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Peanut oil is used as an excipient in pharmaceutical formula- tions primarily as a solvent for sustained-release intramuscular injections. It is also used as a vehicle for topical preparations and as a solvent for vitamins and hormones. In addition, it has been part of sustained-release bead formulations,(2) nasal drug delivery systems,(3) and controlled-release injectables.(4)

Therapeutically, emulsions containing peanut oil have been used in nutrition regimens, in enemas as a fecal softener, and in otic drops to soften ear wax. It is also administered orally, usually with sorbitol, as a gall bladder evacuant prior to cholecystography.

Peanut oil is also widely used as an edible oil.

Description

Peanut oil is a colorless or pale yellow-colored liquid that has a faint nutty odor and a bland, nutty taste. At about 38C it becomes cloudy, and at lower temperatures it partially solidifies.

Pharmacopeial Specifications

See Table I.

Typical Properties

Autoignition temperature: 4438C Density: 0.915 g/cm3 at 258C Flash point: 2838C

Freezing point: —58C

Hydroxyl value: 2.5–9.5

Interfacial tension: 19.9 mN/m at 258C(5)

Refractive index: n25 = 1.466–1.470

Solubility: very slightly soluble in ethanol (95%); soluble in benzene, carbon tetrachloride, and oils; miscible with carbon disulfide, chloroform, ether, and hexane.

Surface tension: 37.5 mN/m at 258C(5)

Viscosity (dynamic): 35.2 mPa s (35.2 cP) at 378C(5)

Viscosity (kinematic): 39.0 mm2/s (39.0 cSt) at 378C(5)

Stability and Storage Conditions

Peanut oil is an essentially stable material.(6) However on exposure to air it can slowly thicken and may become rancid. Solidified peanut oil should be completely melted and mixed before use. Peanut oil may be sterilized by aseptic filtration or

506 Peanut Oil

by dry heat, for example, by maintaining it at 1508C for 1 hour.(7)

Peanut oil should be stored in a well-filled, airtight, light- resistant container, at a temperature not exceeding 408C. Material intended for use in parenteral dosage forms should be stored in a glass container.

Incompatibilities

Peanut oil may be saponified by alkali hydroxides.

Method of Manufacture

Refined peanut oil is obtained from the seeds of Arachis hypogaea Linne´ (Fam. Leguminosae). The seeds are separated from the peanut shells and are expressed in a powerful hydraulic press. The crude oil has a light yellow to light brown color, and is then purified to make it suitable for food or pharmaceutical purposes. A suitable antioxidant may be added.

Safety

Peanut oil is mildly laxative at a dosage of 15–60 mL orally or of 100–500 mL rectally as an enema.

Adverse reactions to peanut oil in foods and pharmaceutical formulations have been reported extensively.(8–18) These include severe allergic skin rashes(8,9) and anaphylactic shock following consumption of peanut butter.(10) Some workers have suggested that the use in infancy of preparations containing peanut oil, including infant formula and topical preparations, is associated with sensitization to peanut, with a subsequent risk of hypersensitivity reactions, and that such products should therefore be avoided or banned.(8–12) However, the role of pharmaceutical preparations in later development of hypersen- sitivity is disputed since such preparations contain highly refined peanut oil that should not contain the proteins

associated with allergic reactions in susceptible indivi- duals.(13–15)

Peanut oil is harmful if administered intravenously and it should not be used in such formulations.(16)

See also Section 18.

Handling Precautions

Observe normal handling precautions appropriate to the circumstances and quantity of material handled. Spillages of peanut oil are slippery and should be covered with an inert absorbent material prior to disposal.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM injections, topical preparations, oral capsules, and vaginal emulsions). Included in parenteral and nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Almond oil; canola oil; corn oil; cottonseed oil; sesame oil; soybean oil; sunflower oil.

Comments

As a result of the potentially fatal reactions noted in Section 14, certain food products are now commonly labeled with a

statement that they contain peanut oil. A specification for unhydrogenated peanut oil is contained in the Food Chemicals Codex (FCC).

Specific References

Allen A, Padley GH, Whalley GR. Fatty acid composition of some soapmaking fats and oils. Part 4: groundnut (peanut oil). Soap Perfum Cosmet 1969; 42: 725–726.

Santucci E, Alhaique F, Carafa M, et al. Gellan for the formulation of sustained delivery beads. J Control Release 1996; 42: 157–164.

Maitani Y, Yamamoto T, Takayama K, et al. Modelling analysis of drug absorption and administration from ocular, naso-lacrimal duct, and nasal routes in rabbits. Int J Pharm 1995; 126: 89–94.

Matsubara K, Irie T, Uekama K. Controlled release of the LHRH agonist buserelin acetate from injectable suspensions containing triacetylated cyclodextrins in an oil vehicle. J Control Release 1994; 31: 173–180.

Howard JR, Hadgraft J. The clearance of oily vehicles following intramuscular and subcutaneous injections in rabbits. Int J Pharm 1983; 16: 31–39.

Selles E, Ruiz A. Study of the stability of peanut oil [in Spanish].

Ars Pharm 1981; 22: 421–427.

Pasquale D, Jaconia D, Eisman P, Lachman L. A study of sterilizing conditions for injectable oils. Bull Parenter Drug Assoc 1964; 18(3): 1–11.

Moneret-Vautrin DA, Hatahet R, Kanny G, Ait-Djafer Z. Allergenic peanut oil in milk formulas [letter]. Lancet 1991; 338: 1149.

Brown HM. Allergenic peanut oil in milk formulas [letter]. Lancet 1991; 338: 1523.

De Montis G, Gendrel D, Chemillier-Truong M, Dupont C. Sensitization to peanut and vitamin D oily preparations [letter]. Lancet 1993; 341: 1411.

Lever LR. Peanut and nut allergy: creams and ointments contain- ing peanut oil may lead to sensitisation. Br Med J 1996; 313: 299.

Wistow S, Bassan S. Peanut allergy. Pharm J 1999; 262: 709–710.

Hourihane JO, Bedwani SJ, Dean TP, Warner JO. Randomized, double blind, crossover challenge study of allergenicity of peanut oils in subjects allergic to peanuts. Br Med J 1997; 314: 1084– 1088.

Committee on Toxicity of Chemicals in Food. Consumer Products and the Environment: Peanut Allergy. London: Department of Health, 1998.

Anonymous. Questions raised over new advice following research into peanut oil. Pharm J 2001; 266: 773.

Lynn KL. Acute rhabdomyolysis and acute renal failure after intravenous self-administration of peanut oil. Br Med J 1975; 4: 385–386.

Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. Br Med J 1996; 312: 1074–1078.

Tariq SM, Stevens M, Matthews S, et al. Cohort study of peanut and tree nut sensitisation by age of 4 years. Br Med J 1996; 313: 514–517.

General References

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

Citrus pectin; E440; methopectin; methyl pectin; methyl pectinate; mexpectin; pectina; pectinic acid.

Chemical Name and CAS Registry Number

Pectin [9000-65-5]

Empirical Formula and Molecular Weight

Pectin is a high-molecular-weight, carbohydrate-like plant constituent consisting primarily of chains of galacturonic acid units linked as 1,4-a-glucosides, with a molecular weight of 30 000–100 000.

