| HS Code | 261736 |
| Product | Vitamin K4 Pharma Grade API |
| Active Substance | Menadiol Sodium Diphosphate |
| Chemical Name | Tetrasodium 2-methyl-1,4-naphthalenediol bis(dihydrogen phosphate) |
| Cas Registry Number | 6147-18-8 (as hexahydrate) |
| Molecular Formula | C11H8Na4O8P2·6H2O |
| Molecular Weight | 530.18 g/mol (hexahydrate); 422.08 g/mol (anhydrous) |
| Appearance | White to almost white crystalline powder |
| Odour | Odourless or almost odourless |
| Solubility | Freely soluble in water; practically insoluble in ethanol, chloroform and ether |
| Stability | Light-sensitive and moisture-sensitive; stable under appropriate pharma storage conditions |
| Storage Condition | Store in a tightly closed container in a cool, dry place; protect from light and excessive moisture |
| Pharmaceutical Grade | API grade suitable for pharmaceutical dosage form manufacturing |
| Pharmacological Property | Promotes hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX and X |
| Dosage Form Suitability | Suitable for tablets, capsules, granules, oral preparations and injectable solutions |
| Route Of Administration | Oral and injectable (IM/IV) |
| Product Name | Vitamin K4 Pharma Grade API |
| Active Substance | Menadiol Sodium Phosphate |
| Chemical Family | Synthetic water-soluble vitamin K analogue |
| Synonyms | Vitamin K4 sodium phosphate; Menadiol sodium diphosphate; Soluble Vitamin K4 |
| Cas Number | 6700-42-5 |
| Molecular Formula | C11H8Na4O8P2 |
| Molecular Weight | 422.08 g/mol |
| Physical State | Crystalline solid |
| Appearance | White or almost white crystalline powder |
| Odour | Practically odourless |
| Hygroscopicity | Hygroscopic |
| Water Solubility | Freely soluble in water |
| Organic Solvent Solubility | Sparingly soluble in ethanol; practically insoluble in ether and chloroform |
| Melting Point Behaviour | No sharp melting point; decomposes on strong heating |
| Optical Activity | None; achiral compound |
| Photostability | Sensitive to light; must be protected from light |
| Heat Stability | Stable at controlled room temperature; degrades on prolonged strong heating |
| Grade | Pharma grade |
As an accredited Vitamin K4 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 in 25 kg sealed fiber drums with double polyethylene liners, ensuring purity and stability for oral and injectable pharmaceutical formulations. |
| Container Loading (20′ FCL) | Container loading for 20′ FCL: drums of Vitamin K4 API, palletized, secured, with temperature-controlled, moisture-proof lining ensuring stability for oral and injectable forms. |
| Shipping | Shipping in sealed, light-resistant, moisture-proof pharmaceutical-grade containers to preserve stability. Temperature-controlled transport recommended; avoid extreme heat/humidity. Full documentation including MSDS, COA, and regulatory compliance per international hazardous or pharmaceutical shipping guidelines. Ensure prompt delivery with tamper-evident packaging to maintain API purity for oral and injectable formulations. |
| Storage | Store Vitamin K4 Pharma Grade API in a cool, dry, well-ventilated area, protected from light, moisture, and air. Keep in tightly closed, light-resistant containers away from incompatible materials. Maintain controlled room temperature (20-25°C) or per label directions. Avoid exposure to humidity and oxygen. Ensure packaging integrity until use, and adhere to safety and regulatory storage guidelines. |
| Shelf Life | Shelf life is 24 months when stored in original container below 25°C, protected from light, moisture, and air. |
In direct compression lines processing menadiol sodium phosphate at a target dose of 10 mg per unit, the API particle size distribution is controlled at D90 below 150 µm to prevent segregation on high-speed rotary tablet presses. A pre-sieved blend containing anhydrous dibasic calcium phosphate, microcrystalline cellulose, and sodium starch glycolate is mixed for 15 minutes at 12 rpm in a bin blender. The low drug load shifts the critical control point to content uniformity; USP <905> acceptance value is maintained below 15.0 for 10 mg tablets by keeping the API assay above 98.5% and residual moisture below 3.0% w/w. Loss-on-drying by USP <731> after 2 h at 105°C is monitored before compression. Hardness is set between 40 N and 70 N because lower values increase capping on high-speed turrets and higher values extend disintegration beyond 15 min when tested in 900 mL water at 37°C by USP <701>. Magnesium stearate is limited to 0.5% w/w; levels above 1.0% w/w delay dissolution of the low-dose tablet because the hydrophobic lubricant coats the fine API particles. The tablet is not film-coated due to photosensitivity of menadiol sodium phosphate; when protection is required, a polyvinyl alcohol-based moisture barrier is applied below 60°C.
