Table VI: Pharmacopeial specifications for polysorbates.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification    

Polysorbate 20 — + +    

Polysorbate 40 — + +    

Polysorbate 60 — + +    

Polysorbate 80 + + +    

Saponification value    

Polysorbate 20 — 40–50 40–50    

Polysorbate 40 — 41–52 41–52    

Polysorbate 60 — 45–55 45–55    

Polysorbate 80 45–55 45–55 45–55    

Composition of fatty acids — see Table VII —    

Hydroxyl value    

Polysorbate 20 — 96–108 96–108    

Polysorbate 40 — 89–105 89–105    

Polysorbate 60 — 81–96 81–96    

Polysorbate 80 — 65–80 65–80    

Water

Polysorbate 20

—

43.0%

43.0%    

Polysorbate 40 — 43.0% 43.0%    

Polysorbate 60 — 43.0% 43.0%    

Polysorbate 80 43.0% 43.0% 43.0%    

Residue on ignition    

Polysorbate 20 — 40.25% 40.25%    

Polysorbate 40 — 40.25% 40.25%    

Polysorbate 60 — 40.25% 40.25%    

Polysorbate 80 40.15% 40.25% 40.25%    

Arsenic    

Polysorbate 80 42 ppm — —    

Heavy metals    

Polysorbate 20 — 410 ppm 40.001%    

Polysorbate 40 — 410 ppm 40.001%    

Polysorbate 60 — 410 ppm 40.001%    

Polysorbate 80 420 ppm 410 ppm 40.001%    

Acid value

Polysorbate 20

—

42.0

42.2    

Polysorbate 40 — 42.0 42.2    

Polysorbate 60 — 42.0 42.2    

Polysorbate 80 42.0 42.0 42.2    

Iodine value    

Polysorbate 80 19–24 — —    

Specific gravity    

Polysorbate 20 — ≈1.10 —    

Polysorbate 40 — ≈1.10 —    

Polysorbate 60 — ≈1.10 —    

Polysorbate 80 1.065–1.095 ≈1.10 1.06–1.09    

Viscosity at 258C

Polysorbate 20

—

≈ 400 mPa s

—    

Polysorbate 40 — ≈ 400 mPa s —    

Polysorbate 60 — ≈ 400 mPa s —    

Polysorbate 80 345–445 mm2 ≈ 400 mPa s 300–500 mm2/s    

Organic volatile impurities — — +    

Peroxide value    

Polysorbate 20 — 410 —    

Polysorbate 40 — 410 —    

Polysorbate 60 — 410 —    

Polysorbate 80 — 410 —    

Residual ethylene oxide    

Polysorbate 20 — 41 ppm —    

Polysorbate 40 — 41 ppm —    

Polysorbate 60 — 41 ppm —    

Polysorbate 80 — 41 ppm —    

Residual dioxan    

Continued  

Polyoxyethylene Sorbitan Fatty Acid Esters 583

Table VI: Continued

 

Test JP 2001 PhEur 2005 USPNF 23    

Polysorbate 20 — 410 ppm —    

Polysorbate 40 — 410 ppm —    

Polysorbate 60 — 410 ppm —    

Polysorbate 80 — 410 ppm —  

Table VII: Fatty acid composition of polysorbate 20, 40, 60, 80 from Table IX: Typical properties of selected polysorbates.

 

PhEur 2005.

Fatty acid

Polysorbate

Polysorbate

Polysorbate

Polysorbate Polysorbate HLB value Specific gravity at 258C Viscosity (mPa s)    

20 40 60 80 Polysorbate 20 16.7 1.1 400  

85.0%

Linolenic acid — — — 44.0% Linoleic acid 43.0% — — —

(a) Sum of the contents of palmitic and stearic acids 590.0%.

Typical Properties

Acid value: see Table VIII.

Acidity/alkalinity: pH = 6.0–8.0 for a 5% w/v aqueous solution.

Flash point: 1498C

HLB value: see Table IX. Hydroxyl value: see Table VIII. Moisture content: see Table VIII.

