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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 concentra- tions 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)

D-a-Tocopherol has also been used as a non-ionic surfactant in oral and injectable formulations.(3)

Description

Alpha tocopherol is a natural product. The PhEur 2005 (Suppl. 5.1) describes a-tocopherol as a clear, colorless or yellowish- brown, viscous, oily liquid. See also Section 17.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for alpha tocopherol.

Test JP 2001 PhEur 2005

Optical rotation — –0.018 to +0.018 +

Heavy metals 420 ppm 420 ppm —

Sulfated ash — 40.1% —

Organic volatile — — +

impurities

Absorbance + + —

at 255 nm — 5.5–8.0 —

at 292 nm 71.0–76.0 72.0–76.0 —

Refractive index 1.503–1.507 — —

Specific gravity 0.947–0.955 — —

Clarity and color + — —

of solution

Assay 96.0–102.0% 96.0–101.5% 96.0–

102.0%

Note that the USP 28 describes vitamin E as comprising d- or dl-alpha tocopherol, d- or dl-alpha tocopheryl acetate, or d- or dl-alpha tocopheryl acid succinate. However, the PhEur 2005 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 specifi- cations more complicated; see Section 17.

Alpha Tocopherol 33

Typical Properties

Boiling point: 2358C Density: 0.947–0.951 g/cm3 Flash point: 2408C

Ignition point: 3408C

Refractive index: n20 = 1.503–1.507

Solubility: practically insoluble in water; freely soluble in acetone, ethanol, ether, and vegetable oils.

Stability and Storage Conditions

Tocopherols are oxidized slowly by atmospheric oxygen and rapidly by ferric and silver salts. Oxidation products include tocopheroxide, tocopherylquinone, and tocopherylhydroqui- none, 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.

Incompatibilities

Tocopherols are incompatible with peroxides and metal ions, especially iron, copper, and silver. Tocopherols may be absorbed into plastic.(5)

Method of Manufacture

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.(6) 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 isophy-

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Gloves and eye protection are recommended.

Regulatory Status

GRAS listed. Accepted in Europe as a food additive. Included in the FDA Inactive Ingredients Guide (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.

Related Substances

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; (+)-(2R,4'R,8'R)- 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chro- manol; d-a-tocopherol; vitamin E.

Appearance: a practically odorless, clear, yellow, or greenish- yellow 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

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

Molecular weight: 472.73

CAS number: [58-95-7]

Synonyms: (+)-(2R,4'R,8'R)-2,5,7,8-tetramethyl-2-(4',8',12'- trimethyltridecyl)-6-chromanyl acetate; d-a-tocopheryl acet- ate; vitamin E.

Appearance: a practically odorless, clear, yellow, or greenish- yellow 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]25: +0.258 (10% w/v solution in chloro-

with vitamin E deficiency are usually treated by oral admin- istration of tocopherols, although intramuscular and intra- venous 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 to 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.(8)

form)

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-tri- methyltridecyl)-2H-1-benzopyran-6-ol acetate; ( )- (2RS,4'RS,8'RS)-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl- tridecyl)-6-chromanyl acetate; ( )-a-tocopherol acetate; a- tocopheroli acetas; all-rac-a-tocopheryl acetate; dl-a-toco- pheryl acetate; vitamin E.

34 Alpha Tocopherol

Appearance: a practically odorless, clear, yellow, or greenish- yellow viscous oil.

Density: 0.953 g/cm3

Melting point: –27.58C

Refractive index: n20 = 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 toco- pherol, 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 2005. 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: (+)-a-tocopherol hydrogen succinate; d-a-toco- pheryl 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-toco- pheryl 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; p-xylotocopherol.

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]20: +6.378

Comments: less active biologically than alpha tocopherol. Obtained along with alpha tocopherol and gamma toco- pherol 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-trimethyl- tridecyl)-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-tri- methyltridecyl)-2H-1-benzopyran-6-ol; 7,8-dimethyltocol; E308; dl-g-tocopherol; 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]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 USPNF 23 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.

Comments

Note that most commercially available tocopherols are used as sources of vitamin E, rather than as antioxidants in pharma- ceutical formulations.

Various mixtures of tocopherols, and mixtures of tocopher- ols with other excipients, are commercially available and individual manufacturers should be consulted for specific information on their products. 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.

Specific References

Nielsen PB, Mu¨ llertz A, Norling T, Kristensen HG. The effect of a- tocopherol on the in vitro solubilisation of lipophilic drugs. Int J Pharm 2001; 222: 217–224.

Constantinides PP, Tustian A, Kessler DR. Tocol emulsions for drug solubilization and parenteral delivery. Adv Drug Delivery 2004; 56(9): 1243–1255.

Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res 2004; 21(2): 201–230.

Alpha Tocopherol 35

Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, volume 1. New York: Marcel Dekker, 1988: 415–450.

Allwood MC. Compatibility and stability of TPN mixtures in big bags. J Clin Hosp Pharm 1984; 9: 181–198.

Buck DF. Antioxidants. In: Smith J, ed. Food Additive User’s Handbook. Glasgow: Blackie, 1991: 1–46.

Rudy BC, Senkowski BZ. dl-Alpha-tocopheryl acetate. In: Florey K, ed. Analytical Profiles of Drug Substances, volume 3. New York: Academic Press, 1974: 111–126.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirtieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987; No. 751.

General References

US National Research Council Food and Nutrition Board. Recom- mended Dietary Allowances, 10th edn. Washington DC: National Academy Press, 1989: 99–105.

Aluminum Hydroxide Adjuvant

Nonproprietary Names

PhEur: Aluminii hydroxidum hydricum ad adsorptionem

Synonyms

Alhydrogel; aluminium hydroxide adjuvant; aluminium oxy- hydroxide; poorly crystalline boehmite; pseudoboehmite; Rehydragel.

Chemical Name and CAS Registry Number

Aluminum oxyhydroxide [21645-51-2]

Empirical Formula and Molecular Weight

AlO(OH) 59.99

Structural Formula

Structural hydroxyl groups form hydrogen bonds between AlO(OH) octahedral sheets, where hydroxyl groups are exposed at the surface. The surface hydroxyl groups produce a pH-dependent surface charge by accepting a proton to produce a positive site, or donating a proton to produce a negative site. The pH-dependent surface charge is characterized by the point of zero charge, which is equivalent to the isoelectric point in protein chemistry. The surface hydroxyl groups may also undergo ligand exchange with fluoride, phosphate, carbonate, sulfate, or borate anions.

Functional Category

Adsorbent; vaccine adjuvant.

Applications in Pharmaceutical Formulation or Technology

Aluminum hydroxide adjuvant is used in parenteral human and veterinary vaccines.(1) It activates TH2 immune responses, including IgG and IgE antibody responses. It is also used for the isolation of certain serum components such as blood clotting factors.(2)

Description

Aluminum hydroxide adjuvant is a white hydrogel that sediments slowly and forms a clear supernatant.

Pharmacopeial Specifications

See Table I. Note that the USP 28 includes a monograph for aluminum hydroxide gel, which is a form of aluminum hydroxide that is used as an antacid, in which there is a partial substitution of carbonate for hydroxide.

See Section 17.

Table I: Pharmacopeial specifications for aluminum hydroxide adjuvant.

Bacterial endotoxins +

Assay 90.0–110.0%

Typical Properties

Acidity/alkalinity: pH = 5.5–8.5

Particle size distribution: primary particles are fibrous with average dimensions of 4.5 × 2.2 × 10 nm. The primary particles form aggregates of 1–10 mm.

Point of zero charge: pH = 11.4

Protein binding capacity: >0.5 mg BSA/mg equivalent Al2O3

Solubility: soluble in alkali hydroxides and mineral acids. Heat

may be required to dissolve the aluminum hydroxide adjuvant.

Specific surface area: 500 m2/g.(3)

ray diffractogram: exhibits characteristic x-ray diffraction pattern having diffraction bands at 6.46, 3.18, 2.35, 1.86,

1.44 and 1.31 A˚ .

Stability and Storage Conditions

Aluminum hydroxide adjuvant is stable for at least two years when stored at 4–308C in well-sealed inert containers. It must not be allowed to freeze as the hydrated colloid structure will be irreversibly damaged.

Incompatibilities

When exposed to phosphate, carbonate, sulfate, or borate anions, the point of zero charge for aluminum hydroxide adjuvant decreases.

Method of Manufacture

Aluminum hydroxide adjuvant is prepared by the precipitation of a soluble aluminum salt by an alkali hydroxide, or the precipitation of an alkali aluminate by acid.

Aluminum Hydroxide Adjuvant 37

Safety

Aluminum hydroxide adjuvant is intended for use in parenteral vaccines and is generally regarded as nontoxic. It may cause mild irritation, dryness, and dermatitis on skin contact. On eye contact, aluminum hydroxide adjuvant may also cause redness, conjunctivitis, and short-term mild irritation. Ingestion of large amounts may cause gastrointestinal irritation with nausea, vomiting, and constipation. Inhalation of the dried product may cause respiratory irritation and cough. Type I hypersensi- tivity reactions following parenteral administration have been reported.(4)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended.

