| HS Code | 355272 |
| Product Name | Vitamin K3 MNB 96%/98% Pharma Grade API |
| Chemical Name | Menadione Nicotinamide Bisulfite (Vitamin K3 MNB) |
| Cas Number | 133-15-3 |
| Molecular Formula | C17H15N2NaO6S |
| Molecular Weight | 398.36 g/mol |
| Grade | Pharma Grade API |
| Assay | 96% to 98% as Menadione Nicotinamide Bisulfite |
| Appearance | White to off-white crystalline powder |
| Solubility | Freely soluble in water; suitable for aqueous oral and injectable formulations |
| Pharmacological Function | Vitamin K3 supplement; required for hepatic synthesis of clotting factors II, VII, IX and X |
| Intended Dosage Forms | Tablet, capsule, granule, and injection |
| Administration Route | Oral and injectable |
| Storage Conditions | Store in a cool, dry, light-protected place in tightly closed packaging |
| Shelf Life | 24 months under recommended storage conditions |
As an accredited Vitamin K3 MNB96%/98% 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 | Vitamin K3 MNB 96%/98% Pharma Grade API, 25 kg net per sealed drum, double polyethylene-lined, labelled for oral and injectable pharmaceutical use. |
| Container Loading (20′ FCL) | Vitamin K3 MNB Pharma Grade API packed in 25 kg drums, palletized, securely loaded into one 20′ FCL, approximately 10 metric tons per container. |
| Shipping | Shipment of Vitamin K3 MNB96%/98% Pharma Grade API must follow strict pharmaceutical logistics. Use sealed, moisture-proof drums or bags with UN-approved packaging. Store in a cool, dry, well-ventilated area away from light and incompatible substances. Ensure compliance with IATA/IMDG regulations for oral and injectable APIs. |
| Storage | Store in a tightly sealed, light-resistant container in a cool, dry, well-ventilated area. Protect from moisture, direct sunlight, and strong oxidizing agents. Maintain temperatures below 25°C (77°F) and ensure the container remains closed when not in use to preserve API stability and purity. |
| Shelf Life | Typically 24 months when stored in original unopened containers under controlled conditions, away from light, moisture, and heat. |
Direct compression of menadione nicotinamide bisulfite 96% at a 4.0 mg menadione claim in a 120 mg core is operated only after a two-stage preblend with microcrystalline cellulose PH-102. In production-scale batches, the API is first blended with an equal mass of PH-102 in a 600 L bin blender at 9 rpm for 12 min. The premix is passed through a 600 µm stainless-steel screen to eliminate yellow API agglomerates; visual speck rejection is performed against a white comparator under 1000 lux. The main blend contains lactose monohydrate 200 mesh, crospovidone 3.0 wt%, and magnesium stearate 0.5 wt%, with lubrication limited to 3 min at 15 rpm. Lubrication beyond 5 min increases disintegration time by 40 s and suppresses dissolution at the later sampling point. Compression uses a 16-station rotary press with 6 mm round punches at 32 rpm, precompression force 2.0 kN, main compression force 8–12 kN, and punch penetration 1.5–2.0 mm. Tablet hardness is 40–70 N, thickness 3.0–3.3 mm, and friability is not more than 0.5% tested per Ph. Eur. 2.9.7. Content uniformity is checked per USP <905> and Ph. Eur. 2.9.6; production release is not approved when blend RSD exceeds 3.5% or when any individual unit falls outside 90.0–110.0% label claim. Dissolution is run in 900 mL 0.1 N HCl at 37°C using USP <711> apparatus 2 at 75 rpm; the release criterion is Q=80% at 30 min, and the coating step is not started until both blended tablets and core samples meet the criterion. Film coating with HPMC/PEG 400 to 3.0% weight gain is applied in a perforated pan at 55°C inlet air, 0.2 MPa atomizing air, and pan speed 12 rpm. Because MNB is light sensitive, the coating suspension does not include riboflavin or other photosensitizers, and tablets are packed in amber PVC/PVDC/aluminium blisters. At storage conditions above 60% RH, the API is pre-dried at 45°C for 4 h; moisture is then confirmed by Karl Fischer titration per Ph. Eur. 2.5.12.