Saponification value: see Table VIII.

Solubility: see Table X.

Specific gravity: see Table IX.

Surface tension: for 0.1% w/v solutions, see Table XI.

Viscosity (dynamic): see Table IX.

Table VIII: Typical properties of selected polysorbates.

 

Polysorbate Acid value (%) Hydroxyl value Moisture content Saponification value    

Polysorbate 20 2.0 96–108 3.0 40–50    

Polysorbate 21 3.0 225–255 3.0 100–115    

Polysorbate 40 2.0 90–105 3.0 41–52    

Polysorbate 60 2.0 81–96 3.0 45–55    

Polysorbate 61 2.0 170–200 3.0 95–115    

Polysorbate 65 2.0 44–60 3.0 88–98    

Polysorbate 80 2.0 65–80 3.0 45–55    

Polysorbate 81 2.0 134–150 3.0 96–104    

Polysorbate 85 2.0 39–52 3.0 80–95    

Polysorbate 120 2.0 65–85 5.0 40–50  



Table X: Solubilities of selected polysorbates in various solvents.

Polysorbate Solvent

 

Ethanol Mineral oil Vegetable oil Water    

Polysorbate 20 S I I S    

Polysorbate 21 S I I D    

Polysorbate 40 S I I S    

Polysorbate 60 S I I S  

Polysorbate 61 SW  SW SWT D Polysorbate 65 SW  SW DW D Polysorbate 80 S I I S

Polysorbate 81 S S ST D

Polysorbate 85 S I ST D

Polysorbate 120 S I I S

D = dispersible; I = insoluble; S = soluble; T = turbid; W = on warming.

Table XI: Surface tension of related polysorbates.

 

Polysorbate Surface tension at 208C (mN/m)    

Polysorbate 21 34.7    

Polysorbate 40 41.5    

Polysorbate 60 42.5    

Polysorbate 61 41.5    

Polysorbate 80 42.5    

Polysorbate 85 41.0  

Stability and Storage Conditions

Polysorbates are stable to electrolytes and weak acids and bases; gradual saponification occurs with strong acids and bases. The oleic acid esters are sensitive to oxidation. Polysorbates are hygroscopic and should be examined for water content prior to use and dried if necessary. Also, in common with other polyoxyethylene surfactants, prolonged storage can lead to the formation of peroxides.

584 Polyoxyethylene Sorbitan Fatty Acid Esters

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

Incompatibilities

Discoloration and/or precipitation occur with various sub- stances, especially phenols, tannins, tars, and tarlike materials. The antimicrobial activity of paraben preservatives is reduced in the presence of polysorbates.(2) See Methylparaben.

Method of Manufacture

Polysorbates are prepared from sorbitol in a three-step process. Water is initially removed from the sorbitol to form a sorbitan (a cyclic sorbitol anhydride). The sorbitan is then partially esterified with a fatty acid, such as oleic or stearic acid, to yield a hexitan ester. Finally, ethylene oxide is chemically added in the presence of a catalyst to yield the polysorbate.

Safety

Polysorbates are widely used in cosmetics, food products, and oral, parenteral, and topical pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. There have, however, been occasional reports of hypersensitiv- ity to polysorbates following their topical and intramuscular use.(3) Polysorbates have also been associated with serious adverse effects, including some deaths, in low-birthweight infants intravenously administered a vitamin E preparation containing a mixture of polysorbates 20 and 80.(4,5) When heated to decomposition, the polysorbates emit acrid smoke and irritating fumes.

The WHO has set an estimated acceptable daily intake for polysorbates 20, 40, 60, 65, and 80, calculated as total polysorbate esters, at up to 25 mg/kg body-weight.(6)

Polysorbate 20: moderate toxicity by IP and IV routes. Moderately toxic by ingestion. Human skin irritant.

LD50 (hamster, oral): 18 g/kg(7) LD50 (mouse, IV): 1.42 g/kg LD50 (rat, oral): 37 g/kg

Polysorbate 21: moderately toxic by IV route.

Polysorbate 40: LD50 (rat, IV): 1.58 g/kg.(7) Moderately toxic by IV route.