Structural Formula

Pectin is a complex polysaccharide comprising mainly esterified D-galacturonic acid residues in an a-(1–4) chain. The acid groups along the chain are largely esterified with methoxy groups in the natural product. The hydroxyl groups may also be acetylated.

Pectin gelation characteristics can be divided into two types: high-methoxy and low-methoxy gelation, and sometimes the low-methoxy pectins may contain amine groups. Gelation of high-methoxy pectin usually occurs at pH <3.5. Low-methoxy pectin is gelled with calcium ions and is not dependent on the

presence of acid or high solids content. Amidation may interfere with gelation, causing the process to be delayed. However, gels from amidated pectins have the ability to re-heal after shearing.(1)

The USP 28 describes pectin as a purified carbohydrate product obtained from the dilute acid extract of the inner portion of the rind of citrus fruits or from apple pomace. It consists chiefly of partially methoxylated polygalacturonic acids.

Functional Category

Adsorbent; emulsifying agent; gelling agent; thickening agent; stabilizing agent.

Applications in Pharmaceutical Formulation or Technology

Pectin has been used as an adsorbent and bulk-forming agent, and is present in multi-ingredient preparations for the manage- ment of diarrhea, constipation, and obesity;(2) it has also been used as an emulsion stabilizer.(3)

Experimentally, pectin has been used in gel formulations for the oral sustained delivery of ambroxol.(4) Pectin gel beads have been shown to be an effective medium for controlling the release of a drug within the gastrointestinal (GI) tract.(5) It has also been used in a colon-biodegradable pectin matrix with a pH-sensitive polymeric coating, which retards the onset of drug release, overcoming the problems of pectin solubility in the upper GI tract.(6–9) Amidated pectin matrix patches have been investigated for the transdermal delivery of chloroquine,(10) and gelling pectin formulations for the oral sustained delivery of paracetamol have been investigated in situ.(11) Pectin-based matrices with varying degrees of esterification have been evaluated as oral controlled-release tablets. Low-methoxy pectins were shown to have a release rate more sensitive to the calcium content of the formulation.(12) Pectins have been used as a component in the preparation of mixed polymer microsphere systems with the intention of producing con- trolled drug release.(13)

Description

Pectin occurs as a coarse or fine, yellowish-white, odorless powder that has a mucilaginous taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for pectin.

Test USP 28

Identification +

Loss on drying 410.0%

Arsenic 43 ppm

Lead 45 mg/g

Sugars and organic acids +

Microbial limits +

Assay

Methoxy groups 46.7%

Galacturonic acid 474.0%

Typical Properties

Acidity/alkalinity: pH = 6.0–7.2

Solubility: soluble in water; insoluble in ethanol (95%) and other organic solvents.

Stability and Storage Conditions

Pectin is a nonreactive and stable material; it should be stored in a cool, dry place.

508 Pectin

Incompatibilities

—

Method of Manufacture

Pectin is obtained from the diluted acid extract from the inner portion of the rind of citrus fruits or from apple pomace.

Safety

Pectin is used in oral pharmaceutical formulations and food products and is generally regarded as an essentially nontoxic and nonirritant material.

Low toxicity by the subcutaneous route has been reported.(14)

LD50 (mouse, SC): 6.4 g/kg(14)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When pectin is heated to decomposition, acrid smoke and irritating fumes are emitted.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (dental paste; oral powders; topical pastes). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in nonparent- eral medicines licensed in the UK.

Related Substances

—

Comments

Pectin has been used in film-coating formulations containing chitosan and hydroxypropylmethyl cellulose in the investiga- tion of the biphasic drug-release properties of film-coated paracetamol tablets, both in vitro,(15,16) and in vivo.(17) It has been shown that chitosan acts as a crosslinking agent for concentrated pectin solutions.(18)

Pectin gel systems have been used to show the partition and release of aroma compounds in foods during storage.(19)

A specification for pectin is included in the Food Chemical Codex (FCC). In the food industry it is used as an emulsifying agent, gelling agent, thickener, and stabilizer. Cosmetically, it is used as a binder, emulsifying agent and viscosity-controlling agent.

The EINECS number for pectin is 232-553-0.

Specific References

Cybercolloids Ltd. Introduction to pectins: properties. http://www.cybercolloids.net/library/pectin/properties.php (accessed 26 May 2005).

Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1580.

Lund W, ed. The Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 88.

Kubo W, Miyazaki S, Dairaku M, et al. Oral sustained delivery of ambroxol from in-situ gelling pectin formulations. Int J Pharm 2004; 271(1–2): 233–240.

Murata Y, Miyashita M, Kofuji K, et al. Drug release properties of a gel bead prepared with pectin and hydrolysate. J Control Release 2004; 95(1): 61–66.

Sriamornsak P, Nunthanid J, Wanchana S, Luangtana-Anan M. Composite film-coated tablets intended for colon-specific delivery of 5-aminosalicylic acid: using deesterified pectin. Pharm Dev Technol 2003; 8(3): 311–318.

Liu L, Fishman ML, Kost J, Hicks KB. Pectin-based systems for colon-specific drug delivery via oral route. Biomaterials 2003; 24(19): 3333–3343.

Tho I, Sande SA, Kleinebudde P. Disintegrating pellets from a water-insoluble pectin derivative produced by extrusion/spheroni- sation. Eur J Pharm Biopharm 2003; 56(3): 371–380.

Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci 2003; 6(1): 33–

66.

Musabayane CT, Munjeri O, Matavire TP. Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat. Ren Fail 2003; 25(4); 525–534.

Kubo W, Konno Y, Miyazaki S, Attwood D. In situ gelling pectin formulations for oral sustained delivery of paracetamol. Drug Dev Ind Pharm 2004; 30(6): 593–599.

Sungthongjeen S, Sriamornsak P, Pitaksuteepong T, et al. Effect of degree of esterification of pectin and calcium amount on drug release from pectin-based matrix tablets. AAPS Pharm Sci Tech 2004; 5(1): E9.

Pillay V, Danckwerts MP, Fassihi R. A crosslinked calcium- alginate–pectinate–cellulose acetophthalate gelisphere system for linear drug release. Drug Delivery 2002; 9(2): 77–86.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2825–2826.

Ofori-Kwakye K, Fell JT. Biphasic drug release from film-coated tablets. Int J Pharm 2003; 250(2): 431–440.

Ofori-Kwakye K, Fell JT. Leaching of pectin from mixed films containing pectin, chitosan and HPMC intended for biphasic drug delivery. Int J Pharm 2003; 250(1): 251–257.

Ofori-Kwake K, Fell JT, Sharma HL, Smith AM. Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release. Int J Pharm 2004; 270(1–2): 307–313.

Marudova M, MacDougall AJ, Ring SG. Pectin–chitosan inter- actions and gel formation. Carbohydr Res 2004; 339(11): 1933–

1939.

Hansson A, Leufven A, van Ruth S. Partition and release of 21 aroma compounds during storage of a pectin gel system. J Agric Food Chem 2003; 51(7): 2000–2005.

General References

Lofgren C, Walkenstrom P, Hermansson AM. Microstructure and rheological behavior of pure and mixed pectin gels. Biomacro- molecules 2002; 3(6): 1144–1153.

