Incompatibilities

Generally compatible with most materials encountered in pharmaceutical formulations and food products.

Method of Manufacture

Nitrogen is obtained commercially, in large quantities, by the fractional distillation of liquefied air.

Nitrogen 489

Safety

Nitrogen is generally regarded as a nontoxic and nonirritant material. However, it is an asphyxiant and inhalation of large quantities is therefore hazardous. See also Section 18.

Handling Precautions

Handle in accordance with procedures for handling metal cylinders containing liquefied or compressed gases. Eye protection, gloves, and protective clothing are recommended. Nitrogen is an asphyxiant and should be handled in a well- ventilated environment. The oxygen content of air in the working environment should be monitored and should not be permitted to fall below 19% v/v at normal atmospheric pressure.(1)

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (injections; dental preparations; nasal sprays; oral solutions; rectal gels). Accepted for use as a food additive in Europe. Included in parenteral and nonparenteral medicines licensed in the UK and USA. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Carbon dioxide; nitrous oxide.

Comments

Different grades of nitrogen are commercially available that have, for example, especially low moisture levels.

Nitrogen is commonly used as a component of the gas mixtures breathed by divers. Under high pressure, such as when



diving at great depths, nitrogen will dissolve in blood and lipid. If decompression is too rapid, decompression sickness may occur when the nitrogen effervesces from body stores to form gas emboli.

A specification for nitrogen is contained in the Food Chemicals Codex (FCC). The EINECS number for nitrogen is 231-783-9.

Specific References

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

General References

Johnson MA. The Aerosol Handbook, 2nd edn. New Jersey: WE Dorland, 1982: 361–372.

Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: Van Nostrand Reinhold, 1979: 44–54.

Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 547–574.

Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 2000: 963–979.

Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging.

New York: Wiley, 1974: 137–145.

Authors

CJ Sciarra, JJ Sciarra.

Date of Revision

23 August 2005.

Nitrous Oxide

Nonproprietary Names

BP: Nitrous oxide JP: Nitrous oxide

PhEur: Dinitrogenii oxidum USP: Nitrous oxide

Synonyms

Dinitrogen monoxide; E942; laughing gas; nitrogen monoxide.

Chemical Name and CAS Registry Number

Dinitrogen oxide [10024-97-2]

Empirical Formula and Molecular Weight

N2O 44.01

Structural Formula

N2O

Functional Category

Aerosol propellant; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Nitrous oxide and other compressed gases such as carbon dioxide and nitrogen are used as propellants for topical pharmaceutical aerosols. They are also used in other aerosol products that work satisfactorily with the coarse aerosol spray that is produced with compressed gases, e.g. furniture polish and window cleaner.

The advantages of compressed gases as aerosol propellants are that they are inexpensive, of low toxicity, and practically odorless and tasteless. In contrast to liquefied gases, their pressures change relatively little with temperature. However, there is no reservoir of propellant in the aerosol, and as a result the pressure decreases as the product is used, changing the spray characteristics.

Misuse of a product by the consumer, such as using a product inverted, results in the discharge of the vapor phase instead of the liquid phase. Since most of the propellant is contained in the vapor phase, some of the propellant will be lost and the spray characteristics will be altered. Additionally, the sprays produced using compressed gases are very wet. However, recent developments in valve technology have reduced the risk of misuse by making available valves which will spray only the product (not propellant) regardless of the position of the container. Additionally, barrier systems will also prevent loss of propellant.

Therapeutically, nitrous oxide is best known as an anesthetic administered by inhalation. When used as an anesthetic it has strong analgesic properties but produces little muscle relaxa- tion. Nitrous oxide is always administered in conjunction with oxygen since on its own it is hypoxic.

Description

Nitrous oxide is a nonflammable, colorless and odorless, sweet- tasting gas. It is usually handled as a compressed gas, stored in metal cylinders.

Pharmacopeial Specifications

See Table I.

Table I:  Pharmacopeial specifications for nitrous oxide.

