(2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable
- Product Name: (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable
- Factroy Site: Yudu County, Ganzhou, Jiangxi, China
- Price Inquiry: sales10@sinochem-nanjing.com
- Manufacturer: Ascent Petrochem Holdings Co., Limited
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- (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is typically used in formulations when chiral purity and particle size distribution and temperature and humidity must be controlled within specific ranges.
| HS Code | 365358 |
| Product Name | (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile |
| Chemical Name | (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile |
| Cas Number | 241479-74-3 |
| Molecular Formula | C13H12F2N4O |
| Molecular Weight | 278.26 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay | ≥ 98.0% (HPLC) |
| Grade | Pharma Grade API |
| Dosage Forms | Tablet; Capsule; Granule; Injection |
| Routes Of Administration | Oral; Injectable |
| Storage Conditions | Store in a cool, dry place, protected from light and moisture |
| Packaging | 25 kg fiber drum with double polyethylene bags; 1 kg aluminum foil bag |
| Shelf Life | 24 months when stored properly |
| Solubility | Slightly soluble in water; soluble in methanol, ethanol, DMSO |
| Chiral Purity | ≥ 99.0% (chiral HPLC) |
| Water Content | ≤ 0.5% (Karl Fischer) |
| Heavy Metals | ≤ 20 ppm |
| Residual Solvents | Meets ICH Q3C limits |
As an accredited (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile 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 | Packaged in double LDPE-lined, light-resistant HDPE drums, 25 kg net; optionally sterile sealed containers for oral and injectable manufacturing. |
| Container Loading (20′ FCL) | 20′ FCL loaded with this pharma-grade API in sealed drums on pallets, moisture-protected, labeled, and secured for temperature-controlled shipment. |
| Shipping | This pharma-grade API for oral and injectable use ships in sealed, light-resistant, moisture-proof double LDPE bags inside HDPE drums. Transport at controlled room temperature (15–25°C), avoiding excessive heat, freezing, light, and moisture. Labels include name, batch, quantity, storage, and precautions. Follow IATA/ADR/GMP; include CoA, SDS, and chain-of-custody documentation. |
| Storage | Store pharma-grade API in a cool, dry, well-ventilated area, protected from light and moisture. Keep containers tightly closed, away from oxidizing agents and incompatible materials. Maintain controlled room temperature 20–25°C (68–77°F); excursions 15–30°C. For injectable-grade material, use aseptic handling and store per validated stability data. Do not freeze unless supported. Retain original packaging. Protect from physical damage. |
| Shelf Life | Typically 24–36 months if stored sealed, protected from light/moisture, at controlled room temperature; confirm via stability studies. |
When Does Direct Compression Fail for a Low-Dose Chiral Triazole API?
Direct compression of (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile is evaluated first for oral tablet manufacture because the route eliminates aqueous binder contact and reduces exposure of the nitrile moiety to hydrolytic conditions. The active substance fraction is typically confined to 5.0% w/w–15.0% w/w when total tablet mass is 200 mg–400 mg; microcrystalline cellulose PH102 is used at 60.0% w/w–75.0% w/w, croscarmellose sodium at 2.0% w/w–4.0% w/w, colloidal silicon dioxide at 0.25% w/w–0.50% w/w, and magnesium stearate at 0.50% w/w–0.75% w/w. These values are conservative platform ranges derived from low-dose azole oral solid-dose feasibility batches; published data specific to this compound are limited and should be confirmed by formulation DoE under ICH Q8. The blend is processed through a conical mill with a 0.5 mm screen, then mixed in a 600 L bin blender at 10 rpm for 20 min. Compression is performed on a rotary tablet press with precompression force 2 kN–5 kN, main compression force 8 kN–20 kN, and tablet hardness controlled at 60 N–100 N. The critical failure mode observed in production-scale direct compression is content uniformity loss when the particle-size distribution RSD exceeds 15%; segregation becomes measurable in the bin blender and results in acceptance failures under USP <905>. Over-lubrication with magnesium stearate above 0.75% w/w is also known to slow dissolution in immediate-release triazole systems, so the final dissolution test must follow USP <711> with an appropriate validated method. Elemental impurities are controlled according to ICH Q3D, and manufacturing is executed under 21 CFR 211. Terminal product type: uncoated or film-coated immediate-release oral tablets.
Roller compaction is selected when the direct-compression blend exhibits inadequate flow or when aqueous granulation is excluded because the nitrile group is susceptible to acid- or base-catalyzed hydrolysis. The dry granulation platform uses the API at 10.0% w/w–25.0% w/w of the intragranular mass, with microcrystalline cellulose PH102 at 45.0% w/w–60.0% w/w, crospovidone at 3.0% w/w–5.0% w/w, and magnesium stearate at 0.50% w/w–0.75% w/w. The API is pre-milled if the primary particle morphology is acicular, because needle-shaped crystals reduce ribbon strength and generate excessive fines during milling. Powder is densified on a roller compactor with roll pressure 20 kN/cm–40 kN/cm, roll speed 2 rpm–5 rpm, and gap 1 mm–3 mm. Ribbons are milled through a 1.0 mm screen; the fraction of fines below 150 µm should be limited to 30.0% w/w because higher fines cause capping during tablet compression. Final blend is compressed on a rotary tablet press to hardness 70 N–120 N. Compliance for the resulting dosage form includes USP <905>, USP <711>, and ICH Q3D. Terminal product type: immediate-release oral tablets or powder-filled capsules. A production-scale bottleneck occurs when ribbons are too dense; the milled granule then has low compressibility and requires excess compression force. Published data for this specific configuration is limited; ribbon porosity should be characterized using mercury intrusion porosimetry before lock-in of roller parameters.
If the Fill Weight of a Size 0 Capsule Exceeds 400 mg
Encapsulation of the API in a size 0 hard gelatin or HPMC shell is constrained by both fill weight and blend flow. When the fill weight exceeds 400 mg, powder bridging at the dosator nozzle and shell deformation become limiting; the formulation is then transferred to size 00 shells or the API load is reduced. In a size 0 shell, the filled mass is maintained at 180 mg–320 mg, and the active substance fraction is set at 2.0% w/w–8.0% w/w. Lactose monohydrate or mannitol is used as filler at 70.0% w/w–85.0% w/w, croscarmellose sodium at 2.0% w/w–4.0% w/w, colloidal silicon dioxide at 0.25% w/w–0.50% w/w, and magnesium stearate at 0.25% w/w–0.50% w/w. The low-shear tumble blend is filled on a dosator capsule machine with a 6 mm nozzle, tamping force 10 N–30 N, and automatic checkweighing at 100% of production. The process-control failure mode at this stage is electrostatic adherence of the API to polycarbonate contact surfaces when ambient relative humidity is below 20%; this is managed by charging the blend with colloidal silicon dioxide and controlled room humidity. Gelatin shell moisture is maintained at 13% w/w–16% w/w to avoid brittleness; HPMC shells are used when moisture sensitivity of the API or regional market requirements exclude gelatin. Dissolution testing follows USP <711>, content uniformity follows USP <905>, and residual solvents are controlled according to ICH Q3C. Terminal product type: immediate-release hard capsules.
Extrusion-spheronization is used for granules intended for reconstitution into oral suspension when taste masking and dose flexibility are required for pediatric or dysphagia-limited patients. The API is incorporated onto microcrystalline cellulose spheres of 250 µm–355 µm using a fluid-bed Wurster column; the active substance fraction in the finished granule mass is typically 1.0% w/w–5.0% w/w, with hypromellose E5 as binder at 0.5% w/w–2.0% w/w and talc at 0.5% w/w. The coating suspension is sprayed at 2 g/min/kg–5 g/min/kg with inlet air temperature 40°C–60°C; the dryer is stopped when loss on drying is <1.0% w/w. The granule is then blended with sucrose or sorbitol, sodium benzoate at 0.10% w/w–0.20% w/w, and flavoring agents to form a dry powder for reconstitution. The production-scale failure mode in fluid-bed layering is spray-dried fine generation when droplet size is too small; this reduces yield and shifts particle size distribution. Process parameters are therefore adjusted by atomization pressure and nozzle diameter. The reconstituted suspension is tested according to USP <711> for dissolution, and the dry granule is controlled for moisture and microbial quality according to ICH Q6A. Terminal product type: granules for oral suspension after reconstitution with water.
