| HS Code | 704067 |
| Chemical Name | Calcium (6S)-5-methyltetrahydrofolate (Calcium L-5-methyltetrahydrofolate) |
| Molecular Formula | C20H23CaN7O6 |
| Molecular Weight | 497.50 g/mol |
| Cas Number | 151533-22-1 |
| Appearance | Off-white to pale yellow crystalline powder |
| Solubility | Sparingly soluble in water, practically insoluble in ethanol |
| Assay | 98.0% - 102.0% on dried basis by HPLC |
| Calcium Content | 8.0% - 8.6% on dried basis |
As an accredited CALCIUML-5-METHYLTETRAHYDROFOLATE 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 | Supplied as 25 kg/drum in sealed double-lined containers for calcium L-5-methyltetrahydrofolate pharma grade API, oral/injectable use. |
| Container Loading (20′ FCL) | Container loading of CALCIUM L-5-METHYLTETRAHYDROFOLATE Pharma Grade API into a 20′ FCL, using sealed, palletized drums with moisture protection. |
| Shipping | Ship as a temperature-controlled, light-protected pharmaceutical API. Pack in sealed, moisture-barrier containers with oxygen-absorbing protection. Use insulated cartons with desiccants; avoid excess heat and humidity. Label as “Pharma Grade API, handle with care.” Comply with local/global regulations for non-hazardous active ingredients. Include documentation and stability data. |
| Storage | Store in original tightly closed, light-protected containers under refrigeration (2–8°C), protected from moisture, oxygen, and excessive heat. Keep away from oxidizing agents and incompatible materials. Use clean, dry handling equipment; do not repack into unsealed containers. For oral and injectable dosage forms, maintain a secure, clearly labelled storage area until dispensing. |
| Shelf Life | Calcium L-5-methyltetrahydrofolate API shelf life: 24 months when stored in original sealed containers, protected from moisture, heat, and light. |
In immediate-release oral tablet lines producing calcium L-5-methyltetrahydrofolate-containing formulations, the active is received as a milled or micronized calcium salt and is not discharged directly into the main excipient bed because label claims are concentrated in the 0.4–15 mg range and tablet core masses typically occupy 120–500 mg. A trituration premix is prepared by geometric dilution with microcrystalline cellulose or pregelatinized starch, using a 1.0% w/w API trituration for lower strengths and a 10% w/w trituration for 15 mg strengths; the resulting API fraction in finished cores ranges from 0.1% w/w to 12.5% w/w, with lower values corresponding to mineral-containing prenatal tablets and higher values to single-entity folate tablets. Blending is executed in V-blenders or bin tumblers at 10–25 rpm for 15–30 min after the trituration has passed through a 600 µm screen. Direct compression is preferred when the excipient matrix allows, while high-shear wet granulation is employed only when a poorly flowing mineral premix is required, with granule drying maintained below 50°C because the reduced folate ring degrades at elevated temperature. Compression is performed on rotary presses at 10–25 kN main compression force, and content uniformity is assessed according to USP <905> or Ph. Eur. 2.9.40, with acceptance value limits as specified in the relevant monograph. Dissolution is typically performed using USP <711> Apparatus 2 at 50 rpm in 900 mL of phosphate buffer at pH 6.8, although the registered media must be product-specific. Moisture control is specified above 60% relative humidity; hygroscopic excipients are pre-dried to ≤2% loss on drying before blending. Stability protocols follow ICH Q1A(R2), and elemental impurities are controlled under ICH Q3D because raw mineral excipients can contribute residual catalysts. Terminal product formats include immediate-release film-coated tablets, uncoated single-entity folate tablets, and dietary supplement tablets manufactured under 21 CFR 111 or drug tablets manufactured under 21 CFR 211.