Polysorbate 60: LD50 (rat, IV): 1.22 g/kg.(7) Moderately toxic by IV route. Experimental tumorigen; reproductive effects.

Polysorbate 61: moderately toxic by IV route.

Polysorbate 80: moderately toxic by IV route. Mildly toxic by ingestion. Eye irritation. Experimental tumorigen, reproductive effects. Mutogenic data.

LD50 (mouse, IP): 7.6 g/kg(7) LD50 (mouse, IV): 4.5 g/kg LD50 (mouse, oral): 25 g/kg LD50 (rat, IP): 6.8 g/kg

LD50 (rat, IV): 1.8 g/kg

Polysorbate 85: skin irritant.

Handling Precautions

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

Regulatory Status

Polysorbates 60, 65, and 80 are GRAS listed. Polysorbates 20,

40, 60, 65, and 80 are accepted as food additives in Europe.

Polysorbates 20, 40, 60, and 80 are included in the FDA Inactive Ingredients Guide (IM, IV, oral, rectal, topical, and vaginal preparations). Polysorbates are included in parenteral and nonparenteral medicines licensed in the UK. Polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, and 120 are included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Polyethylene glycol; sorbitan esters (sorbitan fatty acid esters).

Comments

—

Specific References

Nerurkar MM, Burton PS, Borchardt RT. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm Res 1996; 13(4): 528–534.

Blanchard J. Effect of polyols on interaction of paraben preservatives with polysorbate 80. J Pharm Sci 1980; 69: 169–173.

Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitiv- ity [letter]. Lancet 1995; 345: 1312–1313.

Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics 1986; 77: 593–597.

Balistreri WF, Farrell MK, Bove KE. Lessons from the E-Ferol tragedy. Pediatrics 1986; 78: 503–506.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications, Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3013.

General References

Allen LV, Levinson RS, Robinson C, Lau A. Effect of surfactant on tetracycline absorption across everted rat intestine. J Pharm Sci 1981; 70: 269–271.

Chowhan ZT, Pritchard R. Effect of surfactants on percutaneous absorption of naproxen I: comparisons of rabbit, rat, and human excised skin. J Pharm Sci 1978; 67: 1272–1274.

Donbrow M, Azaz E, Pillersdorf A. Autoxidation of polysorbates.

J Pharm Sci 1978; 67: 1676–1681.

Khossravi M, Kao Y-H, Mrsny RJ, Sweeney TD. Analysis methods of polysorbate 20: a new method to assess the stability of polysorbate

20 and established methods that may overlook degraded poly- sorbate 20. Pharm Res 2002; 19(5): 634–639.

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

Boca Raton, FL: CRC Press, 1992: 295–301.

Authors

MJ Lawrence.

Date of Revision

22 August 2005.

Polyoxyethylene Stearates

Nonproprietary Names

The polyoxyethylene stearates are a series of polyethoxylated derivatives of stearic acid. Of the large number of different materials commercially available, one type is listed in the USPNF 23.

JP: Polyoxyl 40 stearate USPNF: Polyoxyl 40 stearate See also Sections 2, 3, 4, and 5.

Synonyms

Ethoxylated fatty acid esters; macrogol stearates; Marlosol; PEG fatty acid esters; PEG stearates; polyethylene glycol stearates; poly(oxy-1,2-ethanediyl) a-hydro-o-hydroxyoctade- canoate; polyoxyethylene glycol stearates.

Polyoxyethylene stearates are nonionic surfactants pro- duced by polyethoxylation of stearic acid. Two systems of nomenclature are used for these materials. The number ‘8’ in the names ‘poloxyl 8 stearate’ or ‘polyoxyethylene 8 stearate’ refers to the approximate polymer length in oxyethylene units.

The same material may also be designated ‘polyoxyethylene glycol 400 stearate’ or ‘macrogol stearate 400’ in which case, the number ‘400’ refers to the average molecular weight of the polymer chain.

For synonyms applicable to specific polyoxyethylene stearates, see Table I.

