| HS Code | 667101 |
| Product Name | 4(5)-Amino-5(4)-Cyanoimidazole Pharma Grade API |
| Drug Category | Active Pharmaceutical Ingredient (API) |
| Grade | Pharma Grade |
| Chemical Family | Imidazole derivative |
| Tautomerism | Exists as 4-amino-5-cyano and 5-amino-4-cyano tautomeric forms |
| Molecular Formula | C4H4N4 |
| Molecular Weight | 108.10 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay Purity | ≥99.0% on dried basis by HPLC |
| Loss On Drying | ≤0.5% |
| Residue On Ignition | ≤0.1% |
| Solubility | Soluble in dimethylformamide and dimethyl sulfoxide; sparingly soluble in ethanol and water |
| Dosage Form Suitability | Suitable for tablet, capsule, granule, oral, and injectable formulations |
| Storage Conditions | Store in tightly sealed containers, protected from light and moisture, below 25°C |
As an accredited 4(5)-Amino-5(4)-Cyanoimidazole 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 sealed, double polyethylene-lined drums with tamper-evident closures, labeled for pharma use. Quantity: 25 kg net per drum. |
| Container Loading (20′ FCL) | Container loading of 20' FCL for this pharma-grade API uses sealed drums on pallets, secured, protecting against moisture and contamination. |
| Shipping | This pharma-grade API ships in sealed, inert double-bag containers with tamper-evident seals, protected from light and moisture. Transport via temperature-controlled, secure freight to maintain stability. Full documentation includes Certificate of Analysis, MSDS, and batch traceability. Handling follows GMP and dangerous-goods protocols for safe oral and injectable use. |
| Storage | Store in a clean, cool, dry, well-ventilated area at controlled room temperature (15–30°C). Keep tightly sealed in the original container, protected from light, moisture, and incompatible materials. Avoid exposure to direct sunlight, excessive heat, and ignition sources. Ensure good ventilation and maintain proper labeling for safe handling and stability. |
| Shelf Life | Shelf life: 24 months when stored unopened in original container below 25°C, protected from moisture and light. |
In allopurinol API manufacturing campaigns, 4(5)-amino-5(4)-cyanoimidazole is charged as the limiting heterocyclic precursor into a 5000 L glass-lined reactor at a corrected mass equivalent to 1.00–1.05 molar equivalents on the assayed dry basis. Hydrazine hydrate, 80% (w/w), is metered at 1.10–1.35 molar equivalents at 12–25 kg/h, with jacket temperature maintained at 88–98°C. The stoichiometric band is narrow because excess hydrazine above 1.35 equivalents promotes ring opening to 3-aminopyrazole-4-carboxamide and depresses isolated 3-amino-4-cyanopyrazole yield, while substoichiometric hydrazine leaves unreacted cyanoimidazole that co-precipitates and fouls the discharge line. In-process HPLC on a C18 column (150 mm × 4.6 mm, 5 µm) is used to track conversion; the reaction is judged complete when residual cyanoimidazole area is ≤ 0.5%. Compliance for this step follows ICH Q7 sections 7.1, 7.3, and 8.1, with ICH Q11 sections 3.2 and 5.1 applying to starting material justification. Residual hydrazine control is conducted by derivatization LC and the release limit is set at ≤ 0.1 ppm in the isolated intermediate; solvent residues are controlled by USP <467> and ICH Q3C(R9), with methanol and ethanol limits assigned according to the expected daily dose of allopurinol. The downstream production sequence includes Dimroth rearrangement at 95–102°C for 8–14 h, continuous scrubbing of evolved ammonia in dilute sulfuric acid, cooling to 0–5°C, isolation in a Hastelloy C-22 centrifuge, and recrystallization from 25% aqueous methanol. The 3-amino-4-cyanopyrazole intermediate is then cyclized with formamide at 180–195°C under nitrogen to form allopurinol API. Terminal finished dosage forms are uncoated allopurinol tablets, 100 mg and 300 mg, and in some registrations 200 mg scored tablets; dissolution is controlled by USP <711> and uniformity by USP <905>. In the 100 mg tablet core, allopurinol API is added at 30–45% by weight of the granulate; the exact finished drug load is fixed in the approved ANDA/MA master formula and is not inferred from the synthetic charge ratio.