What predetermines content uniformity in hard capsule operations using calcium L-5-methyltetrahydrofolate is not the encapsulator type but the carrier-level shear history of the API trituration and the equilibrium moisture content of the fill. For capsule strengths between 0.4 mg and 15 mg, with fill weights of 150–400 mg, the API mass fraction typically spans 0.1–10% w/w, but a direct pour of the neat API into the hopper is not permissible because electrostatic adhesion to capsule body interiors and dosator tips causes label-claim drift. The API is first dispersed at 1–5% w/w in lactose monohydrate or mannitol-based carriers using a low-shear tumble blender, then screened through a 425 µm mesh and re-blended. The final blend is transferred to an automatic capsule filler operating with dosator or tamping-pin stations, with bed relative humidity maintained at 35–45% to suppress triboelectric charging. HPMC capsules are more prone to static-induced powder segregation than gelatin under dry air, so process rooms are equipped with ionising bars and conductive flooring where validated. Content uniformity is verified by USP <905> or Ph. Eur. 2.9.40, and dissolution is assessed by USP <711> Apparatus 1 or 2, depending on the monograph. Because this calcium salt is oxygen-labile, the final blend is not held in open containers for more than 8 h at ambient oxygen levels without a nitrogen overlay. Finished product types are hard gelatin capsules, HPMC vegetarian capsules, and pullulan capsules for pharmaceutical or dietary supplement uses, with batch release documentation aligned to 21 CFR 211.165 for drug products or 21 CFR 111.75 for supplements.
Granule and sachet lines running 1,000–5,000 g batch sizes for paediatric or prenatal stick packs present a separate set of constraints because the finished sachet fill mass is usually 2–10 g while the API label claim is only 0.4–1 mg, yielding API mass fractions as low as 0.004–0.05% w/w. To compensate for the extreme dilution, the API is introduced as a 0.5% w/w trituration in a water-soluble carrier such as mannitol or maltodextrin, and the binder solution for wet granulation is formulated with 0.1–0.2% w/w ascorbic acid or sodium ascorbate as a sacrificial antioxidant. High-shear granulation is run at impeller speeds of 150–300 rpm and chopper speeds of 1,500–3,000 rpm only until the granulate reaches a visually uniform state; the wet mass is transferred to a fluid bed dryer and dried with inlet air at 45–50°C until residual moisture is 1.0–2.5%. The dried granules are milled through a 1,000 µm screen and filled into aluminium-foil laminate sachets with nitrogen flushing. For stick-pack formats, the product is dedusted and flow-conditioned to maintain fill weight variability below ±3%. The relevant uniformity test is Ph. Eur. 2.9.40 or USP <905> performed on sachet contents, and moisture content is controlled under USP <921> or Ph. Eur. 2.2.32. Terminal product types include single-dose oral granules, stick packs, and dual-layer effervescent granules where the API-containing layer is separated from the acid-carbonate layer to reduce oxidative contact. If effervescent presentations are developed, the acid source is not citric acid alone unless the moisture history is tightly controlled; published data for long-term stability of this specific configuration is limited.
| Dosage application | Typical unit strength | Unit mass / fill volume | API mass fraction / concentration | Primary uniformity or quality standard |
|---|---|---|---|---|
| Oral tablet | 0.4–15 mg | 120–500 mg | 0.1–12.5% w/w | USP <905> / Ph. Eur. 2.9.40 |
| Hard capsule | 0.4–15 mg | 150–400 mg | 0.1–10% w/w | USP <905> / Ph. Eur. 2.9.40 |
| Granule sachet | 0.4–1 mg | 2–10 g | 0.004–0.05% w/w | Ph. Eur. 2.9.40 / USP <905> |
| Lyophilized vial | 5–50 mg | 200–1,000 mg cake | 0.5–5% w/w | USP <71> / USP <85> |
| Injectable solution | 0.5–5 mg/mL | 1–10 mL | 0.05–0.5% w/v | USP <788> / USP <85> |
For injectable presentations, the calcium salt must be dissolved under light-shielded, nitrogen-overlay conditions because aqueous solutions of L-5-methyltetrahydrofolate are susceptible to oxidative degradation, particularly in the presence of dissolved oxygen and trace metal ions. Solution strengths are ordinarily formulated at 0.5–5 mg/mL for liquid vials and 5–50 mg per vial for lyophilized presentations; corresponding API mass fractions in reconstituted solution range from 0.05% w/v to 0.5% w/v, while the freeze-dried cake may contain 200–1,000 mg of mannitol or sucrose bulking excipient and 0.1–1.0% w/w antioxidant. The manufacturing process uses Water for Injection cooled to 15–25°C, pH adjustment to 6.5–8.0 with citrate or phosphate buffer, and nitrogen sparging until dissolved oxygen is below 0.2 mg/L. The solution is sterilised by filtration through a 0.22 µm sterilising-grade membrane and aseptically filled into Type I glass vials under Grade A conditions. Terminal sterilisation by steam is generally not applied because the reduced folate ring is thermolabile; the registered process therefore relies on USP <71> sterility assurance, USP <85> bacterial endotoxin limits, USP <788> particulate matter for injections, and Ph. Eur. 2.6.14 where applicable. Lyophilisation cycles include a freezing ramp to −45°C, an annealing step at −15 to −10°C, and primary drying at shelf temperatures not exceeding 0°C until the product temperature remains below the collapse temperature. Residual moisture is controlled to ≤2.0% by USP <921>. Finished product types are single-dose injectable solutions, lyophilized powders for injection, and pharmacy bulk packages where the validated maximum hold time in the unlyophilized state is not exceeded. Published data for terminal sterilisation of this specific configuration is limited; process qualification is required for any deviation from the aseptic-lyophilisation route.
