Polyoxyethylene Sorbitan Fatty Acid Esters 549

41 Liebmann J et al. Cremophor EL, solvent for paclitaxel, and toxicity. 50 Lin SY et al. In vitro release, pharmacokinetic and tissue distribution Lancet 1993; 342: 1428. studies of doxorubicin hydrochloride (adriamycin HCl (R)) encapsu- 42 Badary OA et al. Effect of Cremophor EL on the pharmacokinetics, lated in lipiodolized w/o emulsions and w/o/w multiple emulsions. antitumor activity and toxicity of doxorubicin in mice. Anticancer Pharmazie 1992; 47: 439–443. Drugs 1998; 9: 809–815. 43 Sanchez H et al. Immunosuppressive treatment affects cardiac and 20 General References skeletal muscle mitochondria by the toxic effect of vehicle. J Mol Cell Cardiol 2000; 32: 323–331. BASF Corporation. Technical literature: Cremophor EL, Castor Oil, June 44 Bowers VD et al. The hemodynamic effects of Cremophor-EL. 2008. Transplantation 1991; 51: 847–850. BASF Corporation. Technical literature: Cremophor ELP, July 2008. 45 Verani R. Cyclosporin nephrotoxicity in the Fischer rat. Clin Nephrol BASF Corporation. Technical literature: Cremophor RH 40, November 1986; 25( Suppl 1): S9–13. 2008. 46 Thiel G et al. Acutely impaired renal function during the intravenous Rischin D et al. Cremophor pharmacokinetics in patients receiving 3, 6, and administration of cyclosporin A: a cremophore side-effect. Clin Nephrol 24 hour infusions of paclitaxel. J Natl Cancer Inst 1996; 88: 1297–1301. 1986; 25( Suppl 1): S40–42. 47 Windebank AJ et al. Potential neurotoxicity of the solvent vehicle for cyclosporin. J Pharmacol Exp Ther 1994; 268: 1051–1056. 21 Author 48 Kiorpes AL et al. Pulmonary changes in rats following the administra- KK Singh. tion of 3-methylindole in Cremophor EL. Histol Histopathol 1988; 3: 125–132. 22 Date of Revision 49 Venkatesan N et al. Gastro-intestinal patch system for the delivery of erythropoietin. J Control Rel 2006; 111: 19–26. 10 March 2009.

Polyoxyethylene Sorbitan Fatty Acid Esters

1 Nonproprietary Names 5 Structural Formula BP: 20 Polysorbate 40 Polysorbate 60 JP: Polysorbate 80 PhEur: Polysorbate 40 Polysorbate 60 Polysorbate 80 P USP-NF: Polysorbate 20 Polysorbate 40 Polysorbate 60 Polysorbate 80

2 Synonyms For synonyms of selected , see Table I; see also Section 3.

3 Chemical Names and CAS Registry Numbers See Table II.

4 Empirical Formula and Molecular Weight Approximate molecular weights for selected polysorbates are shown in Table III.

Table III: Empirical formula and molecular weight of selected polysorbates. Polysorbate Formula Molecular weight

Polysorbate 20 C58H114O26 1128 Polysorbate 21 C26H50O10 523 þ þ þ Polysorbate 40 C H O 1284 w x y z = 20 (Polysorbates 20, 40, 60, 65, 80, and 85) 62 122 26 þ þ þ Polysorbate 60 C64H126O26 1312 w x y z = 5 (Polysorbates 81) Polysorbate 61 C32H62O10 607 w þ x þ y þ z = 4 (Polysorbates 21 and 61) Polysorbate 65 C100H194O28 1845 R = fatty acid Polysorbate 80 C64H124O26 1310 Polysorbate 81 C34H64O11 649 Polysorbate 85 C100H188O28 1839 Polysorbate 120 C64H126O26 1312 550 Polyoxyethylene Sorbitan Fatty Acid Esters