 

Test JP 2001 PhEur 2005 USP 28    

Production — + —    

Identification + + +    

Characters — + —    

Acidity or alkalinity + — —    

Carbon dioxide + 4300 ppm 40.03%    

Carbon monoxide + 45 ppm 40.001%    

Nitric oxide — — 41 ppm    

Nitrogen dioxide — — 41 ppm    

Nitric monoxide and

nitrogen dioxide — 42 ppm —    

Halogens — — 41 ppm    

Oxidizing substances + — —    

Potassium permanganate- + — —    

reducing substances    

Ammonia — — 40.0025%    

Chloride + — —    

Air — — 41.0%    

Water — 467 ppm <0.03%    

Assay 597.0% 598.0% 599.0%  

Typical Properties

Boiling point: —88.58C

Critical pressure: 7.27 mPa (71.7 atm)

Critical temperature: 36.58C

Density: 1.53 g/cm3

Flammability: nonflammable, but supports combustion.

Freezing point: —90.88C

Solubility: freely soluble in chloroform, ethanol (95%), ether, and oils; soluble 1 in 1.5 volumes of water at 208C and

101.3 kPa pressure.

Vapor density (absolute): 1.97 g/cm3 at standard temperature and pressure.

Vapor density (relative): 1.52 (air = 1)

Stability and Storage Conditions

Nitrous oxide is essentially nonreactive and stable except at high temperatures; at a temperature greater than 5008C nitrous oxide decomposes to nitrogen and oxygen. Explosive mixtures may be formed with other gases such as ammonia, hydrogen, and other fuels. Nitrous oxide should be stored in a tightly sealed metal cylinder in a cool, dry place.

Nitrous Oxide 491

Incompatibilities

Nitrous oxide is generally compatible with most materials encountered in pharmaceutical formulations, although it may react as a mild oxidizing agent.

Method of Manufacture

Nitrous oxide is prepared by heating ammonium nitrate to about 1708C. This reaction also forms water.

Safety

Nitrous oxide is most commonly used therapeutically as an anesthetic and analgesic. Reports of adverse reactions to nitrous oxide therefore generally concern its therapeutic use, where relatively large quantities of the gas may be inhaled, rather than its use as an excipient.

The main complications associated with nitrous oxide inhalation occur as a result of hypoxia. Prolonged administra- tion may also be harmful. Nitrous oxide is rapidly absorbed on inhalation.

Handling Precautions

Handle in accordance with procedures for handling metal cylinders containing liquefied or compressed gases. Eye protection, gloves, and protective clothing are recommended. Nitrous oxide is an anesthetic gas and should be handled in a well-ventilated environment. In the UK, the recommended long-term (8-hour TWA) occupational exposure limit for nitrous oxide is 183 mg/m3 (100 ppm).(1)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in nonparenteral medicines licensed in the UK and USA. Included in the Canadian List of Acceptable Non- medicinal Ingredients.



Related Substances

Carbon dioxide; nitrogen.

Comments

A mixture of 50% nitrous oxide and 50% oxygen (Entonox, BOC) is commonly used as an analgesic administered by inhalation.

A specification for nitrous oxide is contained in the Food Chemicals Codex (FCC). The EINECS number for nitrous oxide is 233-032-0.

Specific References

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

General References

Johnson MA. The Aerosol Handbook, 2nd edn. New Jersey: WE Dorland, 1982: 361–372.

Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: Van Nostrand Reinhold, 1979: 44–54.

Sciarra JJ. Aerosol suspensions and emulsions. In: Pharmaceutical Dosage Forms; Disperse Systems, 2nd edn, vol. 2. New York: Marcel Dekker, 1996: 319–356.

Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 547–574.

Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 2000: 963–979.

Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging.

New York: Wiley, 1974: 137–145.

Authors

CJ Sciarra, JJ Sciarra.

Date of Revision

23 August 2005.

Octyldodecanol

Nonproprietary Names

PhEur: Octyldodecanolum USPNF: Octyldodecanol

Synonyms

Eutanol G PH; isoarachidyl alcohol; isoeicosyl alcohol; Jarcol 1-20; Jeecol ODD; octildodecanol; 2-octyldecyl alcohol; 2- octyl-1-dodecanol.

Chemical Name and CAS Registry Number

Octyldodecanol [5333-42-6]

Empirical Formula and Molecular Weight

Table I: Pharmacopeial specifications for octyldodecanol.