BP: Yellow soft paraffin JP: Yellow petrolatum PhEur: Vaselinum flavum USP: Petrolatum

Synonyms

Merkur; mineral jelly; petroleum jelly; Silkolene; Snow white; Soft white; yellow petrolatum; yellow petroleum jelly.

Chemical Name and CAS Registry Number

Petrolatum [8009-03-8]

Empirical Formula and Molecular Weight

Petrolatum is a purified mixture of semisolid saturated

Description

Petrolatum is a pale yellow to yellow-colored, translucent, soft unctuous mass. It is odorless, tasteless, and not more than slightly fluorescent by daylight, even when melted.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for petrolatum.

hydrocarbons having the general formula C H , and is

n 2n+2

obtained from petroleum. The hydrocarbons consist mainly of branched and unbranched chains although some cyclic alkanes and aromatic molecules with paraffin side chains may also be present. The USP 28 and PhEur 2005 material may contain a suitable stabilizer (antioxidant) that must be stated on the label. The inclusion of a stabilizer is not discussed in the JP 2001 monograph.

Refractive index: n60 = 1.460–1.474

Emollient; ointment base.

Solubility:

practically insoluble in acetone, ethanol, hot or cold

Applications in Pharmaceutical Formulation or Technology

Petrolatum is mainly used in topical pharmaceutical formula- tions as an emollient-ointment base; it is poorly absorbed by the skin. Petrolatum is also used in creams and transdermal formulations and as an ingredient in lubricant formulations for medicated confectionery together with mineral oil.

Therapeutically, sterile gauze dressings containing petrola- tum may be used for nonadherent wound dressings or as a packing material.(1) Petrolatum is additionally widely used in cosmetics and in some food applications. See Table I.

Table I: Uses of petrolatum.

Use Concentration (%)

Emollient topical creams 10–30

Topical emulsions 4–25

Topical ointments Up to 100

ethanol (95%), glycerin, and water; soluble in benzene, carbon disulfide, chloroform, ether, hexane, and most fixed and volatile oils.

Viscosity (dynamic): the rheological properties of petrolatum are determined by the ratio of the unbranched chains to the branched chains and cyclic components of the mixture. Petrolatum contains relatively high amounts of branched and cyclic hydrocarbons, in contrast to paraffin, which accounts for its softer character and makes it an ideal ointment base.(2–5)

Stability and Storage Conditions

Petrolatum is an inherently stable material owing to the unreactive nature of its hydrocarbon components; most stability problems occur because of the presence of small quantities of impurities. On exposure to light, these impurities may be oxidized to discolor the petrolatum and produce an undesirable odor. The extent of the oxidation varies depending upon the source of the petrolatum and the degree of refinement. Oxidation may be inhibited by the inclusion of a suitable

510 Petrolatum

antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, or alpha tocopherol.

Petrolatum should not be heated for extended periods above the temperature necessary to achieve complete fluidity (approximately 708C). See also Section 18.

Petrolatum may be sterilized by dry heat. Although petrolatum may also be sterilized by gamma irradiation, this process affects the physical properties of the petrolatum such as swelling, discoloration, odor, and rheological behavior.(6,7)

Petrolatum should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Petrolatum is an inert material with few incompatibilities.

Method of Manufacture

Petrolatum is manufactured from the semisolid residue that remains after the steam or vacuum distillation of petroleum.(8) This residue is dewaxed and/or blended with stock from other sources, along with lighter fractions, to give a product with the desired consistency. Final purification is performed by a combination of high-pressure hydrogenation or sulfuric acid treatment followed by filtration through adsorbents. A suitable antioxidant may be added.

Safety

Petrolatum is mainly used in topical pharmaceutical formula- tions and is generally considered to be a nonirritant and nontoxic material.

Animal studies, in mice, have shown petrolatum to be nontoxic and noncarcinogenic following administration of a single subcutaneous 100 mg dose. Similarly, no adverse effects were observed in a 2-year feeding study with rats fed a diet containing 5% of petrolatum blends.(9)

Although petrolatum is generally nonirritant in humans following topical application, rare instances of allergic hyper- sensitivity reactions have been reported,(10–12) as have cases of acne, in susceptible individuals following repeated use on facial skin.(13) However, given the widespread use of petrolatum in topical products, there are few reports of irritant reactions. The allergic components of petrolatum appear to be polycyclic aromatic hydrocarbons present as impurities. The quantities of these materials found in petrolatum vary depending upon the source and degree of refining. Hypersensitivity appears to occur less with white petrolatum and it is therefore the preferred material for use in cosmetics and pharmaceuticals.

Petrolatum has also been tentatively implicated in the formation of spherulosis of the upper respiratory tract following use of a petrolatum-based ointment packing after surgery,(14) and lipoid pneumonia following excessive use in the perinasal area.(15) Other adverse reactions to petrolatum include granulomas (paraffinomas) following injection into soft tissue.(16) Also, when taken orally, petrolatum acts as a mild laxative and may inhibit the absorption of lipids and lipid- soluble nutrients.

Petrolatum is widely used in direct and indirect food applications. In the USA, the daily dietary exposure to petrolatum is estimated to be 0.404 mg/kg body-weight.(17)

For further information see Mineral Oil and Paraffin.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. For recommended occupa- tional exposure limits see Mineral Oil and Paraffin.

Regulatory Status

GRAS listed. Accepted for use in certain food applications in many countries worldwide. Included in the FDA Inactive Ingredients Guide (ophthalmic preparations, oral capsules and tablets, otic, topical, and transdermal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Mineral oil; mineral oil light; paraffin; petrolatum and lanolin alcohols; white petrolatum.

White petrolatum

Synonyms: vaselinum album; white petroleum jelly; white soft paraffin.

Appearance: white petrolatum is a white to pale yellow- colored, translucent, soft unctuous mass. It is odorless and tasteless and not more than slightly fluorescent by daylight, even when melted.

Method of manufacture: white petrolatum is petrolatum that has been highly refined so that it is wholly or nearly decolorized.

Comments: white petrolatum is associated with fewer instances of hypersensitivity reactions and is the preferred petrolatum for use in cosmetics and pharmaceuticals, see Section 14.

Comments

Various grades of petrolatum are commercially available, which vary in their physical properties depending upon their source and refining process. Petrolatum obtained from different sources may therefore behave differently in a formulation.(18)

Care is required in heating petrolatum because of its large coefficient of thermal expansion. It has been shown by both rheological and spectrophotometric methods that petrolatum undergoes phase transition at temperatures between 30–408C. Additives, such as microcrystalline wax, may be used to add body to petrolatum. A specification for petrolatum is contained

in the Food Chemicals Codex (FCC).

The EINECS number for petrolatum is 232-373-2.

Specific References

Smack DP, Harrington AC, Dunn C, et al. Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs bacitracin ointment: randomized controlled trial. JAMA 1996; 276: 972–977.

Boylan JC. Rheological estimation of the spreading characteristics of pharmaceutical semisolids. J Pharm Sci 1967; 56: 1164–1169.

Longworth AR, French JD. Quality control of white soft paraffin. J Pharm Pharmacol 1969; 21 (Suppl.): 1S–5S.

Barry BW, Grace AJ. Grade variation in the rheology of white soft paraffin BP. J Pharm Pharmacol 1970; 22 (Suppl.): 147S–156S.

Barry BW, Grace AJ. Structural, rheological and textural proper- ties of soft paraffins. J Texture Studies 1971; 2: 259–279.

Jacob BP, Leupin K. Sterilization of eye–nose ointments by gamma radiation [in German]. Pharm Acta Helv 1974; 49: 12–20.

Davis SS, Khanderia MS, Adams I, et al. Effect of gamma radiation on rheological properties of pharmaceutical semisolids. J Texture Studies 1977; 8: 61–80.

Petrolatum 511

Schindler H. Petrolatum for drugs and cosmetics. Drug Cosmet Ind 1961; 89(1): 36, 37, 76, 78–80, 82.

Oser BL, Oser M, Carson S, Sternberg SS. Toxicologic studies of petrolatum in mice and rats. Toxicol Appl Pharmacol 1965; 7: 382–401.

Dooms-Goossens A, Degreef H. Contact allergy to petrolatums I: sensitivity capacity of different brands of yellow and white petrolatums. Contact Dermatitis 1983; 9: 175–185.

Dooms-Goossens A, Degreef H. Contact allergy to petrolatums II: attempts to identify the nature of the allergens. Contact Dermatitis 1983; 9: 247–256.

Dooms-Goossens A, Dooms M. Contact allergy to petrolatums III: allergenicity prediction and pharmacopeial requirements. Contact Dermatitis 1983; 9: 352–359.

Verhagen AR. Pomade acne in black skin [letter]. Arch Dermatol

1974; 110: 465.

Rosai J. The nature of myospherulosis of the upper respiratory tract. Am J Clin Pathol 1978; 69: 475–481.

Cohen MA, Galbut B, Kerdel FA. Exogenous lipoid pneumonia caused by facial application of petrolatum. JAMA 2003; 49: 1128–

1130.

Crosbie RB, Kaufman HD. Self-inflicted oleogranuloma of breast.

Br Med J 1967; 3: 840–841.

Heimbach JT, Bodor AR, Douglass JS, et al. Dietary exposure to mineral hydrocarbons from food-use applications in the United States. Food Chem Toxicol 2002; 40: 555–571.

Kneczke M, Landersjo¨ L, Lundgren P, Fu¨ hrer C. In vitro release of salicylic acid from two different qualities of white petrolatum. Acta Pharm Suec 1986; 23: 193–204.

General References

Bandelin FJ, Sheth BB. Semisolid preparations. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 14. New York: Marcel Dekker, 1996: 31–61.

Barker G. New trends in formulating with mineral oil and petrolatum.

Cosmet Toilet 1977; 92(1): 43–46.

Davis SS. Viscoelastic properties of pharmaceutical semisolids I: ointment bases. J Pharm Sci 1969; 58: 412–418.

De Muynck C, Lalljie SPD, Sandra P, et al. Chemical and physico- chemical characterization of petrolatums used in eye ointment formulations. J Pharm Pharmacol 1993; 45: 500–503.

De Rudder D, Remon JP, Van Aerde P. Structural stability of ophthalmic ointments containing soft paraffin. Drug Dev Ind Pharm 1987; 13: 1799–1806.

Morrison DS. Petrolatum: a useful classic. Cosmet Toilet 1996; 111(1): 59–66, 69.

Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients.

Boca Raton, FL: CRC Press, 1992: 265–269.

Sucker H. Petrolatums: technological properties and quality assess- ment. Cosmet Perfum 1974; 89(2): 37–43.

Applications in Pharmaceutical Formulation or Technology

Oleic acid is used as an emulsifying agent in foods and topical pharmaceutical formulations. It has also been used as a penetration enhancer in transdermal formulations,(1–14) to improve the bioavailability of poorly water-soluble drugs in tablet formulations,(15) and as part of a vehicle in soft gelatin capsules.

Oleic acid has been reported to act as an ileal ’break’ that

slows down the transit of luminal contents through the distal portion of the small bowel.(16)

Table I: Pharmacopeial specifications for oleic acid.

Test PhEur 2005 USPNF 23

Identification + —

Characters + —

Specific gravity ≈ 0.892 0.889–0.895

Residue on ignition — 41 mg

Total ash 40.1% —

Mineral acids — +

Neutral fat or mineral oil — +

Fatty acid composition + —

Myristic acid 45.0% —

Palmitic acid 416.0% —

Palmitoleic acid 48.0% —

Stearic acid 46.0% —

Oleic acid 65.0–88.0% —

Linoleic acid 418.0% —

Linolenic acid 44.0% —

Fatty acids of chain length 44.0% —

greater than C18

Acid value 195–204 196–204

Iodine value 89–105 85–95

Peroxide value 410.0 —

Congealing temperature — +

From animal sources — 3–108C

From vegetable sources — 10–168C

Margaric acid — —

From animal sources From vegetable sources

Color of solution 44.0%

40.2%

+ —

—

Organic volatile impurities — +

Assay 65–88% —

10 Typical Properties

Acidity/alkalinity: pH = 4.4 (saturated aqueous solution)

Autoignition temperature: 3638C

Boiling point: 2868C at 13.3 kPa (100 mmHg) (decomposition at 80–1008C)

Density: 0.895 g/cm3 Flash point: 1898C Melting point: 48C

Oleic acid labeled with imaging.

Description

131

I and

3H is used in medical

Refractive index: n26 = 1.4585

Solubility: miscible with benzene, chloroform, ethanol (95%), ether, hexane, and fixed and volatile oils; practically insoluble in water.

Vapor pressure: 133 Pa (1 mmHg) at 176.58C

Viscosity (dynamic): 26 mPa s (26 cP) at 258C

A yellowish to pale brown, oily liquid with a characteristic lard- like odor and taste.

Oleic acid consists chiefly of (Z)-9-octadecenoic acid together with varying amounts of saturated and other unsaturated acids. It may contain a suitable antioxidant.

Pharmacopeial Specifications

See Table I.

Stability and Storage Conditions

On exposure to air, oleic acid gradually absorbs oxygen, darkens in color, and develops a more pronounced odor. At atmospheric pressure, it decomposes when heated at 80–1008C.

Oleic acid should be stored in a well-filled, well-closed container, protected from light, in a cool, dry place.

Oleic Acid 495

Incompatibilities

Incompatible with aluminum, calcium, heavy metals, iodine solutions, perchloric acid, and oxidizing agents. Oleic acid reacts with alkalis to form soaps.

Method of Manufacture

Oleic acid is obtained by the hydrolysis of various animal and vegetable fats or oils, such as olive oil, followed by separation of the liquid acids. It consists chiefly of (Z)-9-octadecenoic acid. Oleic acid that is to be used systemically should be prepared from edible sources.

Safety

Oleic acid is used in oral and topical pharmaceutical formula- tions.

In vitro tests have shown that oleic acid causes rupture of red blood cells (hemolysis), and intravenous injection or ingestion of a large quantity of oleic acid can therefore be harmful. The effects of oleic acid on alveolar(17) and buccal(18) epithelial cells in vitro have also been studied; the in vitro and in vivo effects of oleic acid on rat skin have been reported.(19) Oleic acid is a moderate skin irritant; it should not be used in eye preparations.