Regulatory Status

GRAS listed. Accepted for use in human and veterinary parenteral vaccines in Europe and the USA. The limits for use in human vaccines are 0.85 mg aluminum/dose (FDA) and

1.25 mg aluminum/dose (WHO). There are no established limits for use in veterinary vaccines. Reported in the EPA TSCA Inventory.

Related Substances

Aluminum phosphate adjuvant.

Comments

Different grades of aluminum hydroxide adjuvant with various concentrations, protein binding capacities, and points of zero charge are available.

The impurity limits at 2% equivalent Al2O3 are Cl < 0.5%; SO4 < 0.5%; PO4 < 0.1%; NO3 < 0.1%; NH4 < 0.1%; Fe <

ppm; As < 0.6 ppm; and heavy metals < 20 ppm.

The aluminum hydroxide gel referred to in the USP 28 is

used in cosmetics as an emollient, filler, humectant, a mild astringent, and viscosity controlling agent. In pharmaceutical preparations it is used as an adsorbent, and as a protein binder.(5) It is also used therapeutically as an antacid, and as an abrasive in dentrifrices. It is not, however, used as a vaccine adjuvant.

Specific References

Shirodkar S, Hutchinson RL, Perry DL, et al. Aluminum compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 1282–1288.

Prowse CV, Griffin B, Pepper DS, et al. Changes in factor VIII complex activities during the production of a clinical intermediate purity factor VIII concentrate. Thromb Haemost 1981; 46: 597–

601.

Johnston CT, Wang JL, Hem SL. Measuring the surface area of aluminum hydroxide adjuvant. J Pharm Sci 2002; 91: 1702–1706.

Goldenthal KL, Cavagnaro JA, Alving G, Vogel FR. Safety evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 1993: 9 (Suppl. 1): 547–551.

Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. Endicott, NY: Synapse Information Resources, 2002: 298.

General References

Gupta RK, Rost BE, Relyveld E, Siber GR. Adjuvant properties of aluminum and calcium compounds. In: Powell MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995: 229–248.

Hem SL, White JL. Structure and properties of aluminum-containing adjuvants. In: Powel MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995: 249–276.

Lindblad EB. Aluminum adjuvants – in retrospect and prospect.

Vaccine 2004; 22: 3658–3668.

Lindblad EB. Aluminum adjuvants. In: Stewart-Tull DES, ed. The Theory and Practical Application of Adjuvants. New York: Wiley, 1995: 21–35.

Vogel FR, Powell MF. A compendium of vaccine adjuvants and excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995: 229–248.

Vogel FR, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orestein WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2004: 72– 76.

White JL, Hem SL. Characterization of aluminum-containing adju- vants. In: Brown F, Corbel M, Griffiths E, eds. Physico-Chemical Procedures for the Characterization of Vaccines, IABS Symposia Series, Development in Biologicals. New York: Karger, 2000; 103: 217–228.

Authors

SL Hem, PB Klepak, EB Lindblad.

Activated alumina; activated aluminum oxide; alpha aluminum oxide; alumina; alumina, activated; alumina, calcined; alumina, tabular; aluminum oxide alumite; aluminum trioxide.

Chemical Name and CAS Registry Number

Aluminum oxide [1344-28-1]

Empirical Formula and Molecular Weight

Al2O3 101.96

Structural Formula

Aluminum oxide occurs naturally as the minerals bauxite, bayerite, boehmite, corundum, diaspore, and gibbsite.

Functional Category

Adsorbent; dispersing agent.

Applications in Pharmaceutical Formulation or Technology

Aluminum oxide is used mainly in tablet formulations.(1) It is used for decoloring powders and is particularly widely used in antibiotic formulations. It is also used in suppositories, pessaries, and urethral inserts. Hydrated aluminum oxide (see Section 18) is used in mordant dyeing to make lake pigments, in cosmetics, and therapeutically as an antacid.

Description

Aluminum oxide occurs as a white crystalline powder. Aluminum oxide occurs as two crystalline forms. a-aluminum oxide is composed of colorless hexagonal crystals, and g- aluminum oxide is composed of minute colorless cubic crystals that are transformed to the a-form at high temperatures.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Boiling point: 29778C

Density (bulk): 0. 9—1.1 g/cm3

Flammability: nonflammable. Hardness (Mohs): 8.8 Hygroscopicity: very hygroscopic. Melting point: 20508C

Solubility: slowly soluble in aqueous alkaline solutions; practically insoluble in nonpolar organic solvents, diethyl ether, ethanol (95%), and water.

Specific gravity: 2.8 (becomes 4.0 at 8008C)

Vapor pressure: 133.3 Pa at 21588C

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