Name: Alpha Tocopherol
CAS No: ()-(2RS,40 RS,80 RS)-2,5,7,8-Tetramethyl-2-(40 ,80 ,120 -trimethyltridecyl)-6-chromanol [10191-41-0]
BP: RRR-Alpha-Tocopherol JP: Tocopherol PhEur: RRR-a-Tocopherol USP: Vitamin E See also Sections 3, 9, and 17.
Copherol F1300; ()-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12- trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; RRR-a-tocopherolum; synthetic alpha tocopherol; all-rac-a-tocopherol; dl-a-tocopherol; 5,7,8-trimethyltocol.
()-(2RS,40 RS,80 RS)-2,5,7,8-Tetramethyl-2-(40 ,80 ,120 -trimethyltridecyl)-6-chromanol [10191-41-0]
C29H50O2 430.72
Alpha tocopherol is primarily recognized as a source of vitamin E, and the commercially available materials and specifications reflect this purpose. While alpha tocopherol also exhibits antioxidant properties, the beta, delta, and gamma tocopherols are considered to be more effective as antioxidants. Alpha-tocopherol is a highly lipophilic compound, and is an excellent solvent for many poorly soluble drugs.(1–4) Of widespread regulatory acceptability, tocopherols are of value in oil- or fat-based pharmaceutical products and are normally used in the concentration range 0.001–0.05% v/v. There is frequently an optimum concentration; thus the autoxidation of linoleic acid and methyl linolenate is reduced at low concentrations of alpha tocopherol, and is accelerated by higher concentrations. Antioxidant effectiveness can be increased by the addition of oil-soluble synergists such as lecithin and ascorbyl palmitate.(4) Alpha tocopherol may be used as an efficient plasticizer.(5) It has been used in the development of deformable liposomes as topical formulations.(6) d-Alpha-tocopherol has also been used as a non-ionic surfactant in oral and injectable formulations.(3)
Alpha tocopherol is a natural product. The PhEur 6.0 describes alpha-tocopherol as a clear, colorless or yellowish-brown, viscous, oily liquid. See also Section 17.
See Table I. Note that the USP 32 describes vitamin E as comprising d- or dlalpha tocopherol, d- or dl-alpha tocopheryl acetate, or d- or dlalpha tocopheryl acid succinate. However, the PhEur 6.0 describes alpha tocopherol and alpha tocopheryl acetate in separate monographs. The diversity of the tocopherols described in the various pharmacopeial monographs makes the comparison of specifications more complicated; see Section 17.
Boiling point 2358C Density 0.947–0.951 g/cm3 Flash point 2408C Ignition point 3408C Refractive index n D 20 = 1.503–1.507 Solubility Practically insoluble in water; freely soluble in acetone, ethanol, ether, and vegetable oils.
Tocopherols are oxidized slowly by atmospheric oxygen and rapidly by ferric and silver salts. Oxidation products include tocopheroxide, tocopherylquinone, and tocopherylhydroquinone, as well as dimers and trimers. Tocopherol esters are more stable to oxidation than the free tocopherols but are in consequence less effective antioxidants. See also Section 17. Tocopherols should be stored under an inert gas, in an airtight container in a cool, dry place and protected from light.
Tocopherols are incompatible with peroxides and metal ions, especially iron, copper, and silver. Tocopherols may be absorbed into plastic.(7)
Naturally occurring tocopherols are obtained by the extraction or molecular distillation of steam distillates of vegetable oils; for example, alpha tocopherol occurs in concentrations of 0.1–0.3% in corn, rapeseed, soybean, sunflower, and wheat germ oils.(8) Beta and gamma tocopherol are usually found in natural sources along with alpha tocopherol. Racemic synthetic tocopherols may be prepared by the condensation of the appropriate methylated hydroquinone with racemic isophytol.(9)
Tocopherols (vitamin E) occur in many food substances that are consumed as part of the normal diet. The daily nutritional requirement has not been clearly defined but is estimated to be 3.0–20.0 mg. Absorption from the gastrointestinal tract is dependent upon normal pancreatic function and the presence of bile. Tocopherols are widely distributed throughout the body, with some ingested tocopherol metabolized in the liver; excretion of metabolites is via the urine or bile. Individuals with vitamin E deficiency are usually treated by oral administration of tocopherols, although intramuscular and intravenous administration may sometimes be used. Tocopherols are well tolerated, although excessive oral intake may cause headache, fatigue, weakness, digestive disturbance, and nausea. Prolonged and intensive skin contact may lead to erythema and contact dermatitis. The use of tocopherols as antioxidants in pharmaceuticals and food products is unlikely to pose any hazard to human health since the daily intake from such uses is small compared with the intake of naturally occurring tocopherols in the diet. The WHO has set an acceptable daily intake of tocopherol used as an antioxidant at 0.15–2.0 mg/kg body-weight.(10)
Observe normal precautions appropriate to the circumstances and quantity of material handled. Gloves and eye protection are recommended.