An acceptable daily intake for the calcium, sodium, and potassium salts of oleic acid was not specified by the WHO since the total daily intake of these materials in foods was such that they did not pose a hazard to health.(20)

LD50 (mouse, IV): 0.23 g/kg(21) LD50 (rat, IV): 2.4 mg/kg

LD50 (rat, oral): 74 g/kg

Handling Precautions

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

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (inhalation and nasal aerosols, tablets, topical and transdermal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Ethyl oleate.

Comments

Several grades of oleic acid are commercially available ranging in color from pale yellow to reddish brown. Different grades become turbid at varying temperatures depending upon the amount of saturated acid present. Usually, oleic acid contains 7–12% saturated acids, such as stearic and palmitic acid, together with other unsaturated acids, such as linoleic acid. A specification for oleic acid is contained in the Food Chemicals Codex (FCC). The EINECS number for oleic acid is 204-007-1.

Specific References

Cooper ER, Merritt EW, Smith RL. Effect of fatty acids and alcohols on the penetration of acyclovir across human skin in vitro. J Pharm Sci 1985; 74: 688–689.

Francoeur ML, Golden GM, Potts RO. Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery. Pharm Res 1990; 7: 621–627.

Lewis D, Hadgraft J. Mixed monolayers of dipalmitoylphos- phatidylcholine with azone or oleic acid at the air–water interface. Int J Pharm 1990; 65: 211–218.

Niazy EM. Influence of oleic acid and other permeation promoters on transdermal delivery of dihydroergotamine through rabbit skin. Int J Pharm 1991; 67: 97–100.

Ongpipattanakul B, Burnette RR, Potts RO, Francoeur ML. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm Res 1991; 8: 350–354.

Walker M, Hadgraft J. Oleic acid: membrane fluidiser or fluid within the membrane? Int J Pharm 1991; 71: R1–R4.

Gao S, Singh J. Effect of oleic acid/ethanol and oleic acid/propylene glycol on the in vitro percutaneous absorption of 5-fluorouracil and tamoxifen and the macroscopic barrier property of porcine epidermis. Int J Pharm 1998; 165: 45–55.

Murakami T, Yoshioka M, Yumoto R. Topical delivery of keloid therapeutic drug, tranilast, by combined use of oleic acid and propylene glycol as a penetration enhancer: evaluation by skin microdialysis in rats. J Pharm Pharmacol 1998; 50: 49–54.

Santoyo S, Arellano A, Ygartua P, Mart´ın C. Penetration enhancer effects on the in vitro percutaneous absorption of piroxicam through rat skin. Int J Pharm 1995; 117: 219–224.

Kim D-D, Chien YW. Transdermal delivery of dideoxynucleoside- type anti-HIV drugs: 2. The effect of vehicle and enhancer on skin permeation. J Pharm Sci 1996; 85: 214–219.

Singh SK, Roane DS, Reddy IK, et al. Effect of additives on the diffusion of ketoprofen through human skin. Drug Dev Ind Pharm 1996; 22: 471–474.

Bhatia KS, Gao S, Singh J. Effect of penetration enhancers and iontophoresis on the FT-IR spectroscopy and LHRH permeability through porcine skin. J Control Release 1997; 47: 81–89.

Wang Y, Fan Q, Sang Y. Effects of fatty acids and iontophoresis on the delivery of midodrine hydrochloride and the structure of human skin. Pharm Res 2003; 20(10): 1612–1618.

Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers. Drug Dev Ind Pharm 2004; 30(2): 187–194.

Tokumura T, Tsushima Y, Tatsuishi K, et al. Enhancement of the oral bioavailability of cinnarizine in oleic acid in beagle dogs. J Pharm Sci 1987; 76: 286–288.

Dobson CL, Davis SS, Chauhan S, et al. The effects of ileal brake activators on the oral bioavailability of atenolol in man. Int J Pharm 2002; 248(1–2): 61–70.

Wang LY, Ma JKH, Pan WF, et al. Alveolar permeability enhancement by oleic acid and related fatty acids: evidence for a calcium-dependent mechanism. Pharm Res 1994; 11: 513–517.

Turunen TM, Urtti A, Paronen P, et al. Effect of some penetration enhancers on epithelial membrane lipid domains: evidence from fluorescence spectroscopy studies. Pharm Res 1994; 11: 288–294.

Fang JY, Hwang TL, Fang CL. In vitro and in vivo evaluations of the efficay and safety of skin permeation enhancers using flurbiprofen as a model. Int J Pharm 2003; 255(1–2): 153–166.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirty-third report of the joint FAO/WHO expert commit- tee on food additives. World Health Organ Tech Rep Ser 1989: No. 776.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2778.

PhEur: Alcohol oleicus USP: Oleyl alcohol

Synonyms

HD-Eutanol V PH; Ocenol; cis-9-octadecen-1-ol; oleic alcohol; oleo alcohol; oleol.

Chemical Name and CAS Registry Number

(Z)-9-Octadecen-1-ol [143-28-2]

Empirical Formula and Molecular Weight

Table I: Pharmacopeial specifications for oleyl alcohol.

Test PhEur 2005 USPNF 23

Appearance + —

Cloud point <108C <108C

Refractive index 1.458–1.460 1.458–1.460

Acid value 41 41

Hydroxyl value 205–215 205–215

Iodine value — 85–95

Saponification value 42 —

Composition of fatty + —

alcohols

Typical Properties

Boiling point: 182–1848C at 1.5 atm

Density: 0.850 g/cm3 at 208C

Flash point: 1708C

C18H

36O 268.48

Melting point: 13–198C

Partition coefficient: log P (octanol/water) = 7.50.

Refractive index: n25 = 1.4582

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

Structural Formula

Functional Category

Antifoaming agent; dissolution enhancer; emollient; emulsify- ing agent; skin penetrant; sustained-release agent.

Applications in Pharmaceutical Formulation or Technology

Oleyl alcohol is mainly used in topical pharmaceutical formulations and has been used in transdermal delivery formulations.(1–6) It has been utilized in the development of biodegradable injectable thermoplastic oligomers,(7) and in aerosol formulations of insulin(8) and albuterol.(9)

Therapeutically, it has been suggested that oleyl alcohol may exhibit antitumor properties via transmembrane permea- tion.(10)

Description

Oleyl alcohol occurs as a pale yellow oily liquid that gives off acrid fumes when heated.

Pharmacopeial Specifications

See Table I.

Stability and Storage Conditions

The bulk material should be stored in a well-closed container in a cool, dry, place.

Incompatibilities

—

Method of Manufacture

Oleyl alcohol occurs naturally in fish oils. Synthetically, it can be prepared from butyl oleate by a Bouveault–Blanc reduction with sodium and butyl alcohol. An alternative method of manufacture is by the hydrogenation of triolein in the presence of zinc chromite.

Safety

Oleyl alcohol is mainly used in topical pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material at the levels employed as an excipient. However, contact dermatitis due to oleyl alcohol has been reported.(11)

The results of acute oral toxicity and percutaneous studies in animals with products containing 8% oleyl alcohol indicate a very low toxicity.(12) Formulations containing 8% or 20% oleyl alcohol administered by gastric intubation, at doses up to 10 g/kg body weight, caused no deaths and no toxic effects in rats.(12)

Oleyl Alcohol 497

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical emulsions and ointments). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Oleic acid; oleyl oleate.