If the API is to survive direct compression alongside divalent metal oxides and high-density mineral excipients, the premix geometry must be treated as a segregation-limited solid dispersion rather than a conventional trituration. Prenatal multivitamin formulations typically carry 0.4–1 mg calcium L-5-methyltetrahydrofolate in a core mass of 900–1,500 mg, so the API mass fraction is only 0.03–0.1% w/w. This extreme dilution demands a staged blending sequence in which the API is first bound to microcrystalline cellulose or pregelatinized starch at 0.5–1.0% w/w, then mixed with folic-acid-free fractions before contacting iron-containing granulates. The production line operates with bin blenders at 60–70% fill volume to avoid dead zones, and the final lubricant is added for 3–5 min after the main mineral blend has been compressed. Direct compression is performed at 15–25 kN on high-tonnage tablet presses, and content uniformity is monitored by USP <905> or Ph. Eur. 2.9.40, with stratified sampling across the hopper because mineral premixes segregate by particle size. The process must be reconciled with ICH Q3D elemental impurity limits because calcium carbonate, magnesium oxide, and ferrous fumarate introduce metal residues; additionally, oxidative incompatibility with ferrous salts is evaluated in forced degradation studies under ICH Q1A(R2). Finished product types include prenatal multivitamin/mineral tablets, iron-containing maternal capsules, and powder premix intermediates sold to contract supplement manufacturers, with finished goods governed by 21 CFR 111 for dietary supplements or 21 CFR 211 for prenatal drug products.
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Pharmaceutical-grade calcium L-5-methyltetrahydrofolate, released under the model designation CALCIUML-5-MTHF-PG, is the calcium salt of (6S)-5-methyltetrahydrofolic acid. The compound is assigned CAS registry number 151533-22-1; the molecular formula C20H23CaN7O6 corresponds to molecular mass 497.52 g·mol⁻¹. The molecule contains a reduced pteridine ring methylated at N-5, and the 6S configuration is required for one-carbon metabolism. The 6R diastereomer is controlled as a specified impurity because it lacks the same cofactor activity. The API is supplied as a white to off-white crystalline powder in oral and injectable grades. Tablets, capsules, granules, oral liquids, and sterile injectable solutions are specified as target routes; the injectable grade differs from the oral grade by tighter bacterial endotoxin limits, particulate controls, and reduced bioburden.
For tablet and capsule formulation, calcium L-5-methyltetrahydrofolate is a low-dose active with typical unit strengths from 0.4 mg to 60 mg; the active fraction is often below 5 wt% of the core. At unit loads below 1 mg, direct compression without a staged geometric pre-blend is unsuitable because blend segregation and sampling error dominate weight variation. The preferred procedure is a 1:10 pre-blend of active and lactose monohydrate screened through a 0.5 mm conical mill, followed by serial dilution in a bin blender. Blend uniformity is assessed according to USP <905>; stratified sampling at the beginning, middle, and end of compression is necessary because fine active particles migrate during hopper discharge. Laser diffraction particle size is controlled by USP <429>. A D90 above 150 µm shifts processing toward wet granulation rather than direct compression; D50 below 20 µm can increase electrostatic adhesion and powder flow issues. Tablet compression on a rotary press should begin at lower turret speed, and the pre-blend should not be mixed with magnesium stearate beyond 5 min, because overlubrication reduces compact hardness and increases disintegration failure risk. For low-dose tablets, the hardness range 30–50 N is often selected to balance friability and disintegration; friability is tested according to USP <1216>.