| Process control point | Method / instrumentation | Typical acceptance criterion |
|---|---|---|
| Blend uniformity | Stratified thief sampling with HPLC assay | RSD ≤ 5.0% and mean assay 98.5% – 101.5% |
| Tablet weight | In-process check every 15 min | Target weight ± 5.0% |
| Hardness | Rotary tablet press hardness tester | 40 N – 70 N |
| Disintegration | USP <701> | ≤ 15 min in 900 mL water at 37°C |
| Content uniformity | USP <905> | AV ≤ 15.0 |
| Loss on drying | USP <731> | ≤ 3.0% w/w |
High-shear aqueous granulation of menadiol sodium phosphate becomes process-sensitive above 35°C because the water-soluble diphosphate ester dissolves into the granulating fluid and redistributes unevenly during drying. A binder solution of hydroxypropyl cellulose at 3.0% w/w in purified water is sprayed at 20 g/min into a 300 L high-shear granulator with impeller speed 150 rpm and chopper speed 1,800 rpm. The endpoint is identified by a torque rise of 15% over the dry-mix baseline rather than by fixed time. Granules are wet-milled through a 1.5 mm screen and dried in a fluid-bed dryer at inlet air temperature 50°C until loss-on-drying reaches 1.5% – 2.5%. The API is oxidized if the granulation remains wet for more than 4 h at 25°C; therefore vacuum drying at 40°C is substituted when ambient relative humidity exceeds 60%. Dried granules are dry-milled through a 0.8 mm screen and lubricated with 0.25% w/w sodium stearyl fumarate because magnesium stearate forms hydrophobic films on the water-soluble API. Tablets compressed from wet granulation show friability below 0.8% by USP <1216> at hardness 60 N and content uniformity acceptance value below 10.0 by USP <905>. This route is selected when direct compression blends fail flow testing below 6 mm in a Flodex cylinder or when the API content is reduced to 1 mg per unit.
When a 5 mg Vitamin K4 fill is encapsulated on a dosator-style machine, the primary failure mode is powder bed densification after prolonged hopper residence. The formulation is dry-mixed as a pre-blend with lactose monohydrate, pregelatinized starch, and 0.2% colloidal silicon dioxide; the blend is passed through a 0.5 mm sieve and encapsulated at a target fill weight of 250 mg per capsule. Segregation is minimized by matching the API particle size D90 to the diluent D90 within 50 µm. In-process verification of capsule weight is performed at intervals not exceeding 30 minutes per 21 CFR 211.110, and content uniformity is run on a stratified sample across hopper residence times up to 2 h. Dissolution of the capsule shell may be delayed by cross-linking if the fill blend moisture exceeds 4.0% w/w; gelatin shells stored at 25°C/60% RH are used, and moisture is kept below 3.5% w/w by USP <921> Karl Fischer titration. The capsule dosage form avoids direct compression of low-dose menadiol sodium phosphate when tablet tooling wear or capping limits tablet yield.
Terminal sterilization of an aqueous menadiol sodium phosphate injection at 10 mg/mL is specified only after oxygen is displaced from the bulk solution and primary packaging. The formulation is prepared in water for injection at 25°C with sodium metabisulfite 0.1% w/v as antioxidant and sodium hydroxide or hydrochloric acid for pH adjustment to 6.5 – 7.0. The solution is filtered through 0.22 µm PVDF membrane and filled into amber Type I borosilicate glass ampoules under nitrogen flush at residual headspace oxygen below 2.0% v/v. Terminal sterilization by autoclaving at 121°C for 15 minutes is validated by Ph. Eur. 5.1.1; thermal degradation of menadiol sodium phosphate is measured by related substances at not more than 1.5% total impurities. The largest stability risk is not bulk degradation but photoreduction of the naphthoquinone ring; the solution is tested for absorbance at 285 nm and clarity after 5 h exposure to 1.2 million lux·h of cool white and near-UV light per ICH Q1B Option 1. The pH drifts upward above 7.5 when ampoule glass leaches alkali, accelerating dephosphorylation; therefore 0.01 M citrate buffer is added when pH is above 7.0. Per USP <788>, particulate matter in the final injection is limited to not more than 6,000 particles per container at ≥ 10 µm and not more than 600 per container at ≥ 25 µm. Endotoxin testing by USP <85> is set at not more than 0.5 EU/mg for parenteral grade. Sterility testing is conducted by USP <71> after 14 days incubation. The injectable route requires exact headspace oxygen mapping because residual oxygen above 5.0% v/v after sterilization doubles the total oxidation products within 6 months at 40°C.