GRAS listed. Accepted in Europe as a food additive. Included in the FDA Inactive Ingredients Database (IV injections, powder, lyophilized powder for liposomal suspension; oral capsules, tablets, and topical preparations). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in nonparenteral medicines licensed in the UK.
d-Alpha tocopherol; d-alpha tocopheryl acetate; dl-alpha tocopheryl acetate; d-alpha tocopheryl acid succinate; dl-alpha tocopheryl acid succinate; beta tocopherol; delta tocopherol; gamma tocopherol; tocopherols excipient. d-Alpha tocopherol Empirical formula C29H50O2 Molecular weight 430.72 CAS number [59-02-9] Synonyms Natural alpha tocopherol; (þ)-(2R,40 R,80 R)-2,5,7,8- tetramethyl-2-(40 ,80 ,120 -trimethyltridecyl)-6-chromanol; d-atocopherol; vitamin E. Appearance A practically odorless, clear, yellow, or greenishyellow viscous oil. Melting point 2.5–3.58C Solubility Practically insoluble in water; soluble in ethanol (95%). Miscible with acetone, chloroform, ether, and vegetable oils. Specific gravity 0.95 Comments d-Alpha tocopherol is the naturally occurring form of alpha tocopherol. d-Alpha tocopheryl acetate Empirical formula C31H52O3 Molecular weight 472.73 CAS number [58-95-7] Synonyms (þ)-(2R,40 R,80 R)-2,5,7,8-Tetramethyl-2-(40 ,80 ,120 - trimethyltridecyl)-6-chromanyl acetate; d-a-tocopheryl acetate; vitamin E. Appearance A practically odorless, clear, yellow, or greenishyellow colored viscous oil that may solidify in the cold. Melting point 288C Solubility Practically insoluble in water; soluble in ethanol (95%). Miscible with acetone, chloroform, ether, and vegetable oils. Specific rotation [a]D 25 = þ0.258 (10% w/v solution in chloroform) Comments Unstable to alkalis. dl-Alpha tocopheryl acetate Empirical formula C31H52O3 Molecular weight 472.73 CAS number [7695-91-2] Synonyms ()-3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol acetate; ()- (2RS,40 RS,80 RS)-2,5,7,8-tetramethyl-2-(40 ,80 ,120 -trimethyltridecyl)-6-chromanyl acetate; ()-a-tocopherol acetate; a-tocopheroli acetas; all-rac-a-tocopheryl acetate; dl-a-tocopheryl acetate; vitamin E. Appearance A practically odorless, clear, yellow, or greenishyellow viscous oil. Density 0.953 g/cm3 Melting point –27.58C Refractive index n D 20 = 1.4950–1.4972 Solubility Practically insoluble in water; freely soluble in acetone, chloroform, ethanol, ether, and vegetable oils; soluble in ethanol (95%). Comments Unstable to alkali. However, unlike alpha tocopherol, the acetate is much less susceptible to the effects of air, light, or ultraviolet light. Alpha tocopherol acetate concentrate, a powdered form of alpha tocopherol acetate, is described in the PhEur 6.0. The concentrate may be prepared by either dispersing alpha tocopherol acetate in a suitable carrier such as acacia or gelatin, or by adsorbing alpha tocopherol acetate on silicic acid. d-Alpha tocopheryl acid succinate Empirical formula C33H54O5 Molecular weight 530.8 CAS number [4345-03-3] Synonyms (þ)-a-Tocopherol hydrogen succinate; d-a-tocopheryl acid succinate; vitamin E. Appearance A practically odorless white powder. Melting point 76–778C Solubility Practically insoluble in water; slightly soluble in alkaline solutions; soluble in acetone, ethanol (95%), ether, and vegetable oils; very soluble in chloroform. Comments Unstable to alkalis. dl-Alpha tocopheryl acid succinate Empirical formula C33H54O5 Molecular weight 530.8 CAS number [17407-37-3] Synonyms ()-a-Tocopherol hydrogen succinate; dl-a-tocopheryl acid succinate; dl-a-tocopherol succinate; vitamin E. Appearance A practically odorless, white crystalline powder. Solubility Practically insoluble in water; slightly soluble in alkaline solutions; soluble in acetone, ethanol (95%), ether, and vegetable oils; very soluble in chloroform. Comments Unstable to alkalis. Beta tocopherol Empirical formula C28H48O2 Molecular weight 416.66 CAS number [148-03-8] Synonyms Cumotocopherol; ()-3,4-dihydro-2,5,8-trimethyl-2- (4,8,12-trimethyltridecyl)-2H-1-b-benzopyran-6-ol; 5,8- dimethyltocol; neotocopherol; dl-b-tocopherol; vitamin E; pxylotocopherol. Appearance A pale yellow-colored viscous oil. Solubility Practically insoluble in water; freely soluble in acetone, chloroform, ethanol (95%), ether, and vegetable oils. Specific rotation [a]D 20 = þ6.378 Comments Less active biologically than alpha tocopherol. Obtained along with alpha tocopherol and gamma tocopherol from natural sources. Beta tocopherol is very stable to heat and alkalis and is slowly oxidized by atmospheric oxygen. Delta tocopherol Empirical formula C27H46O2 Molecular weight 402.64 CAS number [119-13-1] Synonyms ()-3,4-Dihydro-2,8-dimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E309; 8-methyltocol; dl-d-tocopherol; vitamin E. Appearance A pale yellow-colored viscous oil. Solubility Practically insoluble in water; freely soluble in acetone, chloroform, ethanol (95%), ether, and vegetable oils. Comments Occurs naturally as 30% of the tocopherol content of soybean oil. Delta tocopherol is said to be the most potent antioxidant of the tocopherols. Gamma tocopherol Empirical formula C28H48O2 Molecular weight 416.66 CAS number [7616-22-0] Synonyms ()-3,4-Dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; 7,8-dimethyltocol; E308; dl-gtocopherol; vitamin E; o-xylotocopherol. Appearance A pale yellow-colored viscous oil. Melting point –308C Solubility Practically insoluble in water; freely soluble in acetone, chloroform, ethanol (95%), ether, and vegetable oils. Specific rotation [a]D 20 = –2.48 (in ethanol (95%)) Comments Occurs in natural sources along with alpha and beta tocopherol. Gamma tocopherol is biologically less active than alpha tocopherol. Very stable to heat and alkalis; slowly oxidized by atmospheric oxygen and gradually darkens on exposure to light. Tocopherols excipient Synonyms Embanox tocopherol. Appearance A pale yellow-colored viscous oil. Comments Tocopherols excipient is described in the USP32– NF27 as a vegetable oil solution containing not less than 50.0% of total tocopherols, of which not less than 80.0% consists of varying amounts of beta, delta, and gamma tocopherols.
Note that most commercially available tocopherols are used as sources of vitamin E, rather than as antioxidants in pharmaceutical formulations. Various mixtures of tocopherols, and mixtures of tocopherols with other excipients, are commercially available, and individual manufacturers should be consulted for specific information on their products. Molecularly imprinted polymers for use in the controlled release of alpha tocopherol in gastrointestinal simulating fluids have been investigated.(11) The EINECS number for a-tocopherol is 215-798-8. The EINECS number for d-a-tocopherol is 200-412-2; and the EINECS number for dl-a-tocopherol is 233-466-0. The PubChem Compound ID (CID) for alpha tocopherol includes 14985 and 1548900.