ 10 μm |
| Residual hydrazine | Not routinely tested | ≤1 ppm |
| Elemental impurities | Not controlled | ICH Q3D parenteral limits |
| Packaging | Paper or fiberboard | HDPE drum with LDPE liner and nitrogen |
| Qualified use | Chemical intermediate | Oral and injectable pharmaceutical manufacturing |
Bulk packaging uses double LDPE liners inside HDPE drums with desiccant and nitrogen headspace. Storage is at ≤25 °C and ≤60% RH. The assigned retest period is 24 months from the date of manufacture in unopened containers. Injectable grade is subdivided into siliconized glass vials or aluminum composite closures under ISO 14644-1 Class 5 conditions; once opened, the material is not held because moisture uptake and bioburden control cannot be assured. Containers should be re-sealed immediately after sampling, and any material exposed to ambient conditions for more than 4 hours should be quarantined and tested for water content before use. Stability-indicating parameters are assay, related substances, water content, and, for injectable grade, endotoxin and particulate matter. Published data for prolonged storage of unsubstituted pyrazole in aqueous solution is limited; therefore, solution formulations are assessed by use-specific stability studies rather than assumed from solid-state data.
