| HS Code | 131143 |
| Productname | Daunorubicin Pharma Grade API |
| Drugclass | Anthracycline antibiotic |
| Dosageformcompatibility | Tablet, Capsule, Granule, Injection |
| Administrationroute | Oral and Injectable |
| Chemicalname | (8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione |
| Molecularformula | C27H29NO10 |
| Molecularweight | 527.52 g/mol |
| Casnumber | 20830-81-3 |
| Synonyms | Daunomycin, Rubidomycin |
| Physicalappearance | Orange-red crystalline powder |
| Solubility | Sparingly soluble in water; soluble in dimethyl sulfoxide; slightly soluble in methanol |
| Meltingpoint | 208-210°C (decomposes) |
| Storagecondition | Store at 2-8°C, protected from light and moisture |
| Purityspecification | ≥98% by HPLC |
| Mechanismofaction | Intercalates DNA, inhibits topoisomerase II, and generates free radicals |
| Stability | Stable under recommended storage conditions; avoid prolonged exposure to light and heat |
| Pharmacokineticproperty | Rapid tissue distribution; metabolized to daunorubicinol; terminal half-life approximately 26-48 hours |
As an accredited Daunorubicin 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 | Daunorubicin Pharma Grade API is packed in sealed double polyethylene-lined aluminum bags, 100 g per container, for oral/injectable dosage forms. |
| Container Loading (20′ FCL) | 20′ FCL: Daunorubicin Pharma Grade API packed in sealed drums on pallets, temperature-controlled, light-protected, secure for oral/injectable formulations. |
| Shipping | Daunorubicin API is shipped as a hazardous, cytotoxic substance (UN 2811, Class 6.1) in UN-certified, sealed packaging. Maintain 2–8°C cold chain, protect from light, clearly label “Cytotoxic,” and include SDS and dangerous-goods documentation. Segregate from food products; use triple-layer containment for tablets, capsules, granules, or injectable formulations. |
| Storage | Store Daunorubicin Pharma Grade API in tightly sealed, light-resistant containers under refrigeration (2–8°C), protected from moisture and humidity. Keep away from oxidizing agents and incompatible materials. Maintain a clean, controlled environment to prevent contamination. Handle with strict cytotoxic precautions, following GMP guidelines to ensure stability and safety for oral and injectable formulations. |
| Shelf Life | Shelf life is typically 24 months when stored under recommended conditions, protected from light, and kept at controlled room temperature. |
In the acute myeloid leukemia induction platform, daunorubicin hydrochloride is incorporated into a 7+3 regimen at 60 mg/m²/day on days 1–3 alongside cytarabine 100–200 mg/m²/day continuous infusion on days 1–7. The finished dosage form for this route is a sterile lyophilized powder for concentrate for solution for infusion, supplied as 20 mg daunorubicin base per vial. Compliance baseline for this platform is EU GMP Part II for the API, 21 CFR 210/211 for finished dosage manufacturing, and release testing under Ph. Eur. 2.6.1 for sterility, Ph. Eur. 2.6.14 for bacterial endotoxins, Ph. Eur. 2.9.19 for subvisible particulate matter, and USP <790> for visible particulates. The batch formula uses 20 mg daunorubicin base per vial against 100 mg mannitol, giving a 1:5 active-to-bulking agent ratio; sodium hydroxide 0.1 M or hydrochloric acid 0.1 M is used solely to target pH 5.5 ± 0.5 after reconstitution to 10 mL with Water for Injections. The downstream manufacturing process dissolves the API in Water for Injections at 2 mg/mL under nitrogen-sparged, amber-light conditions at 15–20 °C, passes the bulk solution through a 0.22 µm PVDF double-layer sterilizing-grade filter, fills 10.0 mL ± 0.3 mL into Type I borosilicate glass vials, and lyophilizes with a freeze ramp to -40 °C at 1 °C/min, primary drying at -20 °C and 0.2 mbar for 36 h, secondary drying at 20 °C for 12 h, and final stopper closure under vacuum. Residual moisture is release-tested at ≤2.0% w/w, cake appearance is checked for meltback and collapse, and the terminal product is a lyophilized powder for concentrate for solution for infusion, 20 mg/vial, intended for intravenous administration after reconstitution with 0.9% sodium chloride or 5% dextrose.
