Phytonadione, commonly known as Vitamin K1, Phylloquinone, or Phytomenadione, is a naturally occurring fat-soluble vitamin and an important pharmaceutical active ingredient associated with the vitamin K family. It is chemically classified as a 1,4-naphthoquinone derivative with a long phytyl side chain. Phytonadione is used in pharmaceutical products where vitamin K activity is required and is an established ingredient in medicinal formulations. NIST identifies Phytonadione by CAS No. 84-80-0, molecular formula C31H46O2, and molecular weight 450.6957 g/mol.
A particularly important characteristic of pharmaceutical Phytonadione is that it is not necessarily a single stereochemically pure compound. The current USP definition describes Phytonadione as a mixture of E- and Z-isomers, containing 97.0%–103.0% total Phytonadione isomers and not more than 21.0% Z-isomer.
This is an important distinction for API quality control because the E/Z composition is an integral part of the Phytonadione specification.
| Parameter | Details |
|---|---|
| Product Name | Phytonadione |
| Common Name | Vitamin K1 |
| Synonyms | Phylloquinone, Phytomenadione, Vitamin K1 |
| CAS Number | 84-80-0 |
| Molecular Formula | C31H46O2 |
| Molecular Weight | 450.70 g/mol |
| Chemical Class | 1,4-Naphthoquinone derivative |
| Vitamin Class | Vitamin K |
| Physical Form | Viscous liquid |
| Typical Appearance | Clear yellow to amber liquid |
| Water Solubility | Insoluble in water |
| USP Classification | Mixture of E- and Z-isomers |
| USP Total Phytonadione | 97.0%–103.0% |
| USP Z-Isomer | NMT 21.0% |
NIST confirms the molecular formula, molecular weight and CAS number. The USP/FCC description characterizes Vitamin K/Phytonadione as a clear yellow to amber, very viscous liquid that is insoluble in water.
Phytonadione belongs to the vitamin K family and contains a naphthoquinone ring attached to a highly hydrophobic phytyl side chain. Its chemical structure is responsible for its characteristic lipid-soluble properties.
The compound is also known as 2-methyl-3-(3,7,11,15-tetramethylhexadec-2-en-1-yl)naphthalene-1,4-dione. NIST lists Phytonadione under several chemical and pharmaceutical names, including Vitamin K1, Phylloquinone, Phytomenadione and trans-Phylloquinone.
Because of its long hydrocarbon side chain, Phytonadione is highly lipophilic and is essentially insoluble in water. It is soluble in organic solvents such as dehydrated alcohol, chloroform, ether and vegetable oils.
One of the most important quality characteristics of Phytonadione is its E/Z isomeric composition.
The USP monograph defines Phytonadione as a mixture containing:
The E-isomer is generally referred to as the trans form, while the Z-isomer corresponds to the cis form. Because the proportions of these isomers are relevant to pharmaceutical quality, chromatographic determination of the E/Z profile is an important component of Phytonadione analysis.
The FDA has also specifically recognized the USP drug-substance requirement for total Phytonadione and the Z-isomer limit in its regulatory documentation.
Phytonadione is used in pharmaceutical products as a source of Vitamin K1. Vitamin K is essential to the normal biological process involved in the formation of several vitamin K-dependent coagulation proteins.
Phytonadione API is therefore relevant to pharmaceutical formulations intended for situations where vitamin K supplementation or vitamin K-related pharmacological activity is required.
Potential pharmaceutical applications include:
The specific dosage form and route of administration depend on the approved finished pharmaceutical product and applicable regulatory requirements.
Manufacturing Phytonadione requires particular attention to isomer composition, purity, light protection and analytical control.
Because Phytonadione contains E- and Z-isomers, manufacturing and purification processes should be controlled to achieve a reproducible isomer profile. Exposure to unsuitable environmental conditions can also affect product quality.
Important manufacturing controls can include:
Batch-to-batch consistency is particularly important because the USP specification directly addresses the total amount of Phytonadione and the maximum Z-isomer content.
Liquid chromatography is a key analytical technique for Phytonadione because it allows simultaneous evaluation of the E- and Z-isomers.
The USP procedure calculates total Phytonadione using the combined chromatographic response of the Z- and E-isomers relative to an internal standard. The USP procedure uses cholesteryl benzoate as the internal standard and a mobile phase consisting of n-hexane and n-amyl alcohol.
The current USP acceptance criteria are:
Total Phytonadione: 97.0%–103.0%
The Z-isomer is separately calculated from the chromatographic responses:
Z-isomer: NMT 21.0%
This makes HPLC/LC particularly important for Phytonadione API quality control.
The current USP monograph includes both infrared spectroscopy and ultraviolet-visible spectroscopy as identification procedures.
For the UV identification procedure, the analytical wavelength is 248 nm, using a 10 µg/mL solution in n-hexane. The absorptivities are required to meet the specified comparison criterion.
Using both spectroscopic and chromatographic characterization provides a robust analytical approach for confirming Phytonadione identity.
Phytonadione exhibits characteristic ultraviolet absorption associated with its naphthoquinone structure. The USP identification procedure uses 248 nm as the analytical wavelength in the UV identification test.
UV analysis can therefore provide useful supporting evidence for identity and characterization, while chromatographic analysis is used for quantitative assay and isomer determination.
The current USP Phytonadione monograph includes a specific test for menadione.
The USP procedure uses a color reaction in which a sample of Phytonadione is treated with ammonium hydroxide/alcohol mixture and ethyl cyanoacetate. The acceptance criterion is that no purple or blue color is produced.
This is an important distinction from many conventional small-molecule APIs where impurity specifications are expressed entirely as chromatographic percentage limits.
For Phytonadione, the current USP monograph specifically identifies menadione as an impurity requiring control.
The current USP specification provides a numerical refractive-index range:
Refractive Index: 1.523–1.526
This is a useful physical-quality parameter for Phytonadione and can complement chromatographic and spectroscopic testing.
The refractive-index range is particularly relevant because Phytonadione is a viscous, lipid-soluble liquid rather than a typical crystalline solid API.
Phytonadione differs significantly from many conventional pharmaceutical APIs because it is generally handled as a viscous liquid.
The USP/FCC description characterizes Vitamin K/Phytonadione as:
The material is also sensitive to sunlight, making appropriate light protection important during handling and storage.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 1.0% |
| Residue on Ignition | NMT 0.2% |
| Individual Impurity | NMT 0.5% |
| Total Impurities | NMT 1.0% |
| Water Content | NMT 1.0% |