Oleyl oleate

Empirical formula: C36H68O2

Molecular weight: 532.9

CAS number: [3687-45-4]

Refractive index: n25 = 1.464–1.468

Specific gravity: 0.860–0.884

Solubility: miscible with chloroform and with diethyl ether; slightly soluble in ethanol.

Comments

A specification for oleyl alcohol is included in the Japanese Pharmaceutical Excipients (JPE) 2004.(13) The EINECS number for oleyl alcohol is 205-597-3.

Specific References

Sudimack JJ, Guo W, Tjarks W, Lee RJ. A novel pH-sensitive liposome formulation containing oleyl alcohol. Biochim Biophys Acta 2002; 1564: 31–37.

Agyralides GG, Dallas PP, Rekkas DM. Development and in vitro evaluation of furosemide transdermal formulations using experi- mental design techniques. Int J Pharm 2004; 281: 35–43.

Cooper ER, Merritt EW, Smith RL. Effect of fatty acids and alcohols on the penetration of acyclovir across human skin in vitro. J Pharm Sci 1985; 74: 688–689.

Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers. Drug Dev Ind Pharm 2004; 30: 187–194.

Andega S, Kanikkannan N, Singh M. Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. J Control Release 2001; 77: 17–25.

Monti D, Giannelli R, Chetoni P, Burgalassi S. Comparison of the effect of ultrasound and of chemical enhancers on transdermal

permeation of caffeine and morphine through hairless mouse skin

in vitro. Int J Pharm 2001; 229: 131–137.

Amsden B, Hatefi A, Knight D, Bravo-Grimaldo E. Development of biodegradable injectable thermoplastic oligomers. Biomacro- molecules 2004; 5: 637–642.

Lee SW, Sciarra JJ. Development of an aerosol dosage form containing insulin. J Pharm Sci 1976; 65: 567–572.

Tiwari D, Goldman D, Malick WA, Madan PL. Formulation and evaluation of albuterol metered dose inhalers containing tetra- fluoroethane (P132a), a non-CFC propellant. Pharm Dev Technol 1998; 3: 163–174.

Takada Y, Kageyama K, Yamada R, et al. Correlation of DNA synthesis-inhibiting activity and the extent of transmembrane permeation into tumor cells by unsaturated or saturated fatty alcohols of graded chain-length upon hyperthermia. Oncol Rep 2001; 8: 547–551.

Guidetti MS, Vincenzi C, Guerra L, Tosti A. Contact dermatitis due to oleyl alcohol. Contact Dermatitis 1994; 31: 260–261.

CFTA. Final report on the safety assessment of stearyl alcohol, oleyl alcohol and octyl dodecanol. The Cosmetic Ingredient Review Program 1985: No. 4.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 593–595.

General References

Lee PJ, Langer R, Shastri VP. Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs. Pharm Res 2003; 20: 264–269.

Malcolm RK, McCullagh S, Woolfson AD, et al. A dynamic mechanical method for determining the silicone elastomer solubility of drugs and pharmaceutical excipients in silicone intravaginal drug delivery rings. Biomaterials 2002; 23: 3589–3594.

Murakami R, Takata Y, Ohta A, et al. Aggregate formation in oil and adsorption at oil/water interface: thermodynamics and its applica- tion to the oleyl alcohol system. J Colloid Interface Sci 2004; 270: 262–269.

Murota K, Kawada T, Matsui N, et al. Oleyl alcohol inhibits intestinal long-chain fatty acid absorption in rats. J Nutr Sci Vitaminol (Tokyo) 2000; 46: 302–308.

Rang MJ, Miller CA. Spontaneous emulsification of oils containing hydrocarbon, nonionic surfactant, and oleyl alcohol. J Colloid Interface Sci 1999; 209: 179–192.

BP: Refined olive oil JP: Olive oil

PhEur: Olivae oleum raffinatum USPNF: Olive oil

Synonyms

Gomenoleo oil; pure olive oil; olea europaea oil; oleum olivae.

Chemical Name and CAS Registry Number

Olive oil [8001-25-00]

Empirical Formula and Molecular Weight

Olive oil is a mixture of fatty acid glycerides. Analysis of olive oil shows a high proportion of unsaturated fatty acids, and a typical analysis shows that the composition of the fatty acids is as follows:

Myristic acid (14 : 0), 40.5%

Palmitic acid (16 : 0), 7.5–20.0%

Palmitoleic acid (16 : 1), 0.3–5.0%

Hepatodecenoic acid (17 : 1), 40.3%

Stearic acid (18 : 0), 0.5–5.0%

Oleic acid (18 : 1), 55.0–83.0%

Linoleic acid (18 : 2), 3.5–21.0%

Linoleic acid (18 : 3), 40.9%

Arachidic acid (20 : 0), 40.6%

Eicosaenoic acid (20 : 1), 40.4%

Behenic acid (22:0), 40.2%

Lignoceric acid (24:0), 41.0% Sterols are also present.

Applications in Pharmaceutical Formulation or Technology

Olive oil has been used in enemas, liniments, ointments, plasters, and soap. It has also been used in oral capsules and solutions, and as a vehicle for oily injections.

It has been used in topically applied lipogels of methyl nicotinate.(1) It has also been used to soften ear wax.(2) Olive oil has been used in combination with soybean oil to prepare lipid emulsion for use in pre-term infants.(3)

Olive oil is used widely in the food industry as a cooking oil and for preparing salad dressings. In cosmetics, olive oil is used as a solvent, and also as a skin and hair conditioner. Types of products containing olive oil include shampoos and hair conditioners, cleansing products, topical creams and lotions, and sun-tan products.

Description

Olive oil is the fixed oil from the fruit of Olea europaea. It occurs as a clear, colorless or greenish-yellow, oily liquid.

Pharmacopeial Specifications

See Table I.

Typical Properties

Flash point: 2258C

Refractive index: n25 = 1.4657–1.4893

Smoke point: 160–1888C

Solubility: slightly soluble in ethanol (95%); miscible with ether, chloroform, light petroleum (50–708C), and carbon disulfide.

Stability and Storage Conditions

When cooled, olive oil becomes cloudy at approximately 108C, and becomes a butterlike mass at 08C.

Olive oil should be stored in a cool, dry place in a tight, well- filled container, protected from light.

For refined oil intended for use in the manufacture of parenteral dosage forms, the PhEur 2005 requires that the bulk oil be stored under an inert gas.

Incompatibilities

Olive oil may be saponified by alkali hydroxides. As it contains a high proportion of unsaturated fatty acids, olive oil is prone to oxidation and is incompatible with oxidizing agents.

Method of Manufacture

Virgin olive oil is produced by crushing olives (the fruit of Olea europaea), typically using an edge runner mill. The oil is then expressed from the crushed mass solely by mechanical or other physical methods under conditions that do not cause deteriora- tion of the oil. Any further treatment that the oil undergoes is limited to washing, decantation, centrifugation, and filtration. Refined olive oil is obtained from virgin olive oil by refining methods that do not alter the initial glyceride content of the oil.

Safety

Olive oil is used widely as an edible oil and in food preparations and products such as cooking oils and salad dressings. It is used in cosmetics and topical pharmaceutical formulations. Olive oil is generally regarded as a relatively nonirritant and nontoxic material when used as an excipient.