Within secondary acute myeloid leukemia, fixed-ratio liposomal daunorubicin/cytarabine injection is manufactured by a remote-loaded liposomal platform rather than by simple sterile filling. The terminal product is a liposomal injection for intravenous infusion in which each 20 mL vial contains 44 mg daunorubicin and 100 mg cytarabine, equivalent to 2.2 mg/mL and 5.0 mg/mL respectively; the cytarabine-to-daunorubicin molar ratio is fixed at 5:1 inside the aqueous core to maintain synergistic cell-kill after infusion. Compliance for this product category is driven by ICH Q6A for liposome release specification design, USP <790> for visible particulates, Ph. Eur. 2.6.1 for sterility, Ph. Eur. 2.6.14 for bacterial endotoxins, USP <788> for subvisible particulate matter, and ICH Q3D for elemental impurities. The production process typically includes lipid dissolution in ethanol, injection into aqueous buffer under high-shear dispersion, size reduction through a piston-gap homogenizer or microfluidizer at approximately 15,000 psi, extrusion through 100 nm polycarbonate track-etch membranes, ultrafiltration/diafiltration to remove external solvent and unentrapped drug, and subsequent active loading across a transmembrane ionic gradient. Unencapsulated drug is reduced below 5% of total drug by HPLC, mean particle diameter is controlled at 100–120 nm by dynamic light scattering at 173° backscatter, and zeta potential is monitored as a surrogate for aggregation risk. The finished product is a single-use vial of liposomal injection for intravenous infusion, 44 mg daunorubicin/100 mg cytarabine per 20 mL; dilution is performed only with label-compatible intravenous fluids, and filtration of the final liposomal dispersion through sub-5 µm in-line filters is avoided to prevent liposome rupture.
Liposomal daunorubicin citrate in advanced HIV-associated Kaposi sarcoma is not a conventional solution product; it is a size-restricted unilamellar liposome in which daunorubicin is complexed with citrate and concentrated into the aqueous core of a distearoylphosphatidylcholine/cholesterol bilayer. The clinical formulation contains 2 mg/mL daunorubicin citrate, supplied as a 50 mg/25 mL single-use vial, and is diluted only in 5% dextrose before intravenous infusion; the distearoylphosphatidylcholine-to-cholesterol molar ratio of 2:1 is maintained during lipid hydration to produce a mean particle diameter of approximately 45 nm, which is critical for the tumor-selective pharmacokinetic profile. Compliance is anchored to Ph. Eur. 2.6.1, Ph. Eur. 2.6.14, Ph. Eur. 2.9.19, USP <788>, and ICH Q1B photostability; because the product is a liposomal parenteral, batch release also includes encapsulated-drug percentage determined by centrifugal ultrafiltration with a 100 kDa molecular weight cutoff, with free daunorubicin typically controlled below 10% of total drug. The downstream process uses lipid film rehydration: the phospholipid/cholesterol mixture is dissolved in chloroform, evaporated under reduced pressure to form a thin film, hydrated with citrate buffer at 60–65 °C, extruded through 50 nm and 80 nm polycarbonate membranes, and then loaded with daunorubicin via a transmembrane pH gradient generated by the internal citrate buffer. The loading step is terminated when encapsulation efficiency reaches the release threshold, and unentrapped drug is removed by diafiltration; terminal product type is a liposomal dispersion for intravenous infusion after dilution with 5% dextrose, 2 mg/mL, 50 mg per 25 mL vial, stored at 2–8 °C without freezing.
For ALL induction regimens, a preservative-free aqueous injection is manufactured when lyophilization is not required by the dose presentation. The finished product is a sterile solution for intravenous injection containing daunorubicin hydrochloride equivalent to 5 mg/mL daunorubicin base, sodium chloride 9 mg/mL for isotonicity, hydrochloric acid or sodium hydroxide for pH adjustment to 5.0 ± 0.3, and Water for Injections as vehicle. The formulation addition level is therefore 500 mg API per 100 mL of bulk solution, with sodium chloride fixed at 900 mg per 100 mL. Compliance baseline for this presentation is USP <1>, USP <85>, Ph. Eur. 2.6.1, Ph. Eur. 2.6.14, Ph. Eur. 2.9.19, and ICH Q1B; the solution is not autoclaved because the anthracycline glycoside degrades under terminal heat treatment. The manufacturing process dissolves the API in cooled Water for Injections at 10–15 °C under nitrogen, adjusts pH after complete dissolution, passes the bulk through a 0.22 µm PES sterilizing-grade filter validated for bacterial retention per ASTM F838-20, fills 10 mL or 20 mL into amber Type I glass vials under ISO Class 5 unidirectional airflow, and seals with FluroTec-coated butyl rubber stoppers. The batch hold time between dissolution and filtration is limited to 8 h and the solution is protected from daylight throughout; photodegradation is assessed by ICH Q1B forced-light exposure using HPLC purity and related substance profiling. Terminal product type is a sterile solution for intravenous injection, 5 mg/mL in amber Type I borosilicate glass vials, intended for hospital cytotoxic compounding and direct intravenous administration.