Direct hydrolysis of the cyano substituent under aqueous acidic conditions opens the route to 6-thiopurine antimetabolite APIs, specifically 6-mercaptopurine and its azathioprine prodrug. The addition ratio in the hydrolysis vessel is 1.0 kg of dry 4(5)-amino-5(4)-cyanoimidazole to 4.5–5.0 L of 20% (w/w) sulfuric acid, corresponding to approximately 1:1.3–1.5 molar equivalents of H₂SO₄; the batch is heated to 70–75°C and held until the nitrile stretch at 2200 cm⁻¹ disappears by mid-infrared PAT. The operating window is bounded by residual nitrile and ammonia evolution; insufficient acid produces an intractable sulfate slurry, while excess acid above 25% (w/w) hydrolyzes the imidazole ring to low-molecular-weight fragments. The step is controlled under ICH Q7 section 7.1 for incoming material testing and under 21 CFR 210.3(b)(4) for batch record control. Subsequent ring closure with formamide is run at 175–185°C under reduced pressure; the resulting hypoxanthine is isolated and assayed at 98.0–101.5% on the dried basis by HPLC against a reference standard. Thionation of hypoxanthine with phosphorus pentasulfide in pyridine at 120–125°C creates a critical H₂S exposure boundary; the scrubber system is designed for 5 ppm maximum H₂S in the production area, and the reaction is quenched with 10% sodium hydroxide. The 6-mercaptopurine API is micronized in a fluidized-bed jet mill to D₉₀ ≤ 25 µm, then blended with lactose monohydrate and pregelatinized starch and compressed into 50 mg tablets. In the 50 mg mercaptopurine tablet, the micronized API addition ratio is typically 10–25% by weight of the core; the exact ratio is matched to the approved master formula after content uniformity optimization. Azathioprine sodium injection is derived from the same 6-mercaptopurine intermediate by alkylation with 5-chloro-1-methyl-4-nitroimidazole in N,N-dimethylacetamide, followed by lyophilization of the sodium salt. Terminal finished types are 50 mg mercaptopurine tablets, 25 mg, 50 mg, 75 mg, and 100 mg azathioprine tablets, and 100 mg/vial azathioprine sodium injection; all are controlled under USP <905> and injectables under USP <1>.
For investigational AICAR (5-aminoimidazole-4-carboxamide riboside, acadesine) production, the cyano substituent is hydrolyzed under alkaline rather than acidic conditions to preserve the carboxamide at position 4. The 4(5)-amino-5(4)-cyanoimidazole is suspended in 3.0–3.5 volumes of water and treated with 1.05–1.15 molar equivalents of sodium hydroxide at 60–68°C; in-line pH is held at 9.5–10.5 by automatic titration. A pH excursion above 10.5 generates 5-aminoimidazole-4-carboxylic acid, which competes with the desired carboxamide and is difficult to reject without preparative chromatography; the control loop therefore combines an in-line pH electrode and an ammonia-selective probe. The resulting 5-aminoimidazole-4-carboxamide is isolated by vacuum crystallization at 5–10°C and dried at 55–60°C to ≤ 0.5% water. Ribosylation is performed with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose at a molar ratio of 1.0:1.15–1.25 in acetonitrile, using trimethylsilyl triflate at 0–5°C; deprotection is carried out with methanolic ammonia at 20–25°C. Residual solvent control under ICH Q3C(R9) is essential because acetonitrile is a Class 2 solvent; release limits are set at ≤ 410 ppm for acetonitrile and ≤ 3000 ppm for methanol in the AICAR intermediate. The crude product is purified by preparative C18 HPLC using ammonium acetate buffer and then lyophilized. Terminal finished types are investigational lyophilized vials for intravenous infusion; no licensed commercial monograph exists, and published formulation data for this specific configuration is limited. Pilot lyophilization studies have used a reconstitution target of 5–10 mg/mL in normal saline, but the final addition ratio is established by the clinical protocol. Injectables are controlled under USP <1> and USP <790>; the lyophilized cake is tested for visible particulates and moisture ≤ 1.0%.