Lyophilized Injectable Freeze-Drying Cycle Design Parameters
For parenteral presentation, the API is dissolved in Water for Injection at 20°C–25°C with mannitol as bulking agent at 20.0 mg/mL–50.0 mg/mL and a citrate buffer at 10 mM–25 mM; the solution pH is adjusted to 4.0–5.5 to limit nitrile hydrolysis during processing. The bulk solution is filtered through a 0.22 µm PVDF membrane and filled into 20 mL Type I glass vials at 10 mL fill volume. The vial load is frozen to -40°C for 2 h–4 h. Primary drying is conducted at shelf temperature -20°C–-10°C and chamber pressure 100 mTorr–200 mTorr for 20 h–40 h; secondary drying at 30°C–40°C for 6 h–12 h reduces residual moisture to <1.0% w/w. The critical process failure on commercial lyophilizers is vial-edge collapse when the product temperature exceeds the collapse temperature during primary drying; this is detected by comparative pressure measurement or product temperature probes. Sterility assurance follows USP <71>, bacterial endotoxins USP <85>, particulate matter USP <788>, and visible particles USP <790>; aseptic manufacture follows EU GMP Annex 1. Terminal product type: sterile lyophilized powder for reconstitution into injectable solution.
| Cycle phase | Shelf temperature | Chamber pressure | Duration | Endpoint |
|---|---|---|---|---|
| Freezing | -40°C | atmospheric | 2 h–4 h | product below -35°C |
| Primary drying | -20°C–-10°C | 100 mTorr–200 mTorr | 20 h–40 h | ice disappearance |
| Secondary drying | 30°C–40°C | 50 mTorr–100 mTorr | 6 h–12 h | residual moisture <1.0% w/w |
A ready-to-use parenteral solution containing the API at 0.5 mg/mL–2.0 mg/mL requires a solubilization platform that prevents precipitation on dilution and protects the chiral alcohol from oxidative degradation. Sulfobutylether-β-cyclodextrin at 100.0 mg/mL–200.0 mg/mL is used as a complexing agent, with pH adjusted to 4.0–5.5 using 0.1 N hydrochloric acid or sodium hydroxide. The solution is compounded under nitrogen blanketing, filtered through a 0.22 µm PVDF membrane, and aseptically filled into Type I glass vials; terminal steam sterilization is not applied because the chiral alcohol and nitrile functionalities are thermally sensitive. The finished solution is tested for bacterial endotoxins under USP <85>, particulate matter under USP <788>, and sterility under USP <71>. In-use dilution studies are required because cyclodextrin-complexed drug may dissociate when mixed with large-volume infusion fluids; compatibility with polyolefin containers should be verified before clinical administration. Published data for this specific configuration is limited; cyclodextrin loading should be confirmed by phase-solubility studies according to ICH Q1A. Terminal product type: ready-to-use injectable solution or concentrate for intravenous infusion.
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- (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
- COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales10@sinochem-nanjing.com.
The (2S,3R)-3-(2,5-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a non-sterile, chirally defined active pharmaceutical ingredient released under ICH Q7 good manufacturing practice. The molecular formula is C13H12F2N4O and the relative molecular mass is 278.26 g/mol. The molecule contains two stereogenic centres at C2 and C3; the specified (2S,3R) configuration separates this substance from the enantiomer, racemate, and diastereomeric mixtures. The nitrile group, tertiary alcohol, 1,2,4-triazole ring, and two aromatic fluorines influence moisture uptake, solid-state behaviour, chiral recognition, and residual solvent control. The intended use is as an active ingredient for oral tablets, capsules, and granules, and for injectable manufacturing after downstream aseptic filtration or validated terminal sterilisation of the finished product. It is not a sterile API and is not a finished dosage form. Published data for this specific configuration is limited; therefore route-specific specifications, stability-indicating methods, and process parameters require development on the actual batch.
Why Does the (2S,3R) Configuration Require a Validated Chiral HPLC Method?
Because the substance has two stereogenic centres, an achiral HPLC assay cannot distinguish the desired (2S,3R) isomer from the (2R,3S) enantiomer or from C2/C3 diastereomers. Release testing therefore includes a chiral high-performance liquid chromatography method using a polysaccharide-based chiral stationary phase such as amylose tris(3,5-dimethylphenylcarbamate) or cellulose tris(4-chloro-3-methylphenylcarbamate). The method is validated according to ICH Q2(R1) for specificity, linearity, accuracy, precision, range, and limit of quantification. Chiral purity is reported as area-percent of the specified isomer relative to total stereoisomer area; the acceptance criterion is linked to the qualified exposure of stereoisomeric impurities. System suitability should specify resolution between the (2S,3R) and (2R,3S) peaks of not less than 1.5. Column compartment temperature is controlled between 25 °C and 35 °C because chiral recognition in this structural class is temperature-sensitive. A racemic batch, an inverted-isomer batch, or a batch with uncontrolled diastereomeric content cannot be substituted for this model without a full toxicological and pharmaceutical development assessment.