Olive oil is a demulcent and has mild laxative properties when taken orally. It has been used in topical formulations as an emollient and to sooth inflamed skin; to soften the skin and crusts in eczema; in massage oils; and to soften earwax.(2)

There have been isolated reports that olive oil may cause a reaction in hypersensitive individuals. However, these inci- dences are relatively uncommon.(4–6) Olive oil is an infrequent

Olive Oil 499

Table I: Pharmacoepeial specifications for olive oil.

Test JP 2001 PhEur 2005(a) USPNF 23

Identification — + —

Characters + + —

Acid value 41.0 40.5 — Peroxide value — 45.0 — Saponification value 186–194 — 190–195

Unsaponifiable matter 41.5% 41.5% —

Iodine value 79–88 — 79–88

Specific gravity — — 0.910–0.915

Free fatty acids — — +

Alkaline impurities — + —

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Olive oil spills are slippery and an inert oil absorbent should be used to cover the oil, which can then be disposed of according to the appropriate legal regulations.

Regulatory Status

Olive oil is an edible oil. Included in the FDA Inactive Ingredients Guide (oral capsules and solution; topical solu- tions). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal

Absorbance at

270 nm Composition of fatty

acids

Saturated fatty acids of chain length less

(equivalent chain length on polyethylene- glycol adipate

stigmastadienol, clerosterol, sitostanol, ∆5- avenasterol, and

Crude olive-pomace oil; extra virgin olive oil; fine virgin olive oil; lampante virgin olive oil; olive-pomace oil; refined olive- pomace oil; virgin olive oil.

Crude olive-pomace oil

Comments: crude olive-pomace oil is olive-pomace oil that is intended for refining prior to its use in food for human consumption, or that is intended for technical purposes.

Extra virgin olive oil

Comments: extra virgin oil is a virgin oil that has an organoleptic rating of not less than 6.5, and a free acidity (as oleic acid) of not more than 1.0 g per 100 g.

Fine virgin olive oil

Comments: fine virgin oil has an organoleptic rating of not less than 5.5, and a free acidity (as oleic acid) of not more than

1.5 g per 100 g.

Lampante virgin olive oil

Comments: lampante virgin olive oil is virgin olive oil that is not fit for consumption unless it is further processed. This grade of oil is intended for refining or technical purposes.

Olive-pomace oil

Comments: olive-pomace oil is the oil obtained from the solvent extraction of olive pomace, but does not include oils obtained by reesterification processes or any mixture with oils of any kind. Olive-pomace oil of commerce is a blend of refined olive-pomace oil and virgin olive oil that is fit for human consumption. See also Section 18.

Refined olive-pomace oil

Comments: refined olive-pomace oil is obtained from crude olive-pomace oil by refining methods that do not alter the initial glyceride structure. It is intended for consumption, or blended with virgin olive oil.

Virgin olive oil

Comments: virgin olive oil has an organoleptic rating of not less than 3.5, and a free acidity (as oleic acid) of not more than

3.3 g per 100 g. The PhEur 2005 contains a monograph on virgin olive oil as well as refined olive oil.

(a) The PhEur 2005 material refers to refined olive oil.

sensitizer and does not appear to be a significant allergen in the USA, possibly due to the development of oral tolerance.

Comments

Olive oil is available in a variety of different grades; see Section

17. All olive oils are graded according to the degree of acidity.

500 Olive Oil

The flavor, color, and fragrance of olive oils may vary, depending on the region where the olives are grown, the condition of the crops, and the type of olive used.

Olive-pomace oil is obtained from the olive pomace by solvent extraction. The use of solvent extraction causes small changes in the typical fatty acid composition of the oil, and changes in organoleptic properties and impurities. Other oils can be prepared by reesterification of the appropriate combination of fatty acids with glycerol. Olive-pomace oils or reesterified oils cannot be called olive oil.

Specific References

Realdon N, Ragazzi E, Ragazzi E. Effect of gelling conditions and mechanical treatment on drug availability from a lipogel. Drug Dev Ind Pharm 2001; 27(2): 165–170.

Smythe O. Ear care. N Z Pharm 1998; 18: 25–26, 28.

Koletzko B, Boehles HJ, Emgelberger I, et al. Parenteral fat emulsions based on olive and soybean oils: a randomized clinical trial in preterm infants. J Paed Gastroenterology Nutr 2003; 37(2):

161–167.

Kranke B, Komericki P, Aberer W. Olive oil – contact sensitizer or irritant. Contact Dermatitis 1997; 35(1): 5–10.

Jung HD, Holzegel K. Contact allergy to olive oil. Derm Beruf Umwelt 1987; 35(4): 131–133.

Van Joost T, Smitt JH, Van Ketel WG. Sensitization to olive oil (Olea europeae). Contact Dermatitis 1981; 7(6): 309–310.

General References

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

Croucher P. Olive oil as a functional food. NZ Pharm 2002; 22(8): 40– 42.

Garcia Del Pozo JA, Alvarez Martinez MO. Olive oil: attainment, composition and properties. Farm (El Farmaceutico) 2000; 241: 94,

96, 98–100, 102, 104–105.

PhEur: Acidum palmiticum

Synonyms

Cetylic acid; Edenor C16 98-100; Emersol 140; Emersol 143; n-hexadecoic acid; hexadecylic acid; Hydrofol; Hystrene 9016; Industrene 4516; 1-pentadecanecarboxylic acid.

Chemical Name and CAS Registry Number

Hexadecanoic acid [57-10-3]

Empirical Formula and Molecular Weight

C16H32O2 256.42

Structural Formula

Functional Category

Emulsifying agent; skin penetrant; tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Palmitic acid is used in oral and topical pharmaceutical formulations. Palmitic acid has been used in implants for sustained release of insulin in rats.(1,2)

Description

Palmitic acid occurs as white crystalline scales with a slight characteristic odor and taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for palmitic acid.

Test PhEur 2005

Appearance +

Acidity +

Freezing point 60–668C

Boiling point: 271.58C at 100 mmHg

Flash point: >1108C

Melting point: 63–648C

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

Specific gravity: 0.849–0.851.

Stability and Storage Conditions

The bulk material should be stored in a well-closed container in a cool, dry, place.

Incompatibilities

Palmitic acid is incompatible with strong oxidizing agents and bases.

Method of Manufacture

Palmitic acid occurs naturally in all animal fats as the glyceride, palmitin, and in palm oil partly as the glyceride and partly uncombined. Palmitic acid is most conveniently obtained from olive oil after removal of oleic acid, or from Japanese beeswax. Synthetically, palmitic acid may be prepared by heating cetyl alcohol with soda lime to 2708C or by fusing oleic acid with potassium hydrate.

Safety

Palmitic acid is used in oral and topical pharmaceutical formulations and is generally regarded as nontoxic and nonirritant at the levels employed as an excipient. However, palmitic acid is reported to be an eye and skin irritant at high levels and is poisonous by intravenous administration.

LD50 (mouse, IV): 57 mg/kg(3)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When palmitic acid is heated to decomposition, carbon dioxide and carbon monoxide are formed.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral tablets). Included in nonparenteral medicines licensed in the UK.

Related Substances

Lauric acid; myristic acid; palmitin; sodium palmitate; stearic acid.

