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01 Excipients Prelims 1..9

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01 Excipients Prelims 1..9 Ethyl Oleate 1 Nonproprietary Names Table I: Pharmacopeial specifications for ethyl oleate. BP: Ethyl Oleate Test PhEur 6.0 USP32–NF27 PhEur: Ethyl Oleate þ USP-NF: Ethyl Oleate Characters — Identification þ — Specific gravity 0.866–0.874 0.866–0.874 E 2 Synonyms Viscosity — 55.15 mPa s Refractive index — 1.443–1.450 Crodamol EO; ethylis oleas; ethyl 9-octadecenoate; Kessco EO; Acid value 40.5 40.5 oleic acid, ethyl ester. Iodine value 75–90 75–85 Saponification value 177–188 177–188 4 3 Chemical Name and CAS Registry Number Peroxide value 10 — Oleic acid 560.0% — (Z)-9-Octadecenoic acid, ethyl ester [111-62-6] Water content 41.0% — Total ash 40.1% — 4 Empirical Formula and Molecular Weight C20H38O2 310.51 10 Typical Properties 8 5 Structural Formula Boiling point 205–208 C (some decomposition) Flash point 175.38C Freezing point À328C Moisture content At 208C and 52% relative humidity, the equilibrium moisture content of ethyl oleate is 0.08%. Solubility Miscible with chloroform, ethanol (95%), ether, fixed oils, liquid paraffin, and most other organic solvents; practically insoluble in water. Surface tension 32.3 mN/m (32.3 dynes/cm) at 258C(9) 6 Functional Category Viscosity (dynamic) 3.9 mPa s (3.9 cP) at 258C(9) 2 8 (9) Oleaginous vehicle; solvent. Viscosity (kinematic) 0.046 mm /s (4.6 cSt) at 25 C 11 Stability and Storage Conditions 7 Applications in Pharmaceutical Formulation or Technology Ethyl oleate should be stored in a cool, dry place in a small, well- filled, well-closed container, protected from light. When a partially Ethyl oleate is primarily used as a vehicle in certain parenteral filled container is used, the air should be replaced by nitrogen or preparations intended for intramuscular administration. It has also another inert gas. Ethyl oleate oxidizes on exposure to air, resulting been used as a solvent for drugs formulated as biodegradable in an increase in the peroxide value. It remains clear at 58C, but capsules for subdermal implantation(1) and in the preparation of (2) (3) darkens in color on standing. Antioxidants are frequently used to microemulsions containing cyclosporin and norcantharidin. extend the shelf life of ethyl oleate. Protection from oxidation for Microemulsion formulations containing ethyl oleate have also been over 2 years has been achieved by storage in amber glass bottles (4) (5) proposed for topical and ocular delivery, and for liver targeting with the addition of combinations of propyl gallate, butylated (6) following parenteral administration. Ethyl oleate has been used in hydroxyanisole, butylated hydroxytoluene, and citric or ascorbic (7) topical gel formulations, and in self-microemulsifying drug acid.(11,12) A concentration of 0.03% w/v of a mixture of propyl (8) delivery systems for oral administration. gallate (37.5%), butylated hydroxytoluene (37.5%), and butylated Ethyl oleate is a suitable solvent for steroids and other lipophilic hydroxyanisole (25%) was found to be the best antioxidant for drugs. Its properties are similar to those of almond oil and peanut ethyl oleate.(12) oil. However, it has the advantage that it is less viscous than fixed Ethyl oleate may be sterilized by heating at 1508C for 1 hour. oils and is more rapidly absorbed by body tissues.(9) Ethyl oleate has also been evaluated as a vehicle for subcuta- 12 Incompatibilities neous injection.(10) Ethyl oleate dissolves certain types of rubber and causes others to swell.(13,14) It may also react with oxidizing agents. 