Soybean Oil

Nonproprietary Names

BP: Refined soya oil JP: Soybean oil

PhEur: Soiae oleum raffinatum USP: Soybean oil

Synonyms

Calchem IVO-114; Lipex 107; Lipex 200; Shogun CT; soja bean oil; soyabean oil; soya bean oil.

Chemical Name and CAS Registry Number

Soybean oil [8001-22-7]

Empirical Formula and Molecular Weight

A typical analysis of refined soybean oil indicates the composition of the acids, present as glycerides, to be: linoleic acid 50–57%; linolenic acid 5–10%; oleic acid 17–26%; palmitic acid 9–13%; and stearic acid 3–6%. Other acids are present in trace quantities.(1)

Structural Formula

See Sections 4 and 8.

and Glycine max (L.) Merr. (G. hispida (Moench) Maxim.) by extraction and subsequent refining; it may contain a suitable antioxidant. The PhEur 2005 also includes a monograph for Hydrogenated Soybean Oil. See Vegetable Oil, hydrogenated, type 1.

Soybean oil is a clear, pale-yellow colored, odorless or almost odorless liquid, with a bland taste that solidifies between

—10 and —168C.

9 Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for soybean oil.

 

Test JP 2001 PhEur 2005 USP 28    

Identification — + —    

Characters — + —    

Specific gravity 0.916–0.922 ≈0.922 0.916–0.922    

Refractive index — ≈1.475 1.465–1.475    

Heavy metals — — 40.001%    

Free fatty acids — — +    

Fatty acid — + +  

composition

Acid value 40.2 40.5 —

Iodine value 126–140 — 120–141

Functional Category

Oleaginous vehicle; solvent.

Saponification value

Unsaponifiable matter

188–195 — 180–200

41.0% 41.5% 41.0%

Applications in Pharmaceutical Formulation

Cottonseed oil — — +

Peroxide — 410.0 or 45.0(a)  +

or Technology

In pharmaceutical preparations, soybean oil emulsions are

Alkaline

impurities

— + —

primarily used as a fat source in total parenteral nutrition (TPN) regimens.(2) Although other oils, such as peanut oil, have been used for this purpose, soybean oil is now preferred because it is associated with fewer adverse reactions. Emulsions containing soybean oil have also been used as vehicles for the oral and intravenous administration of drugs;(3,4) drug substances that have been incorporated into such emulsions include amphotericin,(5–7) diazepam, retinoids,(8) vitamins,(9) poorly water-soluble steroids,(10,11) fluorocarbons,(12,13) and insulin.(14) In addition, soybean oil has been used in the formulation of many drug delivery systems such as lipo- somes,(15) microspheres,(16) dry emulsions,(17) self-emulsifying systems,(18) and nanoemulsions and nanocapsules.(19)

Soybean oil may also be used in cosmetics and is consumed as an edible oil. As soybean oil has emollient properties, it is used as a bath additive in the treatment of dry skin conditions.

Description

The USP 28 describes soybean oil as the refined fixed oil obtained from the seeds of the soya plant Glycine max Merr. (Fabaceae). The PhEur 2005 defines refined soya-bean oil as the fatty oil obtained from the seeds of Glycine soja Sieb. and Zucc.

Brassicasterol — 40.3% —

Water — 40.1%(a) —

(a) In soybean oil intended for parenteral use.

Typical Properties

Autoignition temperature: 4458C Density: 0.916–0.922 g/cm3 at 258C Flash point: 2828C

Freezing point: —10 to —168C

Hydroxyl value: 4–8

Interfacial tension: 50 mN/m (50 dynes/cm) at 208C.

Refractive index: n25 = 1.471–1.475

Solubility: practically insoluble in ethanol (95%) and water; miscible with carbon disulfide, chloroform, ether, and light petroleum.

Surface tension: 25 mN/m (25 dynes/cm) at 208C.

Viscosity (dynamic):

172.9 mPa s (172.9 cP) at 08C;

99.7 mPa s (99.7 cP) at 108C;

50.09 mPa s (50.09 cP) at 258C;

28.86 mPa s (28.86 cP) at 408C.

Soybean Oil 723

Stability and Storage Conditions

Soybean oil is a stable material if protected from atmospheric oxygen.

The formation of undesirable flavors in soybean oil is accelerated by the presence of 0.01 ppm copper and 0.1 ppm iron, which act as catalysts for oxidation; this can be minimized by the addition of chelating agents.

Prolonged storage of soybean oil emulsions, particularly at elevated temperatures, can result in the formation of free fatty acids, with a consequent reduction in the pH of the emulsion; degradation is minimized at pH 6–7. However, soybean oil emulsions are stable at room temperature if stored under nitrogen in a light-resistant glass container. Plastic containers are permeable to oxygen and should not be used for long-term storage since oxidative degradation can occur.

The stability of soybean oil emulsions is considerably influenced by other additives in a formulation.(20–26)

Soybean oil should be stored in a well-filled, airtight, light- resistant container at a temperature not exceeding 258C.

Incompatibilities

Soybean oil emulsions have been reported to be incompatible at 258C with a number of materials including calcium chloride, calcium gluconate, magnesium chloride, phenytoin sodium, and tetracycline hydrochloride.(27) Lower concentrations of these materials, or lower storage temperatures, may result in improved compatibility. The source of the material may also affect compatibility; for example, while one injection from a particular manufacturer might be incompatible with a fat emulsion, an injection with the same amount of active drug substance from another manufacturer might be compatible.

Amphotericin B has been reported to be incompatible with soybean oil containing fat emulsions under certain condi- tions.(28)

Soybean oil emulsions are also incompatible with many other drug substances, IV infusion solutions, and ions (above certain concentrations).

When plastic syringes are used to store soybean oil emulsion, silicone oil may be extracted into the emulsion; swelling of the syringe pump also occurs, resulting in the necessity for increased forces to maintain the motion of the plunger.(29)

Method of Manufacture

Obtained by solvent extraction using petroleum hydrocarbons, or to a lesser extent by expression using continuous screw-press operations, of the seeds of either Glycine max (Leguminosae) or Glycine soja (Leguminosae). The oil is refined, deodorized, and clarified by filtration at about 08C. Any phospholipids or sterols present are removed by refining with alkali.

Safety

Soybean oil is widely used intramuscularly as a drug vehicle or as a component of emulsions used in parenteral nutrition regimens; it is also consumed as an edible oil. Generally, soybean oil is regarded as an essentially nontoxic and nonirritant material. However, serious adverse reactions to soybean oil emulsions administered parenterally have been reported. These include cases of hypersensitivity,(30) CNS reactions,(31) and fat embolism.(32) Interference with the antic- oagulant effect of warfarin has also been reported.(33)



Anaphylactic reactions have also been reported following the consumption of foods derived from, or containing, soy beans. Recently there has been concern at the concentration of phytoestrogens in some soy-derived products. Administration of soy protein to humans has resulted in significantly decreased serum lipid concentrations.(34)

In 1999, the UK Medical Devices Agency announced the voluntary withdrawal of a breast implant that contained soybean oil. The decision was taken because not enough was known at that time about the long-term safety and the rate of breakdown of the soybean oil in the filling and its possible effects on the body.(35)

LD50 (mouse, IV): 22.1 g/kg(36) LD50 (rat, IV): 16.5 g/kg

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IV injections, oral capsules, and topical preparations). Included in nonpar- enteral (chewable tablets; oral capsules; topical bath additives) and parenteral (emulsions for IV injection or infusion) medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Canola oil; corn oil; cottonseed oil; peanut oil; sesame oil; sunflower oil.

Comments

The stability of soybean oil emulsions may be readily disturbed by the addition of other materials, and formulations containing soybean oil should therefore be evaluated carefully for their compatibility and stability.

A specification for soybean oil is contained in the Food Chemicals Codex (FCC).

Specific References

British Standards Institute. Specification for Crude Vegetable Fats, BS 7207. London: HMSO, 1990.

McNiff BL. Clinical use of 10% soybean oil emulsion. Am J Hosp Pharm 1977; 34: 1080–1086.

Jeppsson R. Effects of barbituric acids using an emulsion form intravenously. Acta Pharm Suec 1972; 9: 81–90.

Medina J, Salvado´ A, del Pozo A. Use of ultrasound to prepare lipid emulsions of lorazepam for intravenous injection. Int J Pharm 2001; 216(1–2): 1–8.

Wasan KM. Amphotericin B-intralipid. Drugs of the Future 1994;

19(3): 225–227.

Vita E. Intralipid in prophylaxis of amphotericin B nephrotoxicity.

Ann Pharmacother 1994; 28: 1182–1183.

Pascual B, Ayestaran A, Montoro JB, et al. Administration of lipid- emulsion versus conventional amphotericin B in patients with neutropenia. Ann Pharmacother 1995; 29: 1197–1201.

