kywods

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]

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