Palmitin

Empirical formula: C51H98O6

Molecular weight: 807.29

CAS number: [555-44-2]

Refractive index: n25 = 1.4381

502 Palmitic Acid

Specific gravity: 0.886

Solubility: soluble in benzene, chloroform, and ether; practi- cally insoluble in ethanol (95%) and in water.

Sodium palmitate

Synonyms: hexadecanoic acid sodium salt; palmitic acid sodium salt; sodium hexadecanoate.

Empirical formula: C16H31O2Na

Molecular weight: 278.47

CAS number: [408-35-5]

Melting point: 283–2908C

Comments: sodium palmitate is used as a surfactant and emulsifying agent in pharmaceutical formulations. The EINECS number for sodium palmitate is 206-988-1.

Comments

A specification for palmitic acid is included in the Food Chemicals Codex(4) and in the Japanese Pharmaceutical Excipients 2004 (JPE).(5) The EINECS number for palmitic acid is 200-312-9.

Specific References

Wang PY. Palmitic acid as an excipient in implants for sustained release of insulin. Biomaterials 1991; 12: 57–62.

Hashizume M, Douen T, Murakami M, et al. Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats. J Pharm Pharmacol 1992; 44: 555–559.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2813.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 278.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004, Tokyo: Yakuji Nippo, 2004: 601.

General References

Bhattacharya A, Ghosal SK. Permeation kinetics of ketotifen fumarate alone and in combination with hydrophobic permeation enhancers through human cadaver epidermis. Boll Chim Farm 2000; 139: 177–181.

Yagi S, Nakayama K, Kurosaki Y, et al. Factors determining drug residence in skin during transdermal absorption: studies on beta- blocking agents. Biol Pharm Bull 1998; 21: 1195–1201.

BP: Hard paraffin JP: Paraffin

PhEur: Paraffinum solidum USPNF: Paraffin

Synonyms

Hard wax; paraffinum durum; paraffin wax.

Chemical Name and CAS Registry Number

Paraffin [8002-74-2]

Empirical Formula and Molecular Weight

Paraffin is a purified mixture of solid saturated hydrocarbons having the general formula CnH2n+2, and is obtained from petroleum or shale oil.

Structural Formula

See Section 4.

Functional Category

Ointment base; stiffening agent.

Applications in Pharmaceutical Formulation or Technology

Paraffin is mainly used in topical pharmaceutical formulations as a component of creams and ointments. In ointments, it may be used to increase the melting point of a formulation or to add stiffness. Paraffin is additionally used as a coating agent for capsules and tablets, and is used in some food applications. Paraffin coatings can also be used to affect the release of drug from ion-exchange resin beads.(1)

Description

Paraffin is an odorless and tasteless, translucent, colorless, or white solid. It feels slightly greasy to the touch and may show a brittle fracture. Microscopically, it is a mixture of bundles of microcrystals. Paraffin burns with a luminous, sooty flame. When melted, paraffin is essentially without fluorescence in daylight; a slight odor may be apparent.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for paraffin.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Congealing range 50–758C — 47–658C

Reaction — — +

Heavy metals 410 ppm — —

Arsenic 42 ppm — —

Sulfates + + —

Polycyclic aromatic — + —

hydrocarbons

Readily carbonizable + — +

substances

Acidity or alkalinity + + —

Typical Properties

Density: ≈0.84–0.89 g/cm3 at 208C

Melting point: various grades with different specified melting ranges are commercially available.

Solubility: soluble in chloroform, ether, volatile oils, and most warm fixed oils; slightly soluble in ethanol; practically insoluble in acetone, ethanol (95%), and water. Paraffin can be mixed with most waxes if melted and cooled.

Stability and Storage Conditions

Paraffin is stable, although repeated melting and congealing may alter its physical properties. Paraffin should be stored at a temperature not exceeding 408C in a well-closed container.

Incompatibilities

—

Method of Manufacture

Paraffin is manufactured by the distillation of crude petroleum or shale oil, followed by purification by acid treatment and filtration. Paraffins with different properties may be produced by controlling the distillation and subsequent congealing conditions.

Synthetic paraffin, synthesized from carbon monoxide and hydrogen is also available; see Section 17.

Safety

Paraffin is generally regarded as an essentially nontoxic and nonirritant material when used in topical ointments and as a coating agent for tablets and capsules. However, granuloma- tous reactions (paraffinomas) may occur following injection of paraffin into tissue for cosmetic purposes or to relieve pain. Long-term inhalation of aerosolized paraffin may lead to interstitial pulmonary disease. Ingestion of a substantial amount of white soft paraffin has led to intestinal obstruction in one instance.(2–6)

504 Paraffin

See also Mineral Oil for further information.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. In the UK, the recommended occupational exposure limits for paraffin wax fumes are 2 mg/m3 long-term (8-hour TWA) and 6 mg/m3 short-term.(7)

Regulatory Status

Accepted in the UK for use in certain food applications. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets, topical emulsions, and ointments). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Light mineral oil; microcrystalline wax; petrolatum; synthetic paraffin.

Synthetic paraffin

Molecular weight: 400–1400

Appearance: a hard, odorless, white wax consisting of a mixture of mostly long-chain, unbranched, saturated hydrocarbons along with a small amount of branched hydrocarbons.

Melting point: 96–1058C

Viscosity (dynamic): 5–15 mPa s (5–15 cP) at 1358C.

Comments: the USPNF 23 states that synthetic paraffin is synthesized by the Fischer–Tropsch process from carbon monoxide and hydrogen, which are catalytically converted to a mixture of paraffin hydrocarbons. The lower molecular weight fractions are removed by distillation and the residue is hydrogenated and further treated by percolation through activated charcoal. This mixture may be fractionated into its components by a solvent-separation method. Synthetic paraffin may contain not more than 0.005% w/w of a suitable antioxidant.

Comments

The more highly purified waxes are used in preference to paraffin in many applications because of their specifically controlled physical properties such as hardness, malleability, and melting range. A specification for synthetic paraffin is contained in the Food Chemicals Codex (FCC). The EINECS numbers for paraffin are 232-315-6 and 265-154-5.

Specific References

Motyckas S, Nairn J. Influence of wax coatings on release rate of anions form ion-exchange resin beads. J Pharm Sci 1978; 67: 500–

503.

Crosbie RB, Kaufman HD. Self-inflicted oleogranuloma of breast.

Br Med J 1967; 3: 840–841.

Bloem JJ, van der Waal I. Paraffinoma of the face: a diagnostic and therapeutic problem. Oral Surg 1974; 38: 675–680.

Greaney MG, Jackson PR. Oleogranuloma of the rectum produced by Lasonil ointment. Br Med J 1977; 2: 997–998.

Pujol J, Barneon G, Bousquet J, et al. Interstitial pulmonary disease induced by occupation exposure to paraffin. Chest 1990; 97: 234–

236.

Goh D, Buick R. Intestinal obstruction due to ingested Vaseline.

Arch Dis Child 1987; 62: 1167–1168.

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

BP: Arachis oil JP: Peanut oil

PhEur: Arachidis oleum raffinatum USPNF: Peanut oil

Synonyms

Aextreff CT; earthnut oil; groundnut oil; katchung oil; nut oil.

Chemical Name and CAS Registry Number

Peanut oil [8002-03-7]