During GMP manufacture, the final crystallisation solvent determines the residual solvent profile and may influence particle habit. If isolation uses a vacuum tray dryer, the jacket temperature is kept below the start of thermal degradation identified by thermogravimetric analysis and differential scanning calorimetry. The dried powder is passed through a calibrated sifter having a mesh aperture narrower than the largest permitted primary particle. Batch-to-batch variability in particle size and bulk density is a common process bottleneck on a tablet line; therefore each batch is released using the same particle-size method and sampling procedure applied during development. Published data for this specific configuration is limited, so site-specific process validation remains mandatory.
For tablet and capsule manufacturing, the solid-state form is a primary control point. The tertiary alcohol and triazole ring can allow multiple crystalline forms or variable crystallinity. X-ray powder diffraction is performed according to Ph. Eur. 2.9.33 or USP <941>, with the diffractometer checked against a certified silicon standard. The release certificate should state the specified polymorph, and stability studies should monitor polymorphic conversion under ICH Q1A(R2) conditions. Particle-size distribution is measured by laser diffraction according to ISO 13320:2020; D10, D50, and D90 release ranges are more informative than a single average value. If the D90 is above 250 µm or the bulk density is below 0.35 g/mL, segregation in low-dose capsule filling and weight variation on a high-speed tablet press may increase, although published data for this specific configuration is limited and direct measurement remains mandatory.
Controlling Particle Size and Solid-State Form During Tablet and Capsule Manufacture
The API should be handled in a controlled environment with relative humidity below 60% RH unless open-container stability data support a wider range. For direct compression, the API is blended with microcrystalline cellulose, lactose monohydrate or dibasic calcium phosphate dihydrate, croscarmellose sodium, and magnesium stearate. The lubricant level is limited to 0.5% w/w to 1.0% w/w because the hydrophobic film from magnesium stearate can reduce tablet hardness and increase disintegration time if blending is prolonged. A rotary tablet press fitted with precompression rollers and 10 mm round tooling is used for development; compression profiles are generated with main compression force varying from 8 kN to 22 kN. Ejection force, hardness, friability, and disintegration are recorded. Capping or lamination at higher force may indicate elastic recovery from the crystalline API; if this occurs, dry granulation by roller compaction is preferred over wet granulation because the nitrile and tertiary alcohol may interact with moisture.
Wet granulation with hydroxypropyl cellulose or povidone is acceptable only after compatibility screening. Dry granulation by roller compaction can avoid hydrolysis risk; roll force and screen size are selected from flow function coefficient and Flodex measurements. Granules for oral use are milled through a 0.8 mm screen. Final blend uniformity is verified by stratified sampling according to USP <905> or equivalent. Disintegration and dissolution testing are performed with Ph. Eur. 2.9.3 and USP <711>, using the registered medium and apparatus. Published dissolution data for this specific configuration are limited, so the method must be developed and validated during formulation.
Capsule filling with a dosator or tamping-pin machine requires a narrower particle-size range than tableting. Powder flow is characterised by bulk density, tapped density, Carr index, and Hausner ratio. If the Carr index is above 35, glidant addition or granulation is required before encapsulation. Low-dose capsules require assay and content uniformity testing according to Ph. Eur. 2.9.40 or USP <905>. The capsule shell is selected for low moisture permeability if the API is hygroscopic; desiccant is included when stability data show water uptake above 60% RH affects dissolution.
When the API Is Supplied for Injectable Freeze-Dried Products
Injectable manufacture using this API does not require a sterile API, but the downstream process must include aseptic filtration through a 0.22 µm sterilising-grade membrane. Filter compatibility is evaluated according to ASTM F838-20 for bacterial retention, and the selected membrane should be qualified by bubble point, diffusional flow, and product-specific bacterial challenge. The solution is held in stainless steel or glass-lined vessels; contact surfaces should be passivated because the triazole and nitrile functionalities may contribute to metal complexation, although published data for this specific configuration is limited. The drug substance must meet a lower bioburden specification than oral grade and a bacterial endotoxin limit calculated from the intended maximum daily dose using the parenteral threshold of 5 EU/kg body mass. Endotoxin testing follows Ph. Eur. 2.6.14 or USP <85>.