For hard gelatin capsule fill, menadione nicotinamide bisulfite 98% at 5 mg per size 3 HPMC shell is handled under room humidity not exceeding 35% RH; conditioned powder at 25°C and 30% RH produces fill weight drift below 2.0% on a dosator machine. API is first milled through a ConiWitt 150 with 0.8 mm screen at 1000 rpm and then blended with mannitol DC 160, sodium starch glycolate 4.0 wt%, and talc 1.0 wt% in a 200 L V-blender at 12 rpm for 30 min. The dosator fill operates at 40,000 capsules/h with an 8 mm dosing disc and 3 mm compression pin. Fill weight is 180 mg, and empty shell moisture is held below 6.0%. Capsule content uniformity is tested per Ph. Eur. 2.9.6; if the first 10 samples show relative standard deviation above 4.0%, the batch is reblended for an additional 10 min because static charge from mannitol increases adhesion to the dosing chamber. The filled capsules are band-sealed with a PVA solution and dried at 25°C for 45 min. Microbial enumeration uses Ph. Eur. 2.6.12 and specified microorganisms per Ph. Eur. 2.6.13. This capsule format is used for single-dose oral administration; light protection is achieved with a double aluminium blister.
In aqueous injectable formulation, MNB 98% is dissolved at 10 mg/mL menadione equivalent in Water for Injection at 35°C with light exclusion and nitrogen overlay. The solution is buffered to pH 5.8–6.2 using 0.02 M citrate buffer. At pH above 6.5, the bisulfite adduct opens rapidly and menadione precipitates as yellow needles; therefore pH after filtration and before autoclave is confirmed by glass electrode calibrated per Ph. Eur. 2.2.3. The solution is sparged with nitrogen at 0.5 L/min for 15 min, passed through a 0.2 µm polyethersulfone filter, and filled into 2 mL Type I amber borosilicate vials with headspace oxygen below 1.0%. Terminal sterilization at 121°C for 15 min is used only after thermal challenge batches show menadione assay loss below 2.0%; if assay loss exceeds 2.0%, the cycle is reduced to 115°C for 30 min. Endotoxins are controlled by depyrogenation at 250°C for not less than 30 min; bacterial endotoxin limit for the finished solution is set at <0.25 EU/mg using Ph. Eur. 2.6.14. Sterility is per Ph. Eur. 2.6.1 and particulate matter per USP <788>. The product is not combined with tromethamine or phosphate buffers at pH above 7.0, and thiol antioxidants are avoided because adduct displacement changes the chromatographic profile. The finished vial is inspected under 1000 lux and packed in an outer carton to limit light exposure. This injectable form provides aqueous solubility of the menadione derivative without polysorbate.
Granule for sachet administration is manufactured by high-shear wet granulation of MNB 96% at a target content of 2.0 mg menadione per 1.0 g granule. The dry mix contains API, sucrose powder, pregelatinized starch 5.0 wt%, and citric acid 1.0 wt%. Binder solution is purified water added at 12% w/w. Main impeller is set at 150 rpm, chopper at 3000 rpm, and wet massing is 4–6 min. Drying in a fluid-bed dryer at inlet air 60°C, product temperature 35°C, and air flow 600 m³/h continues until loss on drying is 1.5–2.5%. Dried granule is screened through 800 µm and 150 µm sieves; the 400–800 µm fraction should be not less than 70%, and fines below 150 µm are limited to 15% because smaller fines flow into the sachet dosing tube and increase fill-weight relative standard deviation. Sachet fill weight is 1.0 g using a vertical form-fill-seal machine with auger filler; fill weight is checked every 15 min on 20 units, and machine speed is reduced if relative standard deviation exceeds 1.0%. Uniformity of mass is per Ph. Eur. 2.9.5. Moisture is rechecked after 24 h using Ph. Eur. 2.5.12, and sachets are sealed with aluminium-polyethylene laminate. The granule dissolves or disperses in 20 mL water at 25°C within 60 s; the dispersion pH is 4.0–5.0 to avoid conversion to free menadione.
| Dosage-form segment | Critical processing limit | Primary test or equipment reference |
|---|---|---|
| Direct-compression tablet | Blend RSD < 3.5%; lubrication < 5 min; hardness 40–70 N | USP <905>; Ph. Eur. 2.9.6 |
| Hard capsule fill | Ambient humidity < 35% RH; fill weight drift < 2.0%; shell moisture < 6.0% | Ph. Eur. 2.9.6; dosator capsule machine |
| Aqueous injectable | pH 5.8–6.2; headspace O₂ < 1.0%; assay loss after 121°C < 2.0% | Ph. Eur. 2.6.1; USP <788> |
| Wet granule sachet | 400–800 µm fraction ≥ 70%; fines < 150 µm ≤ 15%; LOD 1.5–2.5% | Ph. Eur. 2.9.5; vertical form-fill-seal auger filler |
| Oral liquid drops | Droplet mass ≤ 45 mg; solution pH 5.5 | Calibrated dropper tip; drop weight balance |
| Freeze-dried injection cake | Residual moisture ≤ 2.0%; reconstitution < 60 s; shelf temp ≥ 5°C below collapse temperature | Ph. Eur. 2.5.32; freeze-drying microscopy |
Oral liquid drops prepared from MNB 98% use a simple aqueous vehicle of glycerol 25.0% v/v, propylene glycol 10.0% v/v, sodium benzoate 0.1% w/v, and citric acid to pH 5.5. The API is added at 1.0 mg/mL menadione equivalent and dissolved under a nitrogen sweep at 30°C. The solution is filtered through a 0.45 µm nylon membrane, filled into 30 mL amber dropper bottles, and closed with a child-resistant closure. Dosing accuracy is checked by drop weight using a calibrated orifice; if droplet mass exceeds 45 mg, the dropper tip is replaced before release. This liquid format is used for oral dose adjustment in patients unable to swallow capsules.
Freeze-drying of MNB 98% in injectable form is performed at 50 mg/mL menadione equivalent with mannitol 40 mg/mL or a mannitol-glycine mixture. The critical product temperature is not an API property alone; it moves with the bulking-agent ratio, and a fixed shelf temperature cannot be transferred from one formulation to another. Freeze-drying microscopy is used to determine collapse temperature before cycle design. A cycle that cakes a mannitol-only formula at -20°C primary drying may collapse a glycine-containing formula at the same shelf temperature if the collapse boundary is within 2–3°C of the shelf set point. The chamber is loaded with 6R amber vials at a fill volume of 2 mL, shelf spacing 12 mm. Freezing is conducted at -40°C for 120 min, primary drying at a shelf temperature at least 5°C below collapse temperature with chamber pressure 0.2 mbar, and secondary drying at 30°C for 4 h. The finished cake is white to pale yellow; discoloration to amber indicates menadione oxidation. Reconstitution in 2 mL Water for Injection should occur in less than 60 s; residue after 2 min is a rejection criterion. Residual moisture by Karl Fischer per Ph. Eur. 2.5.32 is not more than 2.0%. Light protection after lyophilization is maintained because the dry cake remains photosensitive. Release includes Ph. Eur. 2.6.1 sterility, Ph. Eur. 2.6.14 endotoxin, and USP <788>. Published process data for this specific MNB concentration in low-glycine formulations is limited; therefore each new scale requires chamber mapping and thermal characterization before freeze-dryer loading.
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Vitamin K3 MNB96%/98% Pharma Grade API is a menadione nicotinamide bisulfite complex supplied as a white to off-white crystalline powder for tablet, capsule, granule, oral solution, and injectable manufacturing. The product designation encodes two assay release windows—not less than 96.0% and not less than 98.0% on the dried basis—rather than two chemical species. The CAS registry number for the complex is 73581-79-0, with a molecular weight of approximately 399.38 and a stoichiometric menadione equivalent of approximately 43.0%. The nicotinamide ligand accounts for roughly 30.6% of the molecular mass; at 98.0% assay, a 100 mg charge of MNB contains approximately 30.0 mg of nicotinamide. Release testing is normally conducted by HPLC per USP <621>, with loss on drying per USP <731>, water content by Karl Fischer per USP <921>, residual solvents by headspace GC per USP <467>, and elemental impurities by ICP-MS per USP <233> against limits from USP <232> and ICH Q3D. Because the product is a bisulfite adduct, its aqueous solutions are mildly acidic and require pH monitoring during compounding.
The two grades are selected by dose accuracy and assay width rather than by pharmaceutical acceptability. The 96.0% grade is frequently used in multivitamin granule premixes and lower-dose capsule blends where the excipient mass permits a wider assay window. The 98.0% grade is preferred for direct-compression single-unit dose tablets and injectable formulations where reduced impurity burden, lower excipient mass, and tighter batch-release arithmetic are required. Both grades share the same residual solvent, heavy metal, and microbial quality requirements, but the higher-assay grade is not automatically suitable for parenteral use unless the lot is additionally released with endotoxin and microbial enumeration data.
Residual solvents in the product are controlled under USP <467> Option 1 or Option 2 depending on the manufacturing site; the most commonly monitored solvents are methanol, ethanol, and isopropanol, with a class 3 limit of 5000 ppm for each unless total daily exposure requires a lower value. Water by Karl Fischer is typically specified at not more than 0.50% for the 98.0% grade and not more than 1.0% for the 96.0% grade. Sulfated ash per USP <281> is typically not more than 0.2%. Elemental impurity limits follow ICH Q3D for the intended route of administration; the permissible daily exposure values are converted to concentration limits based on maximum daily dose, so no single ppm set applies across all tablet strengths.
| Release parameter | Typical specification | Method reference |
|---|---|---|
| Assay on dried basis | 96.0% or 98.0% minimum according to grade | USP <621> |
| Loss on drying | ≤1.0% | USP <731> |
| Water | ≤0.50% for 98.0% grade; ≤1.0% for 96.0% grade | USP <921> |
| Sulfated ash | ≤0.2% | USP <281> |
| Residual solvents | ≤5000 ppm per class 3 solvent unless lower limit applies | USP <467> |
| Bulk density | 0.55–0.75 g/cm³ | USP <616> |
| Tapped density | 0.70–0.95 g/cm³ | USP <616> |
| Particle size D90 | ≤250 µm | laser diffraction |
| Bacterial endotoxin, parenteral grade | ≤0.25 EU/mg | USP <85> |
| Microbial enumeration | ≤10² CFU/g | USP <61> |
MNB 96/98 and menadione sodium bisulfite share the same water-soluble bisulfite adduct chemistry, but the nicotinamide ligand changes molecular weight, menadione activity per unit mass, and powder-blend behavior. The stoichiometric menadione equivalent of MNB is approximately 43.0%, whereas the corresponding figure for menadione sodium bisulfite trihydrate is approximately 52.0%. Direct mass-for-mass substitution therefore under-delivers menadione activity by roughly 17%. A formula written for 10 mg of menadione as MSB trihydrate would require about 19.2 mg of MSB, but the same formula switched to MNB 96/98 at 98.0% assay requires approximately 23.7 mg of MNB. This stoichiometric difference is a common source of batch-assay failure in multivitamin tablet transfer projects when the active-moiety calculation is not updated.
The following comparison summarizes the main formulation-relevant differences among the water-soluble menadione salts and phytomenadione.
| Parameter | MNB 96/98 | Menadione sodium bisulfite | Menadione dimethylpyrimidinol bisulfite | Phytomenadione |
|---|---|---|---|---|
| Water solubility | Freely soluble | Freely soluble | Freely soluble | Practically insoluble |
| Menadione equivalent | 43.0% stoichiometric | 52.0% as trihydrate | Supplier-specific | Not applicable |
| Assay specification | 96.0–98.0% | 96.0–98.0% | 96.0–98.0% | 98.0–102.0% |
| Nicotinamide ligand | Present | Absent | Absent | Absent |
| Primary formulation use | Tablet, capsule, granule, injection | Feed and oral premix | Feed premixtures | Human oral and injectable oil |
For direct-compression tablet and capsule fill operations, MNB 96/98 is commonly milled to a D90 target of ≤250 µm, with bulk density of 0.55–0.75 g/cm³ and tapped density of 0.70–0.95 g/cm³ per USP <616>. Powder-flow characterization per USP <1174> typically shows an angle of repose below 35° and a Hausner ratio between 1.20 and 1.35. These values are supply-chain targets rather than intrinsic physicochemical constants; crystal habit and milling equipment type shift them, and they should be written into the supply agreement only when a specific direct-compression line performance is being qualified. On a rotary tablet press operating at 20,000–60,000 tablets/h, blends containing MNB below 5.0% by weight generally show weight variability controlled by filler flow. When the MNB fraction exceeds 10.0% by weight, needle-like unmilled crystals can increase interparticle friction and reduce die-fill uniformity at high press speeds; a glidant such as colloidal silicon dioxide is then optimized at levels from 0.25% to 1.0%.
During wet granulation with an aqueous binder, the water-soluble MNB fraction dissolves in the binder solution and redistributes during drying; granule potency therefore depends on binder viscosity and wet-mass uniformity rather than on the starting API particle size. In a high-shear granulator with impeller tip speed maintained below 6 m/s, addition of MNB as a solution rather than as a dry powder reduces localized over-concentration and shortens wet massing time by approximately 20–30% compared with dry addition. Drying should be controlled by loss on drying, not fixed time, with a residual moisture target of 1.5–2.5% before compression. Over-drying to below 1.0% may produce brittle granules in formulations containing sucrose or mannitol, while residual moisture above 3.0% can increase tablet sticking and accelerate menadione degradation in the presence of mineral excipients. For capsule filling, granules containing MNB should be stored below 25°C and below 60% RH unless the primary packaging includes a desiccant; the bisulfite adduct can release sulfur dioxide under moist acidic conditions.
On a pilot twin-screw extruder with an L/D ratio of 25:1 used to manufacture MNB-containing granules, side-stuffer addition reduced thermal exposure compared with preblending, but screw torque increased as the API fraction exceeded 8.0% because the water-soluble complex thickens the aqueous binder phase. Barrel temperatures were maintained below 40°C to limit menadione loss; published data for this specific configuration is limited, and the process should be qualified with assay and related-substance testing after extrusion.
The injectable grade of MNB 96/98 must be specified with bacterial endotoxin not more than 0.25 EU/mg by USP <85> and microbial enumeration not more than 10² CFU/g by USP <61>. Terminal sterilization of the API is not a substitute for low-bioburden upstream manufacturing because destroyed bacterial cell walls still leave endotoxin in the bulk powder. Aqueous solutions should be prepared in light-protected vessels at pH between 3.0 and 5.0; above pH 7.0 the bisulfite adduct loses its stabilizing sulfite group and free menadione can separate as an oil or precipitate. Temperature during aseptic filtration should remain below 30°C, and the filtered bulk should not be held longer than 24 h unless formulation-specific chemical stability data support a longer hold time. The API is incompatible with strong oxidizing agents, heavy-metal ions, and alkaline buffer systems.
Photodegradation of aqueous MNB solutions follows first-order loss under ambient light; amber glass or foil-laminated transfer tubing is mandatory during compounding and filling. Nitrogen purging of the bulk solution reduces oxidative degradation, but headspace oxygen should be kept below 5.0% v/v because the reduced bisulfite form is oxygen-sensitive. Published data for this specific injectable formulation configuration is limited; the formulation-specific product specification should include a photostability study according to ICH Q1B and a hold-time study after sterile filtration. Injectable lots should be quarantined until the certificate of analysis confirms assay, pH of solution, endotoxin, particulate matter, and sterility or bioburden of the filtered bulk.
For oral solution and syrup manufacturing, MNB 96/98 is dissolved in purified water at concentrations typically below 5.0% w/v, with pH adjusted to 3.5–5.0 using citric acid or sodium citrate. The preservative system should be selected by stress testing; benzalkonium chloride is not recommended with anionic bisulfite systems because of ionic complexation risk, whereas potassium sorbate at 0.1–0.2% and sodium benzoate at 0.1–0.2% are common alternatives. The finished liquid should be protected from light and stored at controlled room temperature. Accelerated stability testing per ICH Q1A at 40°C/75% RH is used to confirm shelf life because published stability data for open-liquid configurations of this exact grade are limited.