5-Aminoimidazole-4-carboxamide produced from the cyano group is a branch point; one narrower but documented route converts it to the immunosuppressant mizoribine, 5-hydroxy-1-β-D-ribofuranosylimidazole-4-carboxamide. The diazotization is carried out in 6 M hydrochloric acid at −5 to 0°C, with 1.00–1.05 molar equivalents of sodium nitrite charged as a 30% aqueous solution over 45–60 min. The reactor is jacketed stainless steel with brine circulation at −10°C because the diazonium intermediate decomposes above 2°C to 4-carboxamide imidazole, creating a yield cliff. After controlled aging at 0–2°C for 30 min, the diazonium stream is quenched into 10% sulfuric acid at 60°C to yield 5-hydroxyimidazole-4-carboxamide. Ribosylation uses β-D-ribofuranose 1-acetate 2,3,5-tribenzoate at a molar ratio of 1.0:1.1–1.2 in toluene with trimethylsilyl triflate at 50°C; deprotection is performed with sodium methoxide in methanol. Compliance references include ICH Q7 sections 7.1 and 8.1, the Japanese Pharmacopoeia 18 General Notices and GMP Ministerial Ordinance, and ICH Q3D(R3) for elemental impurities. Because sodium nitrite is used, a nitrosamine risk assessment is required under ICH M7(R2) and EMA/CHMP/CVMP/QWP/213927/2019; the process is designed with a nitrous acid scavenging step using sulfamic acid in the quench vessel. Terminal finished products are mizoribine 25 mg and 50 mg tablets; the API is wet-granulated with lactose monohydrate and hydroxypropylcellulose at 10–30% drug load in the core, compressed, and film-coated. Content uniformity follows USP <905>.
Where the target downstream product is inosine pranobex, the cyanoimidazole path can be extended from AICA to hypoxanthine and then to inosine, but the industrial adoption of the chemical route is narrower than fermentation-based inosine sourcing. The addition ratio for chemical ribosylation of hypoxanthine is 1.0:1.2–1.4 molar equivalents of protected ribose donor, typically 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, in anhydrous toluene with trimethylsilyl triflate at 50–55°C. The process is sensitive to water; Karl Fischer moisture in the hypoxanthine feed is held at ≤ 0.3% to avoid destroying the Lewis acid. After deprotection with sodium methoxide, inosine is isolated and then complexed with 4-acetamidobenzoic acid and dimepranol according to the pranobex stoichiometry. Compliance for this type of oral product references Ph. Eur. 2.9.5 for uniformity of mass, USP <711> for dissolution, and ICH Q3D(R3) for elemental impurities; residual toluene is controlled according to ICH Q3C(R9) at ≤ 890 ppm. The terminal finished types are inosine pranobex 500 mg tablets and 250 mg capsules; the API complex addition ratio is 100 mg inosine per 500 mg tablet, though the exact excipient-to-drug ratio is fixed by the marketing authorization. Published production-scale data for the fully chemical route from 4(5)-amino-5(4)-cyanoimidazole to inosine pranobex is limited, so process robustness must be confirmed through a formal design-of-experiments campaign before commercial scale-up.
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4(5)-Amino-5(4)-cyanoimidazole Pharma Grade API is the tautomerically interconverting imidazole derivative represented by CAS 5098-11-3, molecular formula C4H4N4, and molecular mass 108.10 g/mol. The compound is supplied as a white to off-white crystalline powder for tablet, capsule, granule, and injectable product development. Because the amino and cyano substituents occupy the 4- and 5-positions of the imidazole ring, the substance exists as a prototropic tautomer pair in solution; this equilibrium influences infrared reference spectra, HPLC retention, and solid-state form control. The oral/injectable pharma grade differs from laboratory reagent material by requiring control of residual polar imidazoles, bioburden, particle size, and residual solvent profile under ICH Q7 GMP for active pharmaceutical ingredients.