8 Description Ethyl oleate occurs as a pale yellow to almost colorless, mobile, oily 13 Method of Manufacture liquid with a taste resembling that of olive oil and a slight, but not Ethyl oleate is prepared by the reaction of ethanol with oleoyl rancid odor. chloride in the presence of a suitable hydrogen chloride acceptor. Ethyl oleate is described in the USP32–NF27 as consisting of esters of ethyl alcohol and high molecular weight fatty acids, 14 Safety principally oleic acid. A suitable antioxidant may be included. Ethyl oleate is generally considered to be of low toxicity but ingestion should be avoided. Ethyl oleate has been found to cause 9 Pharmacopeial Specifications minimal tissue irritation.(15) No reports of intramuscular irritation See Table I. during use have been recorded. 259 260 Ethyl Oleate 15 Handling Precautions 3 Zhang L et al. Formulation and physicochemical characterisation of Observe normal precautions appropriate to the circumstances and norcantharidin microemulsion coating lecithin-based surfactants. STP Pharma Sci 2004; 14(6): 461–469. quantity of material handled. Eye protection and nitrile gloves are 4 Chen HB et al. Microemulsion-based hydrogel formulation of recommended. Ethyl oleate is flammable. ibuprofen for topical delivery. Int J Pharm 2006; 315(1–2): 52–58. 5 Chan J et al. Phase transition water-in-oil microemulsions as ocular 16 Regulatory Status drug delivery systems: in vitro and in vivo evaluation. Int J Pharm 2007; Included in the FDA Inactive Ingredients Database (transdermal 328(1): 65–71. preparation). Included in parenteral (intramuscular injection) and 6 Zhang L et al. An investigation on liver-targeting microemulsions of nonparenteral (transdermal patches) medicines licensed in the UK. norcantharidin. Drug Deliv 2005; 12(5): 289–295. Included in the Canadian List of Acceptable Non-medicinal 7 El-Megrab NA et al. Formulation and evaluation of meloxicam gels for Ingredients. topical administration. Saudi Pharm J 2006; 14(3–4): 155–162. E 8 Cui SM et al. Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of Pueraria 17 Related Substances lobata isoflavone. Drug Dev Ind Pharm 2005; 31(4–5): 349–356. Methyl oleate; oleic acid. 9 Howard JR, Hadgraft J. The clearance of oily vehicles following intramuscular and subcutaneous injections in rabbits. Int J Pharm Methyl oleate 1983; 16: 31–39. Empirical formula C19H36O2 10 Radwan M. In vivo screening model for excipients and vehicles used in Molecular weight 296.49 subcutaneous injections. Drug Dev Ind Pharm 1994; 20: 2753–2762. CAS number [112-69-9] 11 Alemany P, Del Pozo A. [Autoxidation of ethyl oleate: protection with Synonyms Methyl 9-octadecenoate; (Z)-9-octadecenoic acid, antioxidants.] Galenica Acta 1963; 16: 335–338[in Spanish]. methyl ester. 12 Nikolaeva NM, Gluzman MK. [Conditions for stabilizing ethyl oleate Boiling point 168–1708C during storage.] Farmatsiya 1977; 26: 25–28[in Russian]. Density 0.879 g/cm3 13 Dexter MB, Shott MJ. The evaluation of the force to expel oily injection Iodine number 85.6 vehicles from syringes. J Pharm Pharmacol 1979; 31: 497–500. 26 14 Halsall KG. Calciferol injection and plastic syringes [letter]. Pharm J Refractive index n D = 1.4510 Solubility Miscible with ethanol (95%) and ether. 1985; 235: 99. Comments Prepared by refluxing oleic acid with p-toluenesulfo- 15 Hem SL et al. Tissue irritation evaluation of potential parenteral nic acid in methanol. vehicles. Drug Dev Commun1974–751(5): 471–477. 18 Comments 20 General References The EINECS number for ethyl oleate is 203-889-5. The PubChem Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in parenteral Compound ID (CID) for ethyl oleate includes 8123 and 5364430. products. J Pharm Sci 1963; 52: 917–927. 19 Specific References 21 Author 1 Ory SJ et al. Effect of a biodegradable contraceptive capsule (Capronor) containing levonorgestrel on gonadotropin, estrogen and progesterone CG Cable. levels. Am J Obstet Gynecol 1983; 145: 600–605. 2 Kim C-K et al. Preparation and physicochemical characterisation of 22 Date of Revision phase inverted water/oil microemulsion containing cyclosporin A. Int J Pharm 1997; 147: 131–134. 30 January 2009..
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