Nankevis R, Davis SS, Day NH, et al. Studies on the intravenous pharmacokinetics of three retinoids in the rat. Int J Pharm 1994; 101: 249–256.

724 Soybean Oil

Dahl GB, Svensson L, Kinnander NJG, et al. Stability of vitamins in soybean oil fat emulsion under conditions simulating intra- venous feeding of neonates and children. J Parenter Enteral Nutr 1994; 18(3): 2234–2239.

Malcolmson C, Lawrence MJ. A comparison of the incorporation of model steroids into non-ionic micellar and microemulsion systems. J Pharm Pharmacol 1993; 45: 141–143.

Steroid anaesthetic agents [editorial]. Lancet 1992; 340: 83–84.

Johnson OL, Washington C, Davis SS. Thermal stability of fluorocarbon emulsions that transport oxygen. Int J Pharm 1990; 59: 131–135.

Johnson OL, Washington C, Davis SS. Long-term stability studies of fluorocarbon oxygen transport emulsions. Int J Pharm 1990; 63: 65–72.

Morishita M, Matsuzawa A, Takayama K, et al. Improving insulin enteral absorption using water-in-oil emulsion. Int J Pharm 1998; 172(1–2); 189–198.

Stricker H, Mu¨ ller H. The storage stability of dispersions of soybean-lecithin liposomes [in German]. Pharm Ind 1984; 46: 1175–1183.

Salmero´ n MD, Herna´ndez PJ, Cerezo A. Encapsulation study of 6- methylprednisolone in liquid microspheres. Drug Dev Ind Pharm 1997; 23(2): 133–136.

Pedersen GP, Fa¨ ldt P, Bergensta˚ hl B, et al. Solid state characterisa- tion of a dry emulsion: a potential drug delivery system. Int J Pharm 1998; 171(2): 257–270.

Krishna G, Sheth BB. A novel self emulsifying parenteral drug delivery system. PDA J Pharm Sci Technol 1999; 53(4): 168–176.

Santos-Magalha˜es NS, Pontes A, Pereira VMW, Caetano MNP. Colloidal carriers for benzathine penicillin G: nanoemulsions and nanocapsules. Int J Pharm 2000; 208(1–2): 71–80.

Takamura A, Ishii F, Noro S, et al. Study of intravenous hyperalimentation: effect of selected amino acids on the stability of intravenous fat emulsions. J Pharm Sci 1984; 73: 91–94.

Driscoll DF, Baptista RJ, Bistrian BR, Blackburn GL. Practical considerations regarding the use of total nutrient admixtures. Am J Hosp Pharm 1986; 43: 416–419.

Washington C. The stability of intravenous fat emulsions in total parenteral nutrition mixtures. Int J Pharm 1990; 66: 1–21.

Manning RJ, Washington C. Chemical stability of total parenteral nutrition mixtures. Int J Pharm 1992; 81: 1–20.

Jumaa M, Mu¨ ller BW. The effect of oil components and homogenisation conditions on the physicochemical properties and stability of parenteral fat emulsions. Int J Pharm 1998; 163(1–2): 81–89.

Jumaa M, Mu¨ ller BW. The stabilisation of parenteral fat emulsion using non-ionic ABA copolymer surfactant. Int J Pharm 1998; 174(1–2): 29–37.

Warisnoicharoen W, Lansley AB, Lawrence MJ. Non-ionic oil-in- water microemulsions: the effects of oil type on phase behaviour. Int J Pharm 2000; 198(1): 7–27.

Trissel LA. Handbook on Injectable Drugs, 9th edn. Bethesda, MD: American Society of Hospital Pharmacists, 1996: 435–447.

Trissel LA. Amphotericin B does not mix with fat emulsion [letter].

Am J Health Syst Pharm 1995; 52: 1463–1464.

Capes DF, Herring D, Sunderland VD, et al. The effect on syringe performance of fluid storage and repeated use: implications for syringe pumps. PDA J Pharm Sci Technol 1996; 50 (Jan–Feb): 40–

50.

Hiyama DT, Griggs B, Mittman RJ, et al. Hypersensitivity following lipid emulsion infusion in an adult patient. J Parenter Enteral Nutr 1989; 13: 318–320.

Jellinek EH. Dangers of intravenous fat infusions [letter]. Lancet

1976; ii: 967.

Estebe JP, Malledant Y. Fat embolism after lipid emulsion infusion [letter]. Lancet 1991; 337: 673.

Lutomski DM, Palascak JE, Bower RH. Warfarin resistance associated with intravenous lipid administration. J Parent Enteral Nutr 1987; 11(3): 316–318.

Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333(5): 276–282.

Bradbury J. Breast implants containing soy-bean oil withdrawn in UK [news]. Lancet 1999; 353: 903.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987: 4454.

General References

Benita S, Levy MY. Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical char- acterization. J Pharm Sci 1993; 82: 1069–1079.

Delaveau P, Hotellier F. Oils of pharmaceutical, dietetic, and cosmetic interest, part I: maize, soybean, sunflower [in French]. Ann Pharm Fr 1971; 29: 399–412.

Mirtallo JM, Oh T. A key to the literature of total parenteral nutrition: update 1987. Drug Intell Clin Pharm 1987; 21: 594–606.

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

Boca Raton: FL: CRC Press, 1992: 383–385.

Wolf WJ. In: Kirk-Othmer Encyclopedia of Chemical Technology, vol.

21; 3rd edn. New York: Wiley-Interscience, 1981: 417–442.

Authors

CG Cable.

Date of Revision

23 August 2005.

Starch

Nonproprietary Names

BP: Maize starch Potato starch Rice starch Tapioca starch Wheat starch

JP: Corn starch Potato starch Rice starch Wheat starch

PhEur: Maydis amylum (maize starch) Solani amylum (potato starch) Oryzae amylum (rice starch) Tritici amylum (wheat starch)

USPNF:  Corn starch

Potato starch Tapioca Wheat starch

Note that the USPNF 23 has individual monographs for corn (Zea mays), potato (Solanum tuberosum), tapioca (Manihot utilissima Pohl) and wheat starch (Triticum aestivum). The PhEur 2005 has monographs for each of these starches, except tapioca starch, along with an additional monograph for rice starch, Oryza sativa. Also note that the PhEur 2005 Suppl 5.0 contains an updated monograph for maize (corn) starch. The BP 2004 similarly describes maize, potato, rice, tapioca (cassava), and wheat starch in individual monographs, tapioca starch being obtained from the rhizomes of Manihot utilissima Pohl. The JP 2001 similarly describes corn (maize), rice, potato and wheat starch in separate monographs. See also Section 18.

Synonyms

Amido; amidon; amilo; amylum; Aytex P; C*PharmGel; Fluftex W; Instant Pure-Cote; Melojel; Meritena; Paygel 55; Perfectamyl D6PH; Pure-Bind; Pure-Cote; Pure-Dent; Pure- Gel; Pure-Set; Purity 21; Purity 826; Tablet White.

See also Sections 1 and 18.

Chemical Name and CAS Registry Number

Starch [9005-25-8]

Empirical Formula and Molecular Weight

(C6H10O5)n 50 000–160 000

where n = 300–1000.

Starch consists of amylose and amylopectin, two polysac- charides based on a-glucose. See also Sections 5 and 17.

Structural Formula

 

Functional Category

Glidant; tablet and capsule diluent; tablet and capsule disintegrant; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Starch is used as an excipient primarily in oral solid-dosage formulations where it is utilized as a binder, diluent, and disintegrant.

As a diluent, starch is used for the preparation of standardized triturates of colorants or potent drugs to facilitate subsequent mixing or blending processes in manufacturing operations. Starch is also used in dry-filled capsule formula- tions for volume adjustment of the fill matrix.(1)

In tablet formulations, freshly prepared starch paste is used at a concentration of 5–25% w/w in tablet granulations as a binder. Selection of the quantity required in a given system is determined by optimization studies, using parameters such as granule friability, tablet friability, hardness, disintegration rate, and drug dissolution rate.

Starch is one of the most commonly used tablet disintegrants at concentrations of 3–15% w/w.(2–9) However, unmodified starch does not compress well and tends to increase tablet friability and capping if used in high concentrations. In granulated formulations, about half the total starch content is included in the granulation mixture and the balance as part of the final blend with the dried granulation. Also, when used as a

726 Starch

disintegrant, starch exhibits type II isotherms and has a high specific surface for water sorption.(10)

Starch has been investigated as an excipient in novel drug delivery systems for nasal,(11,12) oral,(13–16) periodontal,(17) and other site-specific delivery systems.(18,19)

Starch is also used in topical preparations; for example, it is widely used in dusting powders for its absorbency, and is used as a protective covering in ointment formulations applied to the skin. Starch mucilage has also been applied to the skin as an emollient, has formed the base of some enemas, and has been used in the treatment of iodine poisoning.

Therapeutically, rice starch-based solutions have been used in the prevention and treatment of dehydration due to acute diarrheal diseases.