| Quality attribute | TestMethod / designation | Typical acceptance criterion |
|---|---|---|
| Sub-visible particulate matter | USP <788> | ≤ 6,000 particles per container at ≥ 10 µm; ≤ 600 at ≥ 25 µm |
| Bacterial endotoxins | USP <85> | ≤ 0.5 EU/mg |
| Sterility | USP <71> | No growth after 14 days |
| pH | USP <791> | 6.5 – 7.0 |
| Related substances | Ph. Eur. 2.2.29 | Total ≤ 1.5% |
| Residual oxygen | Headspace gas chromatography | ≤ 2.0% v/v after nitrogen flush |
Granulation for oral sachets uses menadiol sodium phosphate dry-mixed with sucrose or mannitol, then granulated with isopropanol instead of water because the API is freely water-soluble. Isopropanol granulation in a fluid-bed at inlet temperature 40°C avoids dissolution and yields granules with mean particle size 200 µm – 400 µm. The solvent content is controlled by USP <467> residual solvents to not more than 5,000 ppm for ethanol and 50 ppm for methanol. The granules are dried until residual moisture is below 2.0% w/w and then immediately filled into aluminium foil laminate sachets with desiccant. The sachet filling line is maintained at 25°C and 35% RH; above 60% RH the granules agglomerate and the dose-uniformity of the suspending powder is lost. Reconstitution at 10 mg per 5 mL in water produces a clear solution at pH 6.8 – 7.2; if pH rises above 7.5, the solution yellows due to oxidation. The granule product is used as an oral solution prior to administration; dissolution testing is replaced by disintegration or dispersion testing per Ph. Eur. 2.9.1 at 15°C – 25°C. Sachet products require stability at 30°C/65% RH for 24 months with no change in related substances above 1.0% total. This presentation avoids the need for swallowing a tablet in paediatric or dysphagic populations, but the excipient load increases because the API dose is dispersed in 250 mg – 500 mg of dissolved solids.
Although the aqueous injection is the default parenteral presentation, a lyophilised formulation is occasionally specified when water activity must be reduced below 0.2 to suppress hydrolytic dephosphorylation. The fill solution contains menadiol sodium phosphate 5 mg/mL, mannitol 50 mg/mL, and disodium edetate 0.1 mg/mL in water for injection. After filtration, the solution is filled into 5 mL Type I borosilicate vials with butyl rubber stoppers in a partially stoppered position. Freeze-drying is carried out with product temperature at -35°C during 4 h annealing, then primary drying at shelf temperature -10°C and chamber pressure 100 mTorr for 48 h. Secondary drying at 25°C for 6 h reduces residual moisture below 1.0% w/w by Karl Fischer titration. The removal of water stabilises the diphosphate ester against hydrolysis, but the lyophilised cake is hygroscopic; the stopper is seated under nitrogen and the moisture ingress rate through the seal is verified at 40°C/75% RH for 6 months. The lyophilised product is reconstituted with 5 mL of water for injection to yield a 5 mg/mL solution at pH 6.5 – 7.0. This format is limited by higher unit cost and the need for lyophilizer load uniformity because edge vials and center vials differ in cake appearance when the chamber pressure varies by more than 10 mTorr.
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Vitamin K4 Pharma Grade API is supplied as menadiol sodium diphosphate, CAS 131-69-1, molar mass 422.08 g/mol on an anhydrous basis. The substance is a water-soluble synthetic vitamin K analogue produced by reductive phosphorylation of menadione. Unlike oil-soluble phylloquinone, the diphosphate ester of menadiol dissolves in aqueous media without bile-salt solubilisation, enabling aqueous granulation, direct compression, capsule filling, and sterile filtration for parenteral administration. Model designations are manufacturer-specific, but release documentation typically distinguishes oral grade from injectable grade by bacterial endotoxin limits, particulate matter control, residual solvent profiles, and bioburden specification. The API appears as a white to almost white hygroscopic crystalline powder, freely soluble in water and only slightly soluble in ethanol 96%. Pharmacopoeial monographs, where adopted, define the substance as menadiol sodium diphosphate. Residual menadione is controlled as a related substance because oxidative regeneration of the quinone can occur during storage, especially in the presence of dissolved oxygen, trace metal ions, and light.
