Stability and Storage Conditions

Aluminum oxide should be stored in a well-closed container in a cool, dry, place. It is very hygroscopic.

Incompatibilities

Aluminum oxide should be kept well away from water. It is incompatible with strong oxidizers and chlorinated rubber. Aluminum oxide also reacts with chlorine trifluoride, ethylene oxide, sodium nitrate, and vinyl acetate. Exothermic reactions above 2008C with halocarbon vapors produce toxic hydrogen chloride and phosgene fumes.

Method of Manufacture

Most of the aluminum oxide produced commercially is obtained by the calcination of aluminum hydroxide.

Safety

Aluminum oxide is generally regarded as relatively nontoxic and nonirritant when used as an excipient. Inhalation of finely divided particles may cause lung damage (Shaver’s disease).

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled.(2) In the UK, the occupational exposure limits for aluminum oxide are 10 mg/m3 long-term (8-hour TWA) for total inhalable dust and 4 mg/m3 for respirable dust.(3)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral tablets and topical sponge). Included in nonparenteral medicines licensed in the UK.

Related Substances

—

Comments

A specification for aluminum oxide is included in Japanese Pharmaceutical Excipients 2004 (JPE), see Table I. A specifica- tion for light aluminum oxide is also included. The PhEur 2005 includes a specification for hydrated aluminum oxide that contains the equivalent of 47.0–60.0% of Al2O3. The EINECS number for aluminum oxide is 215-691-6.

Aluminum Oxide 39 

Table I: JPE specification for aluminum oxide.(4)

Test JPE 2004

Identification +

Water-soluble substances +

Heavy metals 430 ppm

Lead 430 ppm

Arsenic 45 ppm

Loss on drying 41.5%

Loss on ignition 42.5%

Assay 596.0%

Specific References

Rupprecht H. Processing of potent substances with inorganic supports by imbedding and coating. Acta Pharm Technol 1980; 26: 13–27.



National Poisons Information Service (1997). Aluminium oxide. http://www.intox.org/databank/documents/chemical/alumoxde/ ukpid33.htm (accessed 25 April 2005).

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 67–68.

General References

—

Authors

LY Galichet.

Date of Revision

17 August 2005.

Aluminum Phosphate Adjuvant

Nonproprietary Names

None adopted.

Synonyms

Aluminum hydroxyphosphate; aluminium hydroxyphosphate;

Adju-Phos; 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 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 groups.

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

Aluminum phosphate adjuvant is used in parenteral human and

Typical Properties

Acidity/alkalinity: 6.0–8.0

Al : P atomic ratio: 1.1–1.15 : 1.0

Aluminum (%): 0.5–0.75

Particle size distribution: primary particles are platy with an average diameter of 50 nm. The primary particles form aggregates of 1–10 mm.

Point of zero charge: pH = 4.6–5.6, depending on the Al : P atomic ratio.

Protein binding capacity: >0.6 mg 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 six months 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 affect 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, vomit- ing, and constipation. Inhalation is unlikely, although the dried product may cause respiratory irritation and cough. Type I hypersensitivity reactions following parenteral administration

veterinary vaccines.(1) It activates TH2 immune responses,

have also been reported.(2)

including IgG and IgE antibody responses.

Description

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

Pharmacopeial Specifications

—



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

Aluminum Phosphate Adjuvant 41 

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 hydroxide adjuvant.

Comments

The USP 28 monograph for aluminum phosphate (ALPO4) gel describes aluminum phosphate, which is used as an antacid, not 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.

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

General References

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



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.

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, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orenstein WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2003.

Vogel FR, Powell MF. A compendium of vaccine adjuvants and excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New York: Plenum, 1995: 142.

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, Developments in Biologicals. New York: Karger, 2000, 103: 217–228.

Authors

SL Hem, PB Klepak, EB Lindblad.

Date of Revision

2 September 2005.

Aluminum Stearate

Nonproprietary Names

None adopted.

Synonyms

Octadecanoic acid aluminum salt; stearic acid aluminum salt.

Chemical Name and CAS Registry Number

Aluminum tristearate [637-12-7]

Empirical Formula and Molecular Weight

C54H105AlO6 877.39

Structural Formula

[CH3(CH2)16COO]3Al

Functional Category

Emollient; emulsion stabilizer; gelling agent; opacifier; stabiliz- ing agent.

Applications in Pharmaceutical Formulation or Technology

Aluminum stearate is mainly used in microencapsulation(1–3) and in the manufacture of ointments. It is also used in cosmetics such as mascara, moisturizers, and sunscreens.

It should be noted that aluminum stearate can also refer to the distearate (CAS number [300-92-5]) and the monostearate (CAS number [7047-84-9]) in addition to the tristearate. The distearate exhibits the same excipient properties as the tristearate and is used in similar pharmaceutical applications. However, the monostearate is more widely used in cosmetics as a colorant.

Description

Aluminum stearate occurs as a white, fine, bulky powder with a slight odor of fatty acid. It is a hard material.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Melting point: 117–1208C

Solubility: practically insoluble in water. Soluble in ethanol (95%), benzene, turpentine oil, and mineral oils when freshly prepared.

Specific gravity: 1.01

Stability and Storage Conditions

Aluminum stearate should be stored in a well-closed container in a cool, dry, place. It is stable under ordinary conditions of use and storage.

Incompatibilities

—

Method of Manufacture

Aluminum stearate is prepared by reacting aluminum with stearic acid.