Filter validation includes product-specific bacterial retention using Brevundimonas diminuta at a minimum challenge of 10⁷ CFU/cm². The maximum allowable pressure differential for the sterilising filter is stated by the filter manufacturer; scale-up records differential pressure across the filter. Bioburden before filtration is controlled to a process-specific limit established by media fills and process simulation. The API solution should be filtered within the validated hold time to avoid bioburden proliferation and particulate formation.
Lyophilisation cycle design uses differential scanning calorimetry and freeze-drying microscopy to identify the collapse temperature of the formulation, not the API alone. The API is dissolved in a vehicle, filtered, filled, and freeze-dried; mannitol, trehalose, or sucrose are used as bulking agents. Residual moisture after lyophilisation is controlled below the stability-justified limit. The injectable route imposes lower residual solvent limits than the oral route for certain ICH Q3C Class 2 solvents. A batch suitable for oral solid dosage release may fail injectable specification for dichloromethane, acetone, or N,N-dimethylacetamide. Route-specific acceptance criteria are assigned before release, and a single certificate of analysis cannot be used to cover both routes unless the stricter injectable limits are met.
Sub-visible particles are tested by light obscuration and microscopic particle count according to USP <788>, Ph. Eur. 2.9.19, and JP 6.07. Insoluble matter and clarity follow Ph. Eur. 2.9.20 and visual inspection. The API is not terminally sterilised as a powder; terminal sterilisation of the finished injection is possible only if the formulation is thermostable and if the container-closure system permits validated moist-heat or irradiation cycles.
Release testing panel and route-specific specifications
The following matrix summarises the analytical controls that should appear on a GMP release certificate. Limits are not universal; they are derived from the intended dose, route, and toxicological qualification.
| Quality attribute | Analytical procedure | Primary standard or guidance |
|---|---|---|
| Appearance | Visual inspection | Ph. Eur. 2.2.1 |
| Identification | Infrared absorption spectrophotometry | Ph. Eur. 2.2.24, USP <197> |
| Assay | HPLC, external reference standard | ICH Q2(R1) |
| Related substances | HPLC with UV detection | Ph. Eur. 2.2.29, USP <621> |
| Chiral purity | HPLC with polysaccharide chiral stationary phase | ICH Q2(R1), validated method |
| Water | Karl Fischer coulometric titration | Ph. Eur. 2.5.12, USP <921> |
| Residue on ignition | Muffle furnace | Ph. Eur. 2.4.14, USP <281> |
| Residual solvents | Headspace gas chromatography | ICH Q3C |
| Elemental impurities | Inductively coupled plasma mass spectrometry | ICH Q3D, USP <232>, USP <233> |
| Particle size | Laser diffraction | ISO 13320:2020, Ph. Eur. 2.9.31 |
| Polymorphism | X-ray powder diffraction | Ph. Eur. 2.9.33 |
| Bioburden | Membrane filtration and plate count | Ph. Eur. 2.6.12, USP <61> |
| Bacterial endotoxins | Limulus amebocyte lysate | Ph. Eur. 2.6.14, USP <85> for injectable route |
The assay procedure must be stability-indicating; forced degradation under heat, acid, base, oxidation, and photolysis according to ICH Q1A(R2) and ICH Q1B demonstrates that the method separates the API from degradation products. Mass balance from forced degradation is reported. Related substances are quantified by area normalisation or external standard; reporting, identification, and qualification thresholds follow ICH Q3A for new drug substances based on the intended daily dose.
Compared with a technical-grade powder of the same nominal chemical name, this Pharma Grade API differs in the level of documented control. The technical grade may be supplied with only a purity value and no chiral purity, residual solvent, elemental impurity, or polymorph data. This Pharma Grade model is released against a stability-indicating assay, a chiral method, and compendial impurity methods. Compared with a sterile API, this item is non-sterile; injectable manufacturing must include sterilising filtration and cannot rely on the powder itself to be sterile. Compared with the racemate, the (2S,3R) model has a defined stereochemical configuration and must demonstrate chiral purity. These differences are operational and regulatory; substitution of another grade in a validated process would require a supplier change under ICH Q10 and prospective variation control.
Process transfer from development to production should include a risk assessment for residual solvents, powder flow, particle-size drift, and chiral purity shift. The manufacturing batch record should state the sifter mesh aperture, drying temperature, and packaging configuration. Finished product release for each dosage form is based on the registered specification; the API model alone does not establish the finished product specification. Where specific stability data for this stereoisomer are unavailable, the development report should state that published data for this specific configuration is limited and that confirmatory studies are required before commercial release.
