Nonproprietary Names

None adopted.

Synonyms

Adju-Phos; aluminum hydroxyphosphate; aluminium hydroxyphosphate; Rehydraphos.

Chemical Name and CAS Registry Number

Aluminum phosphate [7784-30-7]

Empirical Formula and Molecular Weight

Al(OH)x(PO4)y The molecular weight is dependent on the degree of substitution of phosphate groups for hydroxyl groups.

Structural Formula

Aluminum phosphate adjuvant occurs as a precipitate of amorphous aluminum hydroxide in which some sites contain phosphate groups instead of hydroxyl. Both hydroxyl and phosphate groups are exposed at the surface. The hydroxyl groups produce a pHdependent 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. Aluminum phosphate adjuvant is not a stoichiometric compound. Rather, the degree of phosphate group substitution for hydroxyl groups depends on the precipitation recipe and conditions.

Functional Category

Adsorbent; vaccine adjuvant.

Applications in Pharmaceutical Formulation or Technology

Technology Aluminum phosphate adjuvant is used in parenteral human and veterinary vaccines.(1) It activates Th2 immune responses, including IgG and IgE antibody responses.

Description

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

Pharmacopeial Specifications

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Typical Properties

Acidity/alkalinity pH = 6.0–8.0 Al:P atomic ratio 1.0–1.4:1.0 Aluminum (%) 0.5–0.75 Particle size distribution Primary particles are platy with an average diameter of 50nm. The primary particles form aggregates of 1–10mm. Point of zero charge pH = 4.6–5.6, depending on the Al:P atomic ratio. Protein binding capacity >0.6mg lysozyme/mg equivalent Al2O3 Solubility Soluble in mineral acids and alkali hydroxides. X-ray diffractogram Amorphous to x-rays.

Stability and Storage Conditions

Aluminum phosphate adjuvant is stable for at least 2 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

The point of zero charge is related directly to the Al:P atomic ratio. Therefore, the substitution of additional phosphate groups for hydroxyl groups will lower the point of zero charge. Substitution of carbonate, sulfate, or borate ions for hydroxyl groups will also lower the point of zero charge.

Method of Manufacture

Aluminum phosphate adjuvant is formed by the reaction of a solution of aluminum chloride and phosphoric acid with alkali hydroxide.

Safety

Aluminum phosphate adjuvant is intended for use in parenteral vaccines and is generally regarded as safe. It may cause mild irritation, dryness, and dermatitis on skin contact. It may also cause redness, conjunctivitis, and short-term mild irritation on eye contact. Ingestion of large amounts of aluminum phosphate adjuvant may cause respiratory irritation with nausea, vomiting, and constipation. Inhalation is unlikely, although the dried product may cause respiratory irritation and cough. Type I hypersensitivity reactions following parenteral administration have also been reported.(2)

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 vaccines in Europe and the USA. The limits for use in human vaccines are 0.85mg aluminum/dose (FDA) and 1.25mg aluminum/dose (WHO). There are no established limits for use in veterinary vaccines. Reported in the EPA TSCA Inventory. Ammonia Solution 17 Related Substances Aluminum hydroxide adjuvant.

Comments

The USP 32 monograph for aluminum phosphate (AlPO4) gel describes aluminum phosphate, which is used as an antacid, not as a vaccine adjuvant. 19 Specific References 1 Shirodkar S et al. Aluminum compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 1282–1288. 2 Goldenthal KL et al. Safety evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 1993; 9: S47–S51.

General References

Hem SL, Hogenesch H. Aluminum-containing adjuvants: properties, formulation, and use. Singh M, ed. Vaccine Adjuvants and Delivery Systems. New York: Wiley, 2007; 81–114. Gupta RK et al. Adjuvant properties of aluminum and calcium compounds. Powell MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995; 229–248. Lindblad EB. Aluminum adjuvants – in retrospect and prospect. Vaccine 2004; 22: 3658–3668. Lindblad EB. Aluminum adjuvants. Stewart-Tull DES, ed. The Theory and Practical Application of Adjuvants. New York: Wiley, 1995; 21–35. Vogel FR, Hem SL. Immunogenic adjuvants. Plotkin SA et al, ed. Vaccines, 5th edn. New York: W.B. Saunders, 2008; 59–71. Vogel FR, Powell MF. A compendium of vaccine adjuvants and excipients. Powell MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995; 142. White JL, Hem SL. Characterization of aluminum-containing adjuvants. Brown F et al, ed. Physico-Chemical Procedures for the Characterization of Vaccines.IABS Symposia Series: Developments in Biologicals, vol. 103: New York: Karger, 2000; 217–228.

Author

s SL Hem, PB Klepak, EB Lindblad.

Date of Revision

19 February 2009.