Safety

Aluminum stearate is generally regarded as relatively nontoxic and nonirritant when used as an excipient.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled. When heated to decomposition, aluminum stearate emits acrid smoke and irritating vapors.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets, topical creams and ointments). Included in nonparenteral medicines licensed in the UK.

Related Substances

Aluminum distearate; aluminum monostearate.

Aluminum distearate

Empirical formula: C36H71O5·Al

Molecular weight: 610.9

CAS number: [300-92-5]

Synonyms: hydroxyaluminum distearate; aluminum stearate; aluminum monobasic stearate

Description: aluminum distearate occurs as a fine white to off- white colored powder with a slight odor of fatty acid.

Melting point: 150–165 8C

Specific gravity: 1.01

Solubility: soluble in benzene, and in ethanol (95%); practically insoluble in water.

Comments: the EINECS number for aluminum distearate is 206-101-8.

Aluminum monostearate Empirical formula: C18H37O4Al Molecular weight: 344.5

CAS number: [7047-84-9]

Synonyms: dihydroxyaluminum monostearate; aluminum stea- rate; aluminum, dihydroxy (octadecanoato-O-); stearic acid aluminum dihydroxide salt.

Aluminum Stearate 43 

Melting point: 220–2258C

Specific gravity: 1.14

Solubility: soluble in benzene, and in ethanol (95%); practically insoluble in water.

Comments: the EINECS number for aluminum monostearate is 230-325-5.

Comments

A specification for aluminum stearate, described as consisting mainly of the distearate, is included in the Japanese Pharma- ceutical Excipients 2004 (JPE), see Table I. The EINECS number for aluminum tristearate is 211-279-5.

Table I:  JPE specifications for aluminum stearate.(4)

 

Test JPE 2004    

Identification +    

Acid value of fatty acid +    

Free fatty acid +    

Soluble salt +    

Heavy metals 420 ppm    

Lead 420 ppm    

Arsenic 42 ppm    

Loss on drying 42.0%    

Assay (of Al) 4.0–6.0%  



Specific References

Horoz BB, Kilicarslan M, Yuksel N, et al. Effect of different dispersing agents on the characteristics of Eudragit microspheres prepared by a solvent evaporation method. J Microencapsul 2004; 21: 191–202.

Wu PC, Huang YB, Chang JI, et al. Preparation and evaluation of sustained release microspheres of potassium chloride prepared with ethylcellulose. Int J Pharm 2003; 260: 115–121.

Wu PC, Huang YB, Chang JS, et al. Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit. Eur J Pharm Sci 2003; 19: 115–122.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 74–75.

General References

—

Authors

LY Galichet.

Date of Revision

17 August 2005.

Ammonia Solution

Nonproprietary Names

BP: Ammonia solution, concentrated PhEur: Ammoniae solution concentrata USPNF: Strong ammonia solution

Synonyms

Ammoniaca; ammoniacum; aqua ammonia; concentrated ammonia solution; spirit of hartshorn; stronger ammonia water.

Chemical Name and CAS Registry Number

Ammonia [7664-41-7]

Empirical Formula and Molecular Weight

NH3 17.03

Structural Formula

NH3

Functional Category

Alkalizing agent.

Applications in Pharmaceutical Formulation or Technology

Ammonia solution is typically not used undiluted in pharma- ceutical applications. Generally, it is used as a buffering agent or to adjust the pH of solutions. Most commonly, ammonia solution (the concentrated form) is used to produce more dilute ammonia solutions.

Therapeutically, dilute ammonia solution is used as a reflex stimulant in ‘smelling salts’, as a rubefacient, and as a counterirritant to neutralize insect bites or stings.(1)

Description

Strong ammonia solution occurs as a clear, colorless liquid having an exceedingly pungent, characteristic odor. The PhEur 2005 states that concentrated ammonia solution contains not less than 25.0% and not more than 30.0% w/w of ammonia (NH3). The USPNF 23 states that strong ammonia solution contains not less than 27.0% and not more than 31.0% w/w of ammonia (NH3).

See also Section 17.

Pharmacopeial Specifications

See Table I.

Table I:  Pharmacopeial specifications for ammonia solution.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Appearance of solution + —    

Oxidizable substances + +    

Pyridine and related substances 42 ppm —    

Carbonates 460 ppm —    

Chlorides 41 ppm —    

Sulfates 45 ppm —    

Iron 40.25 ppm —    

Heavy metals 41 ppm 40.0013%    

Residue on evaporation 40.02 g/L —    

Limit of nonvolatile residue — 40.05%    

Assay (of NH3) 25.0–30.0% 27.0–31.0%  

Typical Properties

Solubility: miscible with ethanol (95%) and water.

Specific gravity: 0.892–0.910

Stability and Storage Conditions

On exposure to the air, ammonia solution rapidly loses ammonia. Ammonia solution should be stored in a well-closed container, protected from the air, in a cool, dry place. The storage temperature should not exceed 208C.

Incompatibilities

Ammonia solution reacts vigorously with sulfuric acid or other strong mineral acids and the reaction generates considerable heat; the mixture boils.

Method of Manufacture

Ammonia is obtained commercially chiefly by synthesis from its constituent elements, nitrogen and hydrogen, which are combined under high pressure and temperature in the presence of a catalyst. Ammonia solution is produced by dissolving ammonia gas in water.