| Injectable platform | API loading | Critical process parameter | Terminal product label |
|---|---|---|---|
| AML induction lyophilized powder | 20 mg/vial | Primary drying at -20 °C and 0.2 mbar | Powder for concentrate for solution for infusion |
| Secondary AML fixed-ratio liposome | 44 mg/20 mL | Extrusion through 100 nm membranes | Liposomal injection for intravenous infusion |
| Kaposi sarcoma liposomal dispersion | 50 mg/25 mL | 45 nm mean diameter after extrusion | Liposomal dispersion for infusion after dilution |
| ALL aqueous injection solution | 5 mg/mL | 0.22 µm sterilizing filtration at 10–15 °C | Sterile solution for intravenous injection |
Published data for commercial oral daunorubicin solid dosage forms are limited, and no EU or US authorised oral finished product exists. The API is not considered a viable oral active for conventional tablet, capsule, or granule products because its absolute oral bioavailability in humans is insufficient to generate reliable systemic exposure; this is a documented constraint, not a formulation omission. For tablet and capsule development, the industry compliance baseline is ICH M7 for DNA-reactive impurities, ICH Q3D for elemental impurities, Ph. Eur. 2.9.1 for disintegration, Ph. Eur. 2.9.5 for uniformity of mass, USP <905> for uniformity of dosage units, and EU GMP Part II for the API. A commercial formulation addition ratio cannot be codified from pharmacopoeial or regulatory sources; exploratory oral unit designs have been limited by haematological dose-limiting toxicity rather than by a performance-based active-to-excipient ratio, and published data for a release-grade solid oral filler/binder ratio specific to daunorubicin are not available. The downstream production process for any investigational oral granule or capsule uses dry granulation by roller compaction or direct compression under cytotoxic containment; aqueous wet granulation is avoided because the glycosidic bond in the anthracycline is hydrolytically labile, and tablet compression is performed in downflow isolators with separate air handling to prevent cross-contamination. Terminal product type for this segment is not a commercial product: it is an investigational oral capsule, tablet, or granule batch produced only in early-phase clinical pharmacology or bioavailability studies under a clinical trial authorisation.
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Daunorubicin hydrochloride is an anthracycline glycoside antibiotic obtained by fermentation of Streptomyces peucetius var. caesius. The active pharmaceutical ingredient is supplied as an orange-red to red hygroscopic powder with the molecular formula C27H29NO10·HCl, a molecular weight of 563.98 g/mol, and the hydrochloride salt CAS 23541-50-6. The free base carries CAS 20830-81-3. Compendial alignment includes the Ph. Eur. monograph Daunorubicin hydrochloride, the USP monograph, and the JP monograph; the assay requirement is 98.0–102.0% on the anhydrous basis. This product is intended for further manufacture into tablet, capsule, granule, oral liquid, and sterile injectable dosage forms. It is not a finished drug product. Two route-specific profiles are maintained: solid oral grades are controlled for particle size, powder flow, residual solvents, and moisture sensitivity suitable for low-dose cytotoxic blending; injectable grades are additionally controlled for bioburden, bacterial endotoxin, and particulate matter after reconstitution and filtration. Because anthracyclines are classified as hazardous drugs, handling is performed in closed isolators or downflow booths complying with NIOSH hazardous drug containment guidance and with 21 CFR Part 211.84 incoming drug substance testing.
Release specifications are route-dependent rather than uniform. Identification is confirmed by infrared absorption spectrophotometry against a reference standard per Ph. Eur. 2.2.24 and by retention time in the high-performance liquid chromatographic assay per USP <621> and Ph. Eur. 2.2.29. Related substances are determined by reversed-phase HPLC with ultraviolet detection at 254 nm; controlled degradants include daunorubicinone, doxorubicin, and other anthracycline-related compounds. Water content is measured by Karl Fischer titration per USP <921>, with tighter limits for injectable grades because residual moisture influences reconstitution time and hydrolytic degradation. Residual solvents are quantified by headspace gas chromatography per Ph. Eur. 2.4.24; acceptance criteria follow ICH Q3C Table 2 and Table 3. Elemental impurities are controlled according to ICH Q3D; where the parenteral route is intended, the parenteral permitted daily exposure applies, and USP <232>/<233> or Ph. Eur. 2.4.20 analytical procedures are used. For sterile injectable material, bacterial endotoxin is determined by the Limulus amebocyte lysate assay per Ph. Eur. 2.6.14 and USP <85>; the acceptance limit is derived from the maximum intended dose, and a representative specification for parenteral anthracyclines is ≤0.50 EU/mg when the intended dose is 100 mg/day or less. Sub-visible particulate matter in the reconstituted injectable is assessed by light obscuration according to USP <788>, with small-volume injection limits of 6000 particles per container for particles ≥10 µm and 600 particles per container for particles ≥25 µm.
| Quality attribute | Method or standard reference | Representative requirement |
|---|---|---|
| Assay on anhydrous basis | Ph. Eur. 2.2.29 / USP <621> | 98.0–102.0% |
| Bacterial endotoxin, injectable grade | Ph. Eur. 2.6.14 / USP <85> | ≤0.50 EU/mg |
| Sub-visible particulate matter | USP <788> | 6000 particles/container ≥10 µm; 600 particles/container ≥25 µm |
| Residual solvents | ICH Q3C / Ph. Eur. 2.4.24 | Class 2 and Class 3 limits by headspace GC |
| Elemental impurities | ICH Q3D / USP <232>/<233> | Parenteral permitted daily exposure per element |
During tablet and capsule manufacture, the milled API is deagglomerated through a 0.5 mm or 1.0 mm mesh screen and blended with excipients in a diffusion mixer or V-shell blender. Because daunorubicin hydrochloride is a low-dose cytotoxic with hydrolytic sensitivity, direct compression or roller compaction is generally selected over aqueous wet granulation to limit moisture contact. Content uniformity is evaluated per USP <905>; the finished dosage unit acceptance value is ≤15.0. Powder flow is characterized by angle of repose and Carr index according to USP <1174>; angle of repose values above 40° normally require glidant addition or re-milling. Tablets are compressed on a rotary tablet press with instrumented punches; hardness, disintegration, and friability are tested according to USP <1217>, USP <701>, and USP <1216>. Capsule filling is performed on a dosator or tamping-pin machine with fill weight verification after setup and at defined intervals. Dissolution testing for immediate-release tablet or capsule presentations is conducted using USP <711> Apparatus 2 at 50 rpm; acceptance criteria are stage-based and product-specific under ICH Q6A.
Within high-shear granulation trains, a non-aqueous or acidified hydroalcoholic binder system may be used only when the granulation endpoint is controlled by torque or power consumption. Drying is performed in a fluid-bed dryer with inlet air temperature below the validated thermal degradation threshold; product temperature is monitored continuously because elevated temperatures accelerate aglycone formation. The dried granule is milled and screened, and particle-size distribution is verified by sieve analysis per USP <786>. Granule loss on drying is controlled by infrared moisture balance or Karl Fischer titration per USP <921> before compression or encapsulation.
Daunorubicin hydrochloride is not suitable for terminal steam sterilization at 121°C because the anthracycline ring system undergoes hydrolytic and oxidative degradation under autoclave conditions. Aseptic manufacturing is therefore used for sterile dosage forms. The API is dissolved in Water for Injection, the pH is adjusted to the mildly acidic range of 4.5–6.5, and the solution is sterile-filtered through a 0.22 µm double-layer polyvinylidene fluoride or polyethersulfone membrane. Filter compatibility is verified by bubble point, diffusional flow, and extractable/leachable data; drug adsorption on the membrane is measured by recovery studies. The filtrate is filled into glass vials under ISO 14644-1 Class 5 unidirectional airflow in an isolator or restricted-access barrier system. Lyophilization is the stabilization method for this heat-labile anthracycline; the primary drying shelf temperature is maintained below the collapse temperature determined by freeze-drying microscopy, and chamber pressure is controlled with a Pirani gauge for endpoint detection. Residual moisture in the lyophilized cake is measured by Karl Fischer titration per USP <921>; typical acceptance is ≤2.0% w/w for long-term cake stability. The reconstituted solution is tested for sub-visible particles per USP <788>, pH, assay, and related substances. In-use stability after reconstitution is validated per Ph. Eur. 5.1.3; common storage is 2–8°C protected from light, with a hold time not exceeding the validated period. Alkaline buffers, strong oxidizers, and amine-based excipients are incompatible because they accelerate aglycone formation or adduct formation.
On production-scale solid dosage lines, batch-to-batch particle-size variance produces measurable shifts in tableting. If an API lot has a laser diffraction d90 above the qualified range, ejection force and tablet hardness can increase; if the lot is over-milled, flowability declines and die filling becomes erratic. Instrumented rotary press data for compression force, ejection force, and tablet thickness are evaluated against hardness and disintegration results. For capsule filling, segregation is controlled by geometric dilution and fill-depth settings specific to the powder blend density. Because the hydrochloride salt is hygroscopic, open handling time in non-conditioned processing suites is minimized; if relative humidity exceeds 60%, closed transfer and desiccated storage are applied.
Daunorubicin differs from doxorubicin by the absence of a hydroxyl group at C-14; doxorubicin is the 14-hydroxy analogue, which increases polarity and alters tissue distribution. Daunorubicin is used primarily in remission induction for acute myeloid leukemia and acute lymphoblastic leukemia, usually in combination with cytarabine, whereas doxorubicin has broader solid tumor and lymphoma applications. Idarubicin is the 4-demethoxy analogue of daunorubicin with higher lipophilicity and improved oral absorption; reported oral bioavailability is approximately 30–40%. Epirubicin is the 4'-epimer of doxorubicin and is associated with lower cardiotoxicity at equimolar doses. These structural differences affect analytical separation: compendial HPLC methods include a system suitability requirement for resolution between daunorubicin and doxorubicin, often not less than 2.0. In dosage-form development, the choice of anthracycline influences salt selection, particle-size target, and route of administration; daunorubicin hydrochloride is typically supplied as a lyophilized injectable or as a low-dose solid oral intermediate, while idarubicin may additionally be formulated as an oral capsule.
| Agent | Structural relationship | Primary route and use | Key dosage-form consequence |
|---|---|---|---|
| Daunorubicin HCl | No C-14 hydroxyl | Intravenous, AML/ALL induction | Lyophilized injectable; low-dose solid oral blend |
| Doxorubicin HCl | C-14 hydroxyl | Intravenous and liposomal, broad solid tumors | Liposomal encapsulation; higher cumulative cardiotoxicity |
| Idarubicin HCl | 4-demethoxy | Oral and intravenous, AML | Improved oral bioavailability 30–40% |
| Epirubicin HCl | 4'-epimer | Intravenous, breast cancer | Lower cardiotoxicity at equimolar doses |
Residual solvent control for daunorubicin hydrochloride is performed by headspace gas chromatography with flame-ionization detection or mass spectrometry. Solvents that may be present from fermentation isolation and purification, such as methanol, acetone, and dichloromethane, are assigned ICH Q3C Class 2 or Class 3 status. Class 2 solvents are limited to their permitted daily exposure values; Class 3 solvents are limited to 5000 ppm total. Elemental impurities are assessed against ICH Q3D using inductively coupled plasma mass spectrometry per USP <233>. For injectable manufacture, the concentration limits in micrograms per gram are derived from the parenteral permitted daily exposure and the maximum daily dose of daunorubicin. Transition-metal residues from catalysts must be controlled if used in manufacturing. Container-closure materials are evaluated for extractables and leachables per USP <1663> and <1664> for injectable grades, and the packaging system is specified with a moisture vapor transmission rate appropriate for a hygroscopic cytotoxic API.
Stability studies are structured according to ICH Q1A(R2). For the injectable grade and lyophilized finished product, long-term storage is set at 5±3°C; accelerated testing is performed at 25±2°C/60±5% RH; photostability follows ICH Q1B. For oral solid intermediates, long-term storage is commonly 25±2°C/60±5% RH in moisture-barrier packaging. Test attributes include assay, related substances, water content, and appearance. Daunorubicin is light-sensitive; photodegradation is detected as an increase in related substances corresponding to aglycone and photo-oxidation products. Packaging must therefore be light-resistant and constructed from materials that limit oxygen and moisture transport. In addition, the finished injectable pH is controlled to 4.5–6.5 because alkaline hydrolysis of the glycosidic linkage increases rapidly above the validated range. These route-specific controls define the manufacturing boundary for tablet, capsule, granule, and injectable conversion of daunorubicin hydrochloride.