C20H

42O 298.62

Structural Formula

 

Functional Category

Emollient; emulsifying agent; lubricant; solvent; thickening agent.

Applications in Pharmaceutical Formulation or Technology

Octyldodecanol is widely used in cosmetics and pharmaceutical applications as an emulsifying and opacifying agent. It is primarily used in topical applications because of its lubricating and emollient properties.

Octyldodecanol has been used in the preparation of oil/ water microemulsions investigated as the vehicle for the dermal administration of drugs having no or low skin penetration.(1) Octyldodecanol has also been evaluated as a solvent for naproxen when applied topically.(2)

Description

Octyldodecanol occurs as a clear, colorless, or yellowish, oily liquid.

Pharmacopeial Specifications

See Table I.

Typical Properties

Flash point: 1808C—2008C Melting point: < —208C Refractive index: n20 = 1.45–1.46

Solubility: miscible with ethanol (95%); practically insoluble in water.

Specific gravity: 0.83–0.85 at 208C

Viscosity (dynamic): 58–64 mPa s (58–64 cP) at 208C

Stability and Storage Conditions

The bulk material should be stored in a well-closed container in a cool, dry, place protected from light. In the original unopened container, octyldodecanol can be stored for two years protected from moisture at below 308C.

Incompatibilities

Octyldodecanol is generally compatible with most materials encountered in cosmetic and pharmaceutical formulations.

Method of Manufacture

Octyldodecanol is produced by the condensation of two molecules of decyl alcohol. It also occurs naturally in small quantities in plants.

Safety

Octyldodecanol is widely used in cosmetics and topical pharmaceutical formulations and is generally regarded as nontoxic and nonirritant at the levels employed as an excipient. In acute oral toxicity studies in rats fed 5 g/kg of undiluted octyldodecanol, no deaths were observed.(3) In an acute dermal toxicity study, intact and abraded skin sites of guinea pigs were treated with 3 g/kg of undiluted octyldodecanol under occlusive

Octyldodecanol 493

patches; no deaths occurred and no gross skin lesions were observed.(3) Octyldodecanol caused either no ocular irritation or minimal, transient irritation in the eyes of rabbits.(3) However, some sources describe undiluted octyldodecanol as an eye and severe skin irritant.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When heated to decomposi- tion, octyldodecanol emits acrid smoke and irritating fumes.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical, transdermal, and vaginal preparations). Included in nonpar- enteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

A specification for octyldodecanol is included in Japanese Pharmaceutical Excipients (JPE).(4)

The EINECS number for octyldodecanol is 226-242-9.



Specific References

Shukla A, Janich M, Jahn K, et al. Investigation of pharmaceutical oil/water microemulsions by small-angle scattering. Pharm Res 2002: 19(6): 881–886.

Contreras Claramonte MD, Parera Vialard A, Girela Vilchez F. An application of regular solution theory in the study of the solubility of naproxen in some solvents used in topical preparations. Int J Pharm 1993: 94: 23–30.

Elder RL. Final report on the safety assessment of stearyl alcohol, oleyl alcohol and octyl dodecanol. J Am Coll Toxicol 1985: 4: 1– 29.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 583–585.

General References

Allen LV. Featured excipient: oligeanous vehicles. Int J Pharm Compound 2000; 4(6): 470–473, 484–485.

Filippi U, Gibellini M, Guasani G, et al. Proposal for the pharmacopeia; octyl dodecanol. Bell Clin Form 1982; 121: 425–427.

Authors

RT Guest.

Date of Revision

22 August 2005.

Oleic Acid

Nonproprietary Names

BP: Oleic acid

PhEur: Acidum oleicum USPNF: Oleic acid

Synonyms

Crodolene; Crossential 094; elaic acid; Emersol; Glycon; Groco; Hy-Phi; Industrene; Metaupon; Neo-Fat; cis-9-octa- decenoic acid; 9,10-octadecenoic acid; oleinic acid; Priolene.

Chemical Name and CAS Registry Number

(Z)-9-Octadecenoic acid [112-80-1]

Empirical Formula and Molecular Weight

C18H34O2 282.47

Structural Formula

 

Functional Category

Emulsifying agent; skin penetrant.