Wet granulation of this API with water is not the first-line process because the reduced pteridine ring is susceptible to hydrolytic and oxidative degradation under humid heat. A hydroalcoholic binder containing povidone at 2–5 wt% and ethanol or isopropanol is used; fluid-bed inlet temperature is maintained below 55 °C to preserve chiral purity. Roller compaction can be used for dry granulation if the API is pre-blended with microcrystalline cellulose and crospovidone; ribbon density is controlled by hydraulic pressure and mill speed. Granule moisture is dried to ≤5.0% before filling. The major process failure on a production scale is not chemical degradation but segregation of the low-dose active after a large bin blender is discharged. Published data for the specific minimum dilution step count is limited; an 8-step geometric dilution is commonly written into batch records.
Analytical release of the API uses an HPLC method with ultraviolet detection at 280 nm; the mobile phase contains phosphate buffer and acetonitrile to resolve the 6S and 6R diastereomers. Chiral HPLC is necessary because ordinary reversed-phase conditions may coelute the two diastereomers. The retention time of the 6R impurity is reported relative to the active peak, and its area percentage is limited to ≤1.0%. Method validation covers specificity, linearity, accuracy, precision, and quantitation limit according to ICH Q2(R1). Water content is measured by Karl Fischer titration, with loss on drying run at 105 °C; the two values are not interchangeable because the calcium salt may exist as a hydrate. Residual solvents are measured by headspace gas chromatography according to ICH Q3C; ethanol and isopropanol are the most common solvents from final crystallisation and are controlled at ≤0.5%. Elemental impurities are quantified by inductively coupled plasma mass spectrometry, and the sample preparation follows ICH Q3D option 1. The oral grade does not need as low an endotoxin specification as the injectable grade, but should still be controlled because some oral products are given to neonates or pregnant patients.
Injectable-grade calcium L-5-methyltetrahydrofolate is processed under nitrogen because the reduced folate ring is oxidatively labile. Water for injection is sparged to reduce dissolved oxygen before API addition; the bulk solution is maintained under a nitrogen headspace during sterile filtration and filling. Terminal sterilisation at 121 °C for 15 min can be used only when the pH is stabilized between 6.5 and 9.5; below pH 5.5 the calcium salt has reduced aqueous solubility and may precipitate during cooling. The parenteral grade must meet a bacterial endotoxin limit of <0.5 EU/mg by limulus amebocyte lysate testing according to USP <85>, and subvisible particulates are controlled according to USP <788> after filtration through a 0.22 µm membrane. Antioxidants such as ascorbic acid or sodium ascorbate are added at 0.1–0.5 wt% to suppress oxidation; sulphur-based antioxidants are avoided because they can attack the pteridine ring and produce red or brown degradation products. The solution is incompatible with peroxide-containing surfactants, including certain grades of polysorbate 80, and should not be autoclaved in the presence of oxidising agents. For lyophilised presentations, the product is frozen at -40 °C or below, primary dried below the collapse temperature, and sealed under vacuum with residual moisture <2.0%. The stopper and vial headspace should be flushed with nitrogen; rubber stoppers with low moisture vapour transmission reduce moisture ingress during shelf life. Terminal sterilisation can increase the 6R isomer if the starting solution is not protected from light; amber vials or secondary cartons are specified because the API is photolabile.
Oral granules and sachet presentations use the oral grade, but additional control of particle size distribution and surface hydration is required. The calcium salt is prone to static charging after milling; at relative humidity below 30% RH, electrostatic adhesion to laminate can reduce delivered dose from stick packs. Equipment grounding and humidity control between 40% RH and 60% RH are standard countermeasures. Granules are preferably produced by low-shear mixing or fluid-bed granulation; high-shear wet granulation with plain water is not preferred because the API hydrates and can form a sticky mass that is difficult to mill. A hydroalcoholic binder containing 2–5% povidone is used to produce free-flowing granules with poured density above 0.5 g/mL. Sieve analysis according to USP <786> is used to control the granule fraction retained between 20-mesh and 60-mesh sieves; this range improves filling accuracy on vertical form-fill-seal machines. Granules are dried to moisture content ≤5.0% because residual water accelerates hydrolysis of the methylated pteridine ring. The finished sachet should have a low moisture vapour transmission rate; if the laminate contains aluminium foil, the product is protected from light and oxygen. Batch records for granulation should specify a maximum drying inlet temperature of 55 °C and a maximum product temperature of 40 °C.