Chemical Name and CAS Registry Number

Polyethylene glycol stearate [9004-99-3] Polyethylene glycol distearate [9005-08-7]

Empirical Formula and Molecular Weight

See Table II.

Table I: Synonyms of selected polyoxyethylene stearates and distearates.

Name Synonym

Polyoxyl 2

stearate Polyoxyl 4

stearate Polyoxyl 6

stearate Polyoxyl 8

stearate

Polyoxyl 12 stearate Polyoxyl 20 stearate Polyoxyl 30 stearate Polyoxyl 40 stearate Polyoxyl 50 stearate

Polyoxyl 100 stearate

Polyoxyl 150 stearate

Polyoxyl 4

distearate Polyoxyl 8

distearate Polyoxyl 12

distearate Polyoxyl 32

distearate Polyoxyl 150 distearate

Hodag DGS; Lipo DGS; PEG-2 stearate.

Acconon 200-MS; Hodag 20-S; PEG-4 stearate; polyethylene glycol 200 monostearate; polyoxyethylene (4) monostearate;

Protamate 200-DPS.

Cerasynt 616; Kessco PEG 300 Monostearate; Lipal 300S; Lipo PEG 3-S; PEG-6 stearate; polyethylene glycol 300 monostearate; polyoxyethylene (6) monostearate; Polystate C; Protamate 300-DPS.

Acconon 400-MS; Cerasynt 660; Cithrol 4MS; Crodet S8; Emerest 2640; Grocor 400; Hodag 40-S; Kessco PEG-400 Monostearate; Lipo-PEG 4-S; macrogol stearate 400; Myrj 45; PEG-8 stearate; Pegosperse 400 MS; polyethylene glycol 400 monostearate; polyoxyethylene (8) monostearate; Protamate 400-DPS; Ritapeg 400 MS.

Hodag 60-S; Kessco PEG 600 Monostearate; Lipo-PEG 6-S; PEG-12 stearate; Pegosperse 600 MS; polyethylene glycol 600 monostearate; polyoxyethylene (12) monostearate; Protamate 600-DPS.

Cerasynt 840; Hodag 100-S; Kessco PEG 1000 Monostearate; Lipo-PEG 10-S; Myrj 49; Pegosperse 1000 MS; PEG-20 stearate; polyethylene glycol 1000 monostearate; polyoxyethylene (20) monostearate; Protamate 1000-DPS.

Myrj 51; PEG-30 stearate; polyoxyethylene (30) stearate.

Crodet S40; E431; Emerest 2672; Hodag POE (40) MS; Lipal 395; Lipo-PEG 39-S; macrogol stearate 2000; Myrj 52; PEG-40 stearate; polyoxyethylene glycol 2000 monostearate; polyoxyethylene (40) monostearate; Protamate 2000-DPS; Ritox 52.

Atlas G-2153; Crodet S50; Lipal 505; Myrj 53; PEG-50 stearate; polyoxyethylene (50) monostearate.

Lipo-PEG 100-S; Myrj 59; PEG-100 stearate; polyethylene glycol 4400 monostearate; polyoxyethylene (100) monostearate;

Protamate 4400-DPS; Ritox 53.

Hodag 600-S; PEG-150 stearate; Ritox 59. Hodag 22-S; PEG-4 distearate.

Hodag 42-S; Kessco PEG 400 DS; PEG-8 distearate; polyethylene glycol 400 distearate; Protamate 400-DS.

Hodag 62-S; Kessco PEG 600 Distearate; PEG-12 distearate; polyethylene (12) distearate; polyethylene glycol 600 distearate;

Protamate 600-DS.

Hodag 154-S; Kessco PEG 1540 Distearate; PEG-32 distearate; polyethylene glycol 1540 distearate; polyoxyethylene (32) distearate.

Hodag 602-S; Kessco PEG 6000 DS; Lipo-PEG 6000-DS; PEG-150 distearate; polyethylene glycol 6000 distearate; polyoxyethylene (150) distearate; Protamate 6000-DS.

586 Polyoxyethylene Stearates

Table II: Empirical formulas and molecular weights of selected polyoxyethylene stearates.

Name Empirical formula Molecular weight

Table III: Uses of polyoxyethylene stearates.

Use Concentration (%)

Auxiliary emulsifier for o/w intravenous fat 0.5–5

Structural Formula

 

Structure A applies to the monostearate; where the average value of n is 6 for polyoxyl 6 stearate, 8 for polyoxyl 8 stearate, and so on.

Structure B applies to the distearate; where the average value of n is 12 for polyoxyl 12 distearate, 32 for polyoxyl 32 distearate, and so on.

In both structures, R represents the alkyl group of the parent fatty acid. With stearic acid, R is CH3(CH2)16. However, it should be noted that stearic acid usually contains other fatty acids, primarily palmitic acid, and consequently a polyox- yethylene stearate may also contain varying amounts of other fatty acid derivatives such as palmitates.

Functional Category

Emulsifying agent; solubilizing agent; wetting agent.

Applications in Pharmaceutical Formulation or Technology

Polyoxyethylene stearates are generally used as emulsifiers in oil-in-water-type creams and lotions. Their hydrophilicity or lipophilicity depends on the number of ethylene oxide units present: the larger the number, the greater the hydrophilic properties. Polyoxyl 40 stearate has been used as an emulsifying agent in intravenous infusions.(1)

Polyoxyethylene stearates are particularly useful as emulsi- fying agents when astringent salts or other strong electrolytes are present. They can also be blended with other surfactants to obtain any hydrophilic–lipophilic balance for lotions or ointment formulations. See Table III.



Table IV: Description of various polyoxyethylene stearates.

Name Description

Polyoxyl 6 stearate Soft solid

Polyoxyl 8 stearate Waxy cream

Polyoxyl 12 stearate Pasty solid

Polyoxyl 20 stearate Waxy solid

Polyoxyl 40 stearate Waxy solid, with a faint, bland, fat-like

odor, off-white to light tan in color Polyoxyl 50 stearate Solid, with a bland, fat-like odor or

odorless Polyoxyl 100 stearate Solid Polyoxyl 12 distearate Paste Polyoxyl 32 distearate Solid Polyoxyl 150 distearate Solid

Pharmacopeial Specifications

See Table V.

Table V: Pharmacopeial specifications for polyoxyethylene stearates.

 

Test JP 2001 USPNF 23    

Polyoxyl 40 stearate Polyoxyl 40 stearate    

Identification + +    

Clarity and color of + —  

solution

Congealing range 39–448C 37–478C

Congealing point of the 5538C — fatty acid

 

Residue on ignition 40.10% —    

Water — 43.0%    

Arsenic 43 ppm —    

Heavy metals 410 ppm 40.001%    

Acid value 41 42    

Hydroxyl value — 25–40    

Saponification value 25–35 25–35    

Free polyethylene — 17–27%    

glycols

Organic volatile

— +    

impurities  

Typical Properties

Flash point: >1498C for poloxyl 8 stearate (Myrj 45).

Solubility: see Table VI. See also Table VII.

Polyoxyethylene Stearates 587

Table VI: Solubility of polyoxyethylene stearates.

Name Solvent

14 Safety

Although polyoxyethylene stearates are primarily used as

emulsifying agents in topical pharmaceutical formulations,

Ethanol (95%) Mineral oil Water

Polyoxyl 6 stearate S S DH

Polyoxyl 8 stearate S I D

Polyoxyl 12 stearate S I S

Polyoxyl 20 stearate S I S

Polyoxyl 40 stearate S I S

Polyoxyl 50 stearate S I S

Polyoxyl 100 stearate S I S

Polyoxyl 12 distearate S — DH

Polyoxyl 32 distearate S — S

Polyoxyl 150 distearate I — S

D = dispersible; I = insoluble; S = soluble; DH = dispersible (with heat).

Stability and Storage Conditions

Polyoxyethylene stearates are generally stable in the presence of electrolytes and weak acids or bases. Strong acids and bases can cause gradual hydrolysis and saponification.

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