Table I: Synonyms of selected polysorbates. Polysorbate Synonym

Polysorbate 20 Armotan PML 20; Capmul POE-L; Campul POE-L Low PV; Crillet 1; Drewmulse; E432; Durfax 20; E432; Eumulgin SML; Glycosperse L -20; Hodag PSML-20; Lamesorb SML-20; Liposorb L-20; Liposorb L-20K; Montanox 20; Nissan Nonion LT-221; Norfox Sorbo T-20; POE- SML; polysorbatum 20; Ritabate 20; Sorbax PML-20; sorbitan monododecanoate; Sorgen TW-20; T-Maz 20; T-Maz 20K; poly(oxy- 1,2-ethanediyl) derivatives; polyoxyethylene 20 laurate; Protasorb L-20; Tego SML 20; Tween 20. Polysorbate 21 Crillet 11; Hodag PSML-4; Protasorb L-5; Tween 21. Polysorbate 40 Crillet 2; E434; Eumulgin SMP; Glycosperse S-20; Hodag PSMP-20; Lamesorb SMP-20; Liposorb P-20; Lonzest SMP-20; Montanox 40; poly(oxy-1,2-ethanediyl) derivatives; polysorbatum 40; Protasorb P-20; Ritabate 40; sorbitan monohexadecanoate; Sorbax PMP-20; Tween 40. Polysorbate 60 Atlas 70K; Atlas Armotan PMS 20; Capmul POE-S; Cremophor PS 60; Crillet 3; Drewpone 60K; Durfax 60; Durfax 60K; E435; Emrite 6125; Eumulgin SMS; Glycosperse S-20; Glycosperse S-20FG; Glycosperse S-20FKG; Hodag PSMS-20; Hodag SVS-18; Lamsorb SMS-20; Liposorb S-20; Liposorb S-20K; Lonzest SMS-20; Montanox 60; Nikkol TS-10; Norfox SorboT-60; Polycon T 60 K; polyoxyethylene 20 stearate; polysorbatum 60; Protasorb S-20; Ritabate 60; Sorbax PMS-20; sorbitan monooctadecanoate poly(oxy- 1,2-ethanediyl) derivatives; T-Maz 60; T-Max 60KHS; Tween 60; Tween 60K; Tween 60 VS. Polysorbate 61 Crillet 31; Hodag PSMS-4; Liposorb S-4; Protasorb S-4; Tween 61. Polysorbate 65 Alkamuls PSTS-20; Crillet 35; E436; Glycosperse TS-20; Glycosperse TS-20 FG; Glycosperse TS-20 KFG; Hodag PSTS-20; Lamesorb STS- 20; Lanzet STS-20; Liposorb TS-20; Liposorb TS-20A; Liposorb TS-20K; Montanox 65; Protasorb STS-20; Sorbax PTS-20; sorbitan trioctadecanoate poly(oxy-1,2-ethanediyl) derivatives; T-Maz 65K; Tween 65; Tween 65K; Tween 65V. Polysorbate 80 Atlas E; Armotan PMO 20; Capmul POE-O; Cremophor PS 80; Crillet 4; Crillet 50; Drewmulse POE-SMO; Drewpone 80K; Durfax 80; Durfax 80K; E433; Emrite 6120; Eumulgin SMO; Glycosperse O-20; Hodag PSMO-20; Liposorb O-20; Liposorb O-20K; Montanox 80; polyoxyethylene 20 oleate; polysorbatum 80; Protasorb O-20; Ritabate 80;(Z)-sorbitan mono-9-octadecenoate poly(oxy1,2- ethanediyl) derivatives; Tego SMO 80; Tego SMO 80V; Tween 80. Polysorbate 81 Crillet 41; Hetsorb O-5; Hodag PSMO-5; Protasorb O-5; Sorbax PMO-5; sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives; T-Maz 81; Tego SMO 81; Tween 81. Polysorbate 85 Alkamuls PSTO-20; Crillet 45; Glycosperse TO-20; Hodag PSTO-20; Liposorb TO-20; Lonzest STO-20; Montanox 85; Protasorb TO-20; Sorbax PTO-20; sorbitan tri-9-octadecenoate poly(oxy1,2-ethanediyl) derivatives; Tego STO 85; Tween 85. Polysorbate 120 Crillet 6.

6 Functional Category Table II: Chemical names and CAS Registry Numbers of selected polysorbates. Dispersing agent; emulsifying agent; nonionic ; solubiliz- ing agent; suspending agent; wetting agent. Polysorbate Chemical name CAS number Polysorbate 20 Polyoxyethylene 20 sorbitan [9005-64-5] monolaurate 7 Applications in Pharmaceutical Formulation or Polysorbate 21 Polyoxyethylene (4) sorbitan [9005-64-5] monolaurate Technology Polysorbate 40 Polyoxyethylene 20 sorbitan [9005-66-7] Polyoxyethylene sorbitan fatty acid esters (polysorbates) are a series P monopalmitate of partial fatty acid esters of and its anhydrides Polysorbate 60 Polyoxyethylene 20 sorbitan [9005-67-8] copolymerized with approximately 20, 5, or 4 moles of ethylene monostearate Polysorbate 61 Polyoxyethylene (4) sorbