| HS Code | 398474 |
| Productname | Pemetrexed disodium Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | Pemetrexed disodium; LY231514 disodium; Pemetrexed sodium salt |
| Chemicalname | N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt |
| Casnumber | 150399-23-8 |
| Molecularformula | C20H19N5Na2O6 |
| Molecularweight | 471.38 g/mol (anhydrous disodium salt); 597.49 g/mol (heptahydrate) |
| Appearance | White to off-white crystalline powder |
| Assay | 98.0% to 102.0% (on anhydrous basis) |
| Pharmagrade | Pharma Grade / API Grade |
| Dosageforms | Tablet; Capsule; Granule; Injection |
| Routesofadministration | Oral; Injectable |
| Therapeuticcategory | Antineoplastic; Antifolate |
| Solubility | Soluble in water; slightly soluble in methanol; practically insoluble in ethanol and acetone |
| Storageconditions | Store in a cool, dry, well-ventilated area; protect from light and moisture |
| Shelflife | 24 to 36 months when stored properly in unopened original packaging |
| Packaging | Double polyethylene bags inside aluminum foil bag; sealed in fiber drum |
| Pharmacopoeiastandard | USP; EP; BP; IP or in-house specification |
| Hs Code | 2934999099 |
| Residualsolvents | Meets ICH Q3C limits |
As an accredited Pemetrexed disodium 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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Aseptic processing of pemetrexed disodium into a lyophilized single-dose injection begins with bulk solution preparation in a closed stainless steel mixing vessel. The API is dissolved in water for injection. Mannitol is added as a crystalline bulking agent. Hydrochloric acid or sodium hydroxide adjusts the pH. The target pH is product-specific and is validated for hydrolytic stability. The solution is clarified through a 0.45 µm filter. It is then sterilized through a 0.22 µm sterilizing-grade membrane. Filter selection requires a product-specific adsorption study. PDA Technical Report 26 defines the validation requirements. Pemetrexed disodium is a small polar molecule. Membrane materials such as polyethersulfone and nylon may interact with the API. Published data for specific membrane-pemetrexed binding efficiencies are limited. The sterile filtrate is filled into Type I borosilicate glass vials. USP <660> sets the glass hydrolytic resistance limits. Elastomeric closures are selected for low extractables and container closure integrity. The filling operation occurs in an ISO 14644-1 Class 5 environment. FDA 21 CFR 211.42 and 211.65 govern facility and equipment design. Aseptic assembly is used unless terminal sterilization is validated. The filled vials are partially stoppered and loaded onto lyophilizer shelves. A validated freeze-drying cycle controls shelf temperature, chamber pressure, and time. Primary drying removes ice by sublimation. Secondary drying reduces residual moisture. Residual water is determined by USP <921> Method Ia. The stopper closes under vacuum or a nitrogen environment. Release testing includes USP <71> sterility, USP <85> bacterial endotoxins, USP <788> subvisible particulate matter, and USP <790> visible particulates. Elemental impurities are controlled per ICH Q3D. The product is cytotoxic and handled under USP <800> and the NIOSH List of Antineoplastic and Other Hazardous Drugs.
Diluent and container choices define the practical administration window for a ready-to-administer pemetrexed disodium infusion. The reconstituted solution is typically transferred to an infusion bag containing 0.9% sodium chloride injection. Calcium-containing diluents require specific compatibility validation before use. The API contains a glutamate moiety. This can interact with polyvalent cations. The admixture must be prepared in a controlled environment. USP <797> defines compounding requirements. The final infusion is a cytotoxic preparation. Closed-system transfer devices limit operator exposure. The container material may be polyolefin, polyvinyl chloride, or polypropylene. Each material requires sorption and leachables testing. USP <1663> and USP <1664> provide extractables and leachables assessment frameworks. ICH Q1A(R2) defines storage stability. ICH Q1B defines photostability. If light sensitivity is observed, protect from light during preparation and administration. The administration time is product-specific. Published data for extended room temperature holding configurations are limited. A visual inspection is performed after dilution. Precipitation or discoloration indicates admixture failure. The final infusion is delivered through a standard infusion set. In-line filtration may be used only if the filter is validated for the drug product. Aseptic compounding is not replaced by terminal filtration or terminal sterilization. Release tests and their standard designations are listed in Table 1.
| Test | Standard | Test condition or acceptance anchor |
|---|---|---|
| Visible particulates | USP <790> | Essentially free from visible foreign matter |
| Subvisible particulates | USP <788> Light Obscuration Particle Count Test | ≤ 6000 particles/container ≥ 10 µm and ≤ 600 particles/container ≥ 25 µm for small-volume injection |
| Bacterial endotoxins | USP <85> | Limit calculated from maximum bolus dose and patient weight |
| Sterility | USP <71> | Membrane filtration, 14-day incubation |
| Water content | USP <921> Method Ia | Karl Fischer titration, release limit validated against stability data |
| Assay | USP <621> HPLC | Product-specific release range validated per ICH Q2(R1) |
| Elemental impurities | ICH Q3D | Permitted daily exposure limits for parenteral route |
High-dose oral tablet development places the API at the centre of the powder rheology problem. Pemetrexed disodium is an ionisable molecule with multiple carboxylic acid groups. It may exhibit poor flow and high sticking tendency on tablet tooling. Direct compression is feasible only when the API particle-size distribution is controlled by sieving or micronization. The blend is passed through a 0.5–1.0 mm screen before compression. An instrumented rotary tablet press records upper and lower punch force. Compression dwell time and precompression force are adjusted to reduce capping. Powder flow is measured by USP <1174>. Bulk density and tapped density are determined by USP <616>. The compressibility index and Hausner ratio are calculated from these values. Tablet weight uniformity follows USP <905>. Tablet breaking force is measured by USP <1217>. Dissolution is tested per USP <711>. The dissolution medium and rotation speed are product-specific. They are not fixed by the API monograph. Dry granulation by roller compaction is preferred when direct compression fails. The roller compactor compresses the blend into ribbons. An oscillating mill with a 0.8–1.0 mm screen granulates the ribbons. The granules are lubricated with a low level of magnesium stearate. Excessive lubricant reduces tensile strength. The lubricant level is optimized by compaction simulator studies. If the tablet is enteric-coated, gastric resistance and intestinal release are tested per USP <711> with pH shift. Published data for a commercial oral pemetrexed tablet are limited. The formulation package is therefore developed from first-principles powder characterisation rather than from a compendial monograph.
Where capsule filling is selected instead of tablet compression, the primary risk shifts from compaction to particle-size distribution and encapsulation weight variation. The API is pre-processed by dry granulation or wet granulation. The granulate is milled to a defined size. An automated capsule filler with tamping pins or dosator chambers doses the powder into hard gelatin or HPMC capsules. Machine speed is balanced against fill weight variability. Capsule fill weight is monitored by in-process weight control. Statistical process control follows FDA 21 CFR 211.68. Powder bridging is controlled by glidant addition. The glidant level is optimized by powder flow tests per USP <1174>. Dissolution from capsules is tested per USP <711>. Fasted and fed state differences are relevant for oral pemetrexed; published data for a specific oral dosage form are limited. The capsule shell moisture interacts with the fill. Hard gelatin capsules require storage at low relative humidity. HPMC capsules may be less hygroscopic. Product stability is evaluated per ICH Q1A(R2). The final capsule must meet disintegration requirements per USP <701>. Capsule weight uniformity follows USP <905>. If granules are placed into sachets, fill weight and seal integrity are controlled. Seal integrity is tested by dye penetration or vacuum decay.
Fluid-bed granulation of pemetrexed disodium is justified when the API has poor flow, low bulk density, or segregation tendency. The process is performed in a top-spray fluid-bed granulator. The binder solution is sprayed onto the fluidised API and filler particles. Inlet air temperature, spray rate, and atomisation pressure are critical. The granulation endpoint is controlled by product temperature and filter pressure drop. Oversized agglomerates are milled. The milled granules are dried to a target loss on drying. Loss on drying is measured by USP <731>. Moisture affects chemical stability and flow. The dried granules are blended with disintegrant and lubricant. Disintegrant level is optimized by disintegration testing per USP <701>. The blend is compressed into tablets or filled into capsules. For oral granules in sachets, the granule is filled by volumetric or gravimetric filling equipment. The filled sachet must meet seal integrity and dose uniformity. Dose uniformity follows USP <905> for unit-dose packages. Stability protocols follow ICH Q1A(R2). Photostability follows ICH Q1B. Published data for a commercial pemetrexed granule product are limited.
Particle control in the injectable finished product continues after lyophilization. The lyophilized cake is inspected for color, collapse, and meltback. Cake appearance is controlled by the freezing and primary drying segment. Collapsed cake indicates product temperature above the collapse temperature during primary drying. The collapse temperature is product-specific. The cake is reconstituted with a specified diluent volume. The reconstituted solution is visually inspected before transfer. Subvisible particles are measured by USP <788> after reconstitution. Light obscuration and microscopic particle count tests are used. The acceptance limits for small-volume injections are followed. The final infusion bag is also inspected for visible particles. Leachables from the vial elastomer are controlled by USP <1663> and USP <1664>. Container closure integrity is tested by dye ingress or helium leak. The test method is validated to detect defects at the specified closure force. During scale-up, batch-to-batch variability in lyophilized cake moisture is tracked. Karl Fischer titration per USP <921> Method Ia is used. The residual moisture release limit is linked to stability data. If the residual moisture exceeds the validated range, the product may show hydrolytic degradation. Pemetrexed disodium degradation products are monitored by HPLC. The method is validated per ICH Q2(R1). System suitability follows USP <621>. The chromatographic run includes a system suitability injection before each set. The release of injectable product is controlled by real-time process data and end-product testing. Published data for specific degradation pathways in the lyophilized formulation are limited.
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Pemetrexed disodium Pharma Grade API, model PEM-DS-API-102, is supplied as a crystalline heptahydrate disodium salt of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid. The product is designated for tablet, capsule, granule, and injection manufacture; separate non-sterile oral-grade and sterile injectable-grade materials are available. The anhydrous molecular formula is C20H19N5Na2O6 with a molecular weight of 471.37 g·mol⁻¹; the heptahydrate formula is C20H19N5Na2O6·7H2O with a molecular weight of 597.49 g·mol⁻¹. The disodium salt CAS is 357166-30-4. Manufacturing is conducted under ICH Q7 good manufacturing practice for active pharmaceutical ingredients. Pharmacopoeial alignment includes the USP Pemetrexed Disodium monograph and the current Ph. Eur. monograph where applicable, with residual solvents controlled under ICH Q3C and elemental impurities under ICH Q3D. The compound is a multi-target antifolate whose approved clinical route is intravenous infusion; oral solid-dose development is possible when formulation strategies address solubility, hydration state, and bioavailability.
X-ray powder diffraction is used to confirm the heptahydrate crystalline lattice against a reference diffractogram. The uncompacted powder appears as a white to off-white crystalline material. The heptahydrate water content is 19.0%–22.0% by Karl Fischer titration; the theoretical water value is 21.1%. Because the water is part of the crystal lattice, loss on drying is not a sufficient moisture parameter and may produce false low values without indicating desolvation. Assay by HPLC is 98.0%–102.0% on the anhydrous, solvent-free basis. The pH of a 1% aqueous solution is 6.5–8.0. Related substances are separated with a compendial HPLC gradient; total impurities are controlled at ≤1.0%, and unspecified impurities at ≤0.10%. Chiral purity is controlled because the compound possesses a single stereogenic center in the glutamic acid portion; the undesired enantiomer is limited to ≤0.5% by chiral HPLC. Particle-size distribution for oral-grade powder is measured by laser diffraction per USP <429> and Ph. Eur. 2.9.31; D90 is ≤150 µm to support blend uniformity in low-dose tablet and capsule formulations. Injectable-grade powder is not necessarily micronized because the drug is dissolved before sterile filtration; the release criterion is reconstitution time in Water for Injection at 25°C, specified at ≤5 min for a 25 mg/mL solution.
Residual solvents are controlled under ICH Q3C using USP <467> and Ph. Eur. 2.4.24; Class 3 solvents are limited to ≤0.5% w/w each because the API is not a high-volume solvent user. Elemental impurities are controlled according to ICH Q3D; limits are route-specific. For oral-grade material, microbial content is tested by USP <61> and <62> or Ph. Eur. 2.6.12 and 2.6.13, with total aerobic microbial count ≤1000 CFU/g, total yeast and mold count ≤100 CFU/g, and absence of Escherichia coli. Injectable-grade material is tested for sterility by USP <71> and Ph. Eur. 2.6.1; bacterial endotoxin is limited to ≤0.10 EU/mg by USP <85> and Ph. Eur. 2.6.14, derived from the maximum intravenous dose and the 5 EU/kg/hour threshold. Strongly oxidizing agents and calcium-containing diluents are incompatibilities relevant to handling and finished-product compounding.
The same chemical entity is used for both routes, but the control strategy differs because injectable manufacture demands sterility, low endotoxin, and controlled reconstitution, whereas oral solid-dose manufacture demands blend uniformity, flowability, and compatibility with common tableting excipients. The table summarizes the critical attribute boundaries for the two grades.
| Critical attribute | Oral-grade PEM-DS-API-102 | Injectable-grade PEM-DS-API-102 | Method / standard |
|---|---|---|---|
| Assay | 98.0%–102.0% anhydrous basis | 98.0%–102.0% anhydrous basis | USP <621>, Ph. Eur. 2.2.29 |
| Water content | 19.0%–22.0% heptahydrate | 19.0%–22.0% heptahydrate | USP <921> Method Ia, Ph. Eur. 2.5.12 |
| pH of 1% solution | 6.5–8.0 | 6.5–8.0 | Potentiometric |
| Total related substances | ≤1.0% | ≤1.0% | USP <621>, Ph. Eur. 2.2.29 |
| Unspecified impurities | ≤0.10% | ≤0.10% | USP <621>, Ph. Eur. 2.2.29 |
| Particle size D90 | ≤150 µm by laser diffraction | Not specified; reconstitution ≤5 min at 25°C | USP <429>, Ph. Eur. 2.9.31 |
| Sterility | Not required | Complies with sterility test | USP <71>, Ph. Eur. 2.6.1 |
| Bacterial endotoxin | Not specified | ≤0.10 EU/mg | USP <85>, Ph. Eur. 2.6.14 |
| Microbial content | TAMC ≤1000 CFU/g, TYMC ≤100 CFU/g | Controlled through aseptic processing | USP <61>, <62>, Ph. Eur. 2.6.12, 2.6.13 |
| Elemental impurities | Oral PDE limits | Parenteral PDE limits | ICH Q3D, USP <232>, <233> |
Packaging for both grades is double LDPE liners inside an aluminum foil or HDPE drum with desiccant. The material should be stored below 25°C in a tightly closed container protected from light and moisture. Dispensing for high-potency solid-dose operations is performed in a containment isolator or downflow booth with relative humidity ≤40% to reduce handling-related moisture uptake and cross-contamination. When the heptahydrate is exposed to dry conditions for extended periods, dehydration may alter the crystallinity; therefore, open-container storage should be minimized and the package sealed immediately after weighing.
The disodium salt is preferred over the free acid for parenteral formulation because the free acid has limited aqueous solubility. At pH 6.5–7.0, the disodium salt provides a clear solution at 25 mg/mL pemetrexed base equivalents in Water for Injection, whereas the free acid may require more extensive pH manipulation and may not reach the same concentration under isotonic conditions. The stoichiometric factor is relevant during API weighing: 500 mg pemetrexed free acid equivalent corresponds to 551.4 mg anhydrous disodium salt or 699.0 mg heptahydrate disodium salt. The two sodium equivalents per molecule also contribute to solution tonicity calculation and must be accounted for when mannitol and sodium chloride are added to the finished injection. In solid dosage forms, the salt form can influence hygroscopicity, compatibility with acidic excipients, and dissolution in buffered media.
Compared with methotrexate, pemetrexed disodium has a different heterocyclic scaffold, a pyrrolo[2,3-d]pyrimidine core rather than a pteridine ring, and, after intracellular polyglutamation, inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Methotrexate is primarily a dihydrofolate reductase inhibitor. The multi-target antifolate activity does not remove the clinical requirement for folic acid and vitamin B12 supplementation; standard regimens include folic acid 350–1000 µg daily and vitamin B12 1000 µg intramuscular before treatment to reduce hematologic and gastrointestinal toxicity. Pemetrexed disodium also differs from raltitrexed, which is a quinazoline-based thymidylate synthase inhibitor with a narrower enzyme inhibition profile. These mechanistic distinctions do not directly alter the API specification, but they affect dose selection, concomitant use of immunosuppressive agents, and safety monitoring in the finished dosage form.
For tablet, capsule, and granule manufacture, the oral-grade powder is typically dry-blended with mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate in a bin blender at 60–70% of fill volume. Direct compression may be acceptable when the API fraction is below 10–15% w/w; above this range, dry granulation with a roller compactor at roll pressure 4–6 MPa and sieve size 0.8–1.25 mm is used to improve flow and content uniformity. Aqueous wet granulation introduces a hydration-state risk for the heptahydrate lattice; if aqueous granulation is required, the binder solution is added at 20–25°C, and drying is performed under vacuum at ≤40°C. Process qualification should include Karl Fischer water content and X-ray powder diffraction after drying to confirm that the crystalline form has not changed. Published data for this specific configuration is limited; therefore, each granulation endpoint must be established experimentally.
For capsule filling, the D90 ≤150 µm powder is generally suitable for dosator or tamping-pin machines; if the formulation is wet granulated, the dried granules are milled through a 0.8 mm screen. Granule final moisture is maintained at 19.0%–22.0% for the heptahydrate, but if an anhydrous grade is used for moisture-sensitive blends, the water limit is ≤2.0%. Dissolution testing for development batches follows USP <711> and Ph. Eur. 2.9.3 using media at pH 1.2, 4.5, and 6.8; the acceptance criterion is product-specific and not defined in this API specification.
For injection manufacture, the injectable-grade API is dissolved in Water for Injection at 15–25°C to 25 mg/mL pemetrexed base equivalents. The solution pH is adjusted with 0.1 N hydrochloric acid or 0.1 N sodium hydroxide to 6.5–7.0. Mannitol may be added as a bulking agent. The solution is filtered through a 0.22 µm PVDF or PES membrane, aseptically filled into Type I glass vials, and lyophilized. The reconstituted product should be a clear solution free of visible particulate matter, with pH 6.6–7.8. Do not reconstitute or dilute with Ringer’s lactate or other calcium-containing diluents because incompatibility may lead to particulate formation. The lyophilization cycle is product-specific; published data for the exact cycle of this API at all fill volumes is limited, so thermal characterization and freeze-drying microscopy are required before cycle scale-up.