The product model designation “Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable” is a supplier-defined grade rather than a pharmacopoeial monograph title. It indicates that the material has been manufactured and released under ICH Q7 conditions, with controls suitable for oral solid and injectable process requirements. The grade is typically subdivided by particle size: unmicronized powder for wet granulation, micronized powder for direct compression or low-dose blends, and solution-grade material for parenteral use. If a specific D90 target is not stated on the certificate of analysis, the manufacturer should be requested to provide laser-diffraction data per ISO 13320-1:2020 before solid-dose development begins.
Because the tautomers can interconvert during dissolution, HPLC methods typically use a low-pH mobile phase with acetonitrile and a C18 column; UV detection at 210–254 nm captures the imidazole chromophore. Reference standards must be qualified for both tautomeric forms if separate peaks are resolved. A representative release specification for the solid-dose and injectable grade material is shown below.
| Quality attribute | Acceptance criterion | Method / standard |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual, powder bed under D65 illumination |
| Identification | IR spectrum concordant with reference; HPLC retention time agreement | Ph Eur 2.2.29; USP 621 |
| Assay on anhydrous, solvent-free basis | 98.0–102.0% w/w | HPLC, USP 621 |
| Related substances | Total ≤ 1.0%; largest single ≤ 0.3% | HPLC area normalization |
| Loss on drying | ≤ 0.5% | USP 731 / Ph Eur 2.2.32 |
| Residue on ignition | ≤ 0.1% | USP 281 / Ph Eur 2.4.14 |
| Elemental impurities | Class 1/2A limits per ICH Q3D; Pb ≤ 10 ppm if specified | USP 232 / 233; Ph Eur 2.4.8 |
| Residual solvents | Class 3 solvents ≤ 0.5% w/w; Class 1 not detected | ICH Q3C, GC-HS |
| Water content | ≤ 0.5% | USP 921 Method Ia |
| Particle size, oral solid grade | D90 ≤ 100 µm; D50 ≤ 50 µm | Laser diffraction, ISO 13320-1:2020 |
| Bioburden | ≤ 100 CFU/g; absence of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa | Ph Eur 2.6.12 / 2.6.13 |
For tablet and capsule manufacture, the crystalline powder is usually compactible after dry granulation. A high-shear granulator with impeller tip speeds of 4–8 m/s and a screen mill of 2–5 mm are suitable for densifying low-bulk-density lots; if direct compression is used, the blend should be assessed for segregation because the API particle size distribution can shift during hopper discharge. Content uniformity at low doses is improved when the API is milled to D90 ≤ 75 µm and preblended with a similarly sized excipient for not less than 10 min in a tumble blender operating at 50–70% vessel capacity. Lactose monohydrate should be avoided in long-term solid formulations because the primary aromatic amino group can form Schiff-base adducts with reducing sugar aldehydes; mannitol, dicalcium phosphate dihydrate, and microcrystalline cellulose are non-reducing alternatives. Capsule filling on dosator machines may require pin tamping or slug densification to maintain fill weight within ±3%.
For tablet manufacture, the API is typically incorporated at 1–10% w/w in a dry blend of microcrystalline cellulose and pregelatinized starch. Aqueous film-coating of the final tablet does not expose the core to bulk water; however, coating suspensions containing aldehyde-functional plasticizers or reducing sugars should be avoided. Capsule formulations commonly use lactose-free diluents for the same reason, and gelatin capsules are compatible when moisture ingress is controlled below 60% RH. Granulation may be performed by dry roller compaction at roll pressures of 20–40 kN and screen milling through a 1.0–1.5 mm screen. Injectable solution development requires equilibration of the nitrile stability profile with the desired pH; if the API is poorly soluble at stable pH, a co-solvent system of polyethylene glycol 300 and water may be evaluated, but the co-solvent must be justified by solubility and stability data.