Substitution is not a simple mass equivalent. Folic acid must undergo reduction by dihydrofolate reductase and methylation before it enters the active folate pool; calcium L-5-methyltetrahydrofolate is already the principal circulating folate and does not require MTHFR C677T gene product. In individuals with reduced MTHFR activity, folic acid may remain as unmetabolized folic acid, whereas levomefolate calcium bypasses that step. The effective dose conversion is not established solely by molecular weight; dissolution, particle size, and tabletting behaviour also differ between folic acid and the calcium salt. Reformulated prenatal tablets show that the more hygroscopic calcium salt may require lower tablet hardness, typically shifted from 40 N to 30 N, to maintain disintegration time. The calcium ion released from the API can interact with phosphate buffers and produce haze in injectable combinations; citrate or tartrate buffers are preferred. In capsule formulations, combinations with anhydrous dibasic calcium phosphate can increase disintegration time under 0.1 N hydrochloric acid; formulation compatibility should be evaluated by USP <701> or equivalent disintegration testing. The API should not be combined with amine-containing excipients that induce oxidative coupling. Published data for this specific combination is limited.
The release specification below is representative for oral and injectable grades; the certificate of analysis for each batch is the controlling document.
| Parameter | Acceptance criterion | Test standard / method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual |
| Assay (as is) | 95.0–102.0% | HPLC external standard |
| Specific optical rotation | Positive, consistent with 6S reference | Polarimetry |
| 6R diastereomer | ≤1.0% | Chiral HPLC |
| Loss on drying | ≤8.0% | USP <731> |
| Residual solvents | Conforms | ICH Q3C |
| Elemental impurities | Conforms for oral and parenteral | ICH Q3D |
| Bacterial endotoxins (injectable) | <0.5 EU/mg | USP <85> |
Unlike calcium folinate, which is the 5-formyl derivative and must be converted to methyltetrahydrofolate before methionine synthase can use the methyl group, levomefolate calcium is already methylated. It is transported across the intestinal membrane by the proton-coupled folate transporter and reduced folate carrier; folic acid shows different transport kinetics. The calcium salt is also more sensitive to oxidation than folic acid, which is fully aromatic in the pteridine portion and less reactive. This difference is visible in accelerated stability studies: the calcium L-5-methyltetrahydrofolate product requires nitrogen-flushed packaging and lower storage temperature, whereas folic acid can tolerate ordinary pharmaceutical packaging with wider moisture limits. The product is stored double-bagged under nitrogen with desiccant at 2–8 °C; it must be protected from light according to ICH Q1B photostability testing. Long-term and accelerated stability programs follow ICH Q1A(R2); in-use testing for opened bulk containers is specified because moisture uptake above 60% RH can reduce flow and shorten shelf life. The injectable grade is incompatible with strong oxidising agents, peroxide-containing surfactants, and residual concentrated nitric acid cleaning agents; cleaning validation of tablet and granulation suites should include swab testing for folate residues to prevent cross-contamination into methotrexate-containing lines.
Because the API is a water-soluble calcium salt with pH-dependent solubility, dissolution testing of finished tablets is performed in 0.1 N hydrochloric acid for the first 60 min, then pH 6.8 phosphate buffer; the method is defined in the product submission rather than a general monograph. Published data for a discriminating dissolution model for this specific API is limited. Capsules containing coated pellets may show a lag time if the coating polymer is an enteric material; the reduced folate is acid-labile in the stomach and enteric coating protects it from gastric degradation. However, enteric coating can retard release and lower the maximal plasma concentration; the formulator must balance protection with absorption rate. Riboflavin and vitamin B12 are often included in combination products; riboflavin is a light-sensitive compound, so packaging must protect both active species. The combination with ascorbic acid is generally compatible and may improve stability; combination with metallic ions such as ferrous bisglycinate can cause color change in solution but does not necessarily reduce potency. These interactions are evaluated by forced degradation studies per ICH Q1A(R2).