Description

Starch occurs as an odorless and tasteless, fine, white-colored powder comprising very small spherical or ovoid granules whose size and shape are characteristic for each botanical variety.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 5.5–6.5 for a 2% w/v aqueous dispersion of corn starch, at 258C.

Compressibility: see Figure 1.

Density (bulk): 0.462 g/cm3 for corn starch. Density (tapped): 0.658 g/cm3 for corn starch. Density (true): 1.478 g/cm3 for corn starch.

Flowability: 10.8–11.7 g/s for corn starch;(9) 30% for corn starch (Carr compressibility index).(20) Corn starch is cohesive and has poor flow characteristics.

Gelatinization temperature: 738C for corn starch; 728C for potato starch; 638C for wheat starch.

Moisture content: all starches are hygroscopic and rapidly absorb atmospheric moisture.(21,22) Approximate equili- brium moisture content values at 50% relative humidity are 11% for corn starch; 18% for potato starch; 14% for rice starch; and 13% for wheat starch. Between 30% and 80% relative humidity, corn starch is the least hygroscopic starch and potato starch is the most hygroscopic. Commercially available grades of corn starch usually contain 10–14% water. See also Figures 2 and 3.

Particle size distribution: Corn starch: 2–32 mm; Potato starch: 10–100 mm; Rice starch: 2–20 mm; Tapioca starch: 5–35 mm; Wheat starch: 2–45 mm.

Median diameter for corn starch is 17 mm and for wheat starch is 23 mm.

Solubility: practically insoluble in cold ethanol (95%) and in cold water. Starch swells instantaneously in water by about 5–10% at 378C.(2,22) Polyvalent cations produce more swelling than monovalent ions, but pH has little effect.

Specific surface area:

0.41–0.43 m2/g for corn starch;

0.12 m2/g for potato starch; 0.27–0.31 m2/g for wheat starch.

Swelling temperature: 658C for corn starch; 648C for potato starch; 558C for wheat starch.

Viscosity (dynamic): 13.0 mPa s (13.0 cP) for a 2% w/v aqueous dispersion of corn starch at 258C.

 

Table I: Pharmacopeial specifications for starch.    

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +(a)    

Microbial limits — + +    

pH    

Corn starch — 4.0–7.0(b) 4.0–7.0    

Potato starch — 5.0–8.0 5.0–8.0    

Tapioca — — 4.5–7.0    

Wheat starch — 4.5–7.0 4.5–7.0    

Acidity (rice starch) — + —    

Loss on drying    

Corn starch 415.0% 415.0% 415.0%    

Rice starch 415.0% 415.0% —    

Potato starch 418.0% 420.0% 420.0%    

Tapioca — — 416.0%    

Wheat starch 415.0% 415.0% 415.0%    

Residue on ignition

Sulfated ash — — 40.6%(a)    

Corn starch 40.5% 40.6% —    

Rice starch 41.0% 41.0% —    

Potato starch 40.5% 40.6% —    

Wheat starch 41.0% 40.6% —    

Iron    

Corn starch — 410 ppm 410 ppm    

Potato starch — 410 ppm 410 ppm    

Tapioca starch — — 40.002%    

Wheat starch — 410 ppm 410 ppm    

Oxidizing substances    

Corn starch — 420 ppm 420 ppm    

Potato starch — 420 ppm 420 ppm    

Tapioca starch — — 40.002%    

Wheat starch — 420 ppm 420 ppm    

Sulfur dioxide    

Corn starch — 450 ppm 450 ppm    

Potato starch — 450 ppm 450 ppm    

Tapioca — — 40.005%    

Wheat starch — 450 ppm 450 ppm    

Total protein    

Corn starch — — —    

Rice starch — — —    

Potato starch — — —    

Wheat starch — 40.3% —  

Foreign matter — + —

(a) See USPNF 23 Suppl 1.0.

(b) See PhEur 2005 Suppl 5.0.

Starch 727

SEM: 1

Excipient: Corn starch Manufacturer: Anheuser Busch Lot No.: 96A-3 (67)

Magnification: 2400×

Voltage: 20 kV

 

SEM: 2

Excipient: Corn starch Manufacturer: AE Staley Mfg. Co. Lot No.: 96A-4 (G77912)

Magnification: 2400×

 Voltage: 20 kV



SEM: 3

Excipient: Potato starch Manufacturer: Starchem Lot No.: 96A-5 (1179)

Magnification: 2400×

Voltage: 20 kV