Release testing for oral grades typically includes assay, related substances, water content, pH of aqueous solution, residual solvents, and elemental impurities. Injectable grade adds bacterial endotoxin testing, particulate matter control after reconstitution, and bioburden before sterilisation. A representative release specification is shown in Table 1. Limits reflect current compendial monographs for menadiol sodium diphosphate where adopted, and should be confirmed against the specific manufacturer’s certificate of analysis.
| Parameter | Oral grade limit | Parenteral grade limit | Test standard |
|---|---|---|---|
| Assay, anhydrous basis | 98.0–102.0% | 98.0–102.0% | Ph.Eur. current monograph, HPLC |
| Menadione related substance | ≤ 0.5% | ≤ 0.5% | Ph.Eur. current monograph, HPLC |
| Unspecified impurity | ≤ 0.10% | ≤ 0.10% | Ph.Eur. current monograph, HPLC |
| Total impurities | ≤ 1.0% | ≤ 1.0% | Ph.Eur. current monograph, HPLC |
| Water content | ≤ 10.0% | ≤ 10.0% | USP <921> method Ia / Ph.Eur. 2.5.12 |
| pH of 5% aqueous solution | 6.0–8.0 | 6.0–8.0 | Ph.Eur. 2.2.3 |
| Residual solvents | Complies with ICH Q3C | Complies with ICH Q3C | Headspace GC |
| Elemental impurities | Complies with ICH Q3D | Complies with ICH Q3D, parenteral PDE | ICP-MS |
| Bacterial endotoxins | Not required | Limit calculated per USP <85> based on maximum dose | USP <85> / Ph.Eur. 2.6.14 |
Related-substance control is technically important because menadiol sodium diphosphate can undergo oxidative regeneration to menadione in aqueous solution. HPLC methods using octadecylsilyl silica columns and ultraviolet detection at 230 nm or 254 nm are typical; mobile phases contain phosphate buffer and methanol to resolve menadiol, menadione, and phosphate ester derivatives. Forced degradation studies under oxidative, thermal, and photolytic conditions are used to demonstrate specificity and to identify degradation products. If the analytical procedure is validated under ICH Q2(R2), the assay and impurity method should demonstrate specificity, linearity, accuracy, precision, and robustness across the expected specification range.
Particle size distribution is a critical processing attribute when Vitamin K4 API is formulated as a low-dose tablet or capsule. For wet granulation with povidone K30 or pregelatinised starch, a particle size D90 between 75 µm and 150 µm is often specified to prevent segregation. For direct compression with lactose monohydrate, microcrystalline cellulose, crospovidone, and magnesium stearate, a finer grade with D90 ≤ 50 µm may be requested. Bulk density typically ranges from 0.35 g/mL to 0.60 g/mL, but published data for this specific API configuration is limited. Blend uniformity should be verified with stratified sampling under USP <905> or Ph.Eur. 2.9.40. Batch-to-batch variation in water content shifts Carr Index and can cause weight variation or capping on rotary tablet presses operating above 60 rpm, particularly when residual moisture exceeds 8.0% or the granulation is over-dried below 2.0%. Chromium nitride coated tableting tools reduce sticking caused by hygroscopic powder adhesion to punch faces.
For dry granulation by roller compaction, the API may be blended with microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate. Ribbon density between 0.9 g/cm³ and 1.2 g/cm³ is often targeted to produce granules with acceptable compressibility. The API’s hygroscopicity requires controlled relative humidity below 50% during handling to prevent surface tack and feed-frame blockage. If the particle size distribution is bimodal or contains excessive fines below 10 µm, weight variation and capping can appear on high-speed rotary presses. Ribbon milling through an oscillating granulator with a 1.0 mm screen yields granules acceptable for tablet compression. For capsule filling, powder densification through slugging or roller compaction reduces dusting and improves flow; a Hausner ratio below 1.25 is generally accepted for high-speed encapsulation.
Menadiol sodium diphosphate is freely soluble in water, permitting aqueous formulation without lecithin or glycocholate. For injection, the finished solution can be sterilised by moist heat if stability data support that choice; otherwise sterile filtration through a 0.22 µm polyethersulfone or polyvinylidene fluoride membrane is used before aseptic filling. In both cases, the solution is protected from light because ultraviolet exposure accelerates oxidation of menadiol to menadione. pH is measured after dilution to a 5% solution; values outside 6.0–8.0 may indicate phosphate ester hydrolysis or contamination with acidic degradation products. Nitrogen overlay during compounding and filling reduces dissolved oxygen below 2.0 mg/L; headspace oxygen is controlled to below 2.0% v/v in the sealed primary container. Amber glass vials or ampoules are used unless light-protective secondary packaging is applied.
Parenteral-grade release testing includes bacterial endotoxin control. Because the API is not sterile but may be used in aseptic processing, the parenteral grade is managed with a bioburden limit, sometimes not more than 100 CFU/g, and a bacterial endotoxin limit derived from the maximum adult dose. Endotoxin limits are dose-based and must be calculated from the finished product maximum dose and route of administration; no single API limit is universally applicable. Microbial enumeration tests per USP <61> and <62> or Ph.Eur. 2.6.12 and 2.6.13 are performed on oral grades only when specified by the customer or when the oral formulation is intended for immunocompromised patient populations. Injectable-grade API should also be evaluated for particulate matter after dissolution using USP <788> or Ph.Eur. 2.9.19, with limits defined by the finished product specification rather than the API alone.
Granule formulations for oral suspension are prepared by wet granulation with povidone and mannitol. The API may be dissolved in the binder solution or dry-mixed depending on dose. If the API is dissolved, the solution should be protected from light and used within 24 h due to oxidative degradation. If dry-mixed, granule drying temperature should not exceed 50 °C to avoid phosphate ester hydrolysis. Drying in fluid-bed equipment with inlet air dew point below 5 °C and product temperature below 40 °C preserves chemical stability. The dried granule is milled through a 1.25 mm screen and packaged with silica gel desiccant. For oral solution, the API is dissolved in purified water with a suitable antimicrobial preservative if the product is multi-dose; light-protective amber glass bottles with nitrogen headspace are used.
Vitamin K4 differs from phylloquinone and menaquinone-7 in side-chain architecture and formulation behaviour. Phylloquinone has a phytyl side chain, menaquinone-7 has an isoprenoid chain, while menadiol sodium diphosphate lacks a long lipophilic side chain and is esterified with phosphate. This difference removes the requirement for micellar solubilisation in oral absorption. In hepatic tissue, menadiol may be metabolically alkylated to menaquinone-4 or exert cofactor activity after phosphorylation. Unlike phylloquinone and menaquinone-7, the initial absorptive step does not depend on lymphatic chylomicron transport. For injectable use, phylloquinone requires a mixed micelle or lipid emulsion, while Vitamin K4 forms a clear aqueous solution. That is the primary manufacturing and clinical handling difference.
| Property | Vitamin K4 menadiol sodium diphosphate | Phylloquinone K1 | Menaquinone-7 K2 | Menadione K3 |
|---|---|---|---|---|
| Water solubility | Freely soluble in water | Practically insoluble in water | Practically insoluble in water | Low aqueous solubility |
| Oral absorption dependency | Not bile-salt dependent | Bile-salt dependent | Bile-salt dependent | Not used routinely in human oral therapy |
| Primary dosage form | Aqueous injection, oral solution, tablet, capsule, granule | Lipid emulsion injection, softgel, oil-based drops | Softgel, lipid-based delivery | Feed premix |
| Human therapeutic use | Hemorrhagic states responsive to vitamin K; antidote to coumarin anticoagulants | Neonatal prophylaxis, anticoagulant reversal | Nutritional supplement; bone and cardiovascular research | Limited due to hemolytic risk |
| Key manufacturing concern | Oxidation to menadione; phosphate ester hydrolysis | Light degradation; lipid oxidation | Fermentation-derived isomeric variability; lipid oxidation | Genotoxic and hemolytic potential; feed use only |
Residual solvent and elemental impurity control follows ICH Q3C and ICH Q3D. If methanol, ethanol, or isopropanol is used in the phosphorylation step, class 3 limits apply. If dichloromethane or another class 2 solvent is present, the API certificate of analysis should report concentrations below the permitted daily exposure. Elemental impurity risk is typically low for this molecule because the synthesis does not require platinum or palladium catalysts, but nickel, chromium, and arsenic may be present from reagents. ICP-MS is used for quantification. Oral and parenteral permitted daily exposure values differ, so injectable grade may be tested against lower limits for cadmium, lead, arsenic, and mercury. Residual solvents and elemental impurities should be reported in the API release documentation because they affect finished product compliance under USP <232>, USP <233>, and ICH Q3D.