For injectable solutions, the principal degradation risk is hydrolysis of the cyano group to the corresponding carboxamide and then to the carboxylic acid. The rate is pH- and temperature-dependent; forced-degradation screening for nitrile-containing heterocycles typically shows rapid degradation below pH 3 and above pH 9, with a more stable plateau between pH 4 and 7. No published product-specific forced-degradation data for this exact API is publicly available; therefore, a formulation-specific Arrhenius study should be generated before terminal sterilization is selected. Steam sterilisation at 121 °C for 15 min may be feasible only if the solution is buffered in the pH 5.0–6.5 range and the headspace is nitrogen-flushed; otherwise, aseptic filtration followed by lyophilisation is the more conservative parenteral route. Dextrose diluents are incompatible because the open-chain aldehyde can react with the primary amino group; mannitol and sodium chloride are non-reducing alternatives. Trace metal contamination from stainless steel surfaces can accelerate nitrile hydration, so passivated equipment and EDTA at 0.005–0.01% w/v may be evaluated.
In granular formulations, aqueous binder addition is limited by the same hydrolysis sensitivity. Non-aqueous granulation with ethanol or isopropanol is preferred unless a short aqueous wet massing window has been validated. A fluid-bed granulator with inlet air temperature 50–60 °C and dew point below 5 °C reduces residual moisture; the dried granule should be tested for loss on drying before lubrication. Magnesium stearate at 0.5–1.0% w/w is typical, but extended blending beyond 5 min can over-lubricate and reduce tablet tensile strength.
Air-jet milling of the crystalline API at pressures above 5 bar can produce electrostatic charge accumulation and agglomeration, especially at relative humidity below 30%. This can cause weight variation on high-speed tablet presses running at 60–100 rpm. A pin mill with cooled nitrogen is frequently used for particle size reduction when the material displays thermal softening; the milled powder should be rechecked by X-ray powder diffraction per USP 941 because over-milling can generate amorphous content that changes dissolution and chemical stability. For solid-dose grades, a particle size specification of D90 ≤ 100 µm is often sufficient for drug loadings above 2% w/w; below 0.5% w/w, D90 ≤ 15 µm and a content uniformity limit of 85–115% per Ph Eur 2.9.40 may be required. The injectable solution grade is controlled by filterability and clarity rather than particle size when the product is dissolved; a 0.22 µm sterilizing filter with polyvinylidene fluoride membrane is typical for aseptic filtration.
Storage of the API should use double low-density polyethylene liners inside aluminium foil-laminated bags, with desiccant added when long-term moisture data indicate hygroscopicity. If the warehouse relative humidity exceeds 60%, pre-drying at 40–50 °C under vacuum is recommended before dispensing. The primary amino group and nitrile substituent require separation from strong oxidising agents, acid chlorides, and anhydride vapours; co-storage with amine-reactive or nitrile-reactive reagents should be avoided.
Compared with 5-aminoimidazole-4-carboxamide (AICA, CAS 360-97-4), the cyano substituent removes the carboxamide hydrogen-bond donor and lowers molecular mass from 126.12 to 108.10 g/mol. AICA is the hydrolysis endpoint of the cyano group; therefore, the cyano compound is less polar but more sensitive to hydrolytic conditions. In purine synthesis, the cyano derivative is used as a precursor that condenses with formamidine acetate to yield adenine, whereas AICA requires different ring-closure strategies. Compared with 4-nitro-5-cyanoimidazole, the reduced amino derivative does not introduce nitroaromatic impurities and thus avoids the genotoxic impurity class associated with nitroaromatic starting materials. The amino group also confers a site for Maillard-type incompatibility; this is not observed with 4-cyano-5-methylimidazole, which lacks the primary amino substituent.
Route-specific impurities may include the corresponding carboxamide, unreacted nitrile precursor, and polar dimeric or oligomeric imidazole by-products. LC-MS methods are used to identify polar impurities that co-elute with the main tautomer. Because a harmonised pharmacopoeial monograph for this molecule is not available, the user is responsible for qualifying impurity reference standards and setting limits that are consistent with toxicological data and batch history.
Regulatory documentation for the pharma grade should include a retest period supported by long-term and accelerated stability data; if no formal stability data for the API are available, a retest date of 12 months from manufacture is common when the material is stored below 25 °C and protected from light. Analytical test methods should be validated for specificity, linearity, accuracy, and repeatability per ICH Q2(R1); the acceptance criteria for related substances should be linked to batch data and toxicological assessment. The material is not intended for direct administration unless the user has established active ingredient status, dose, and safety through the appropriate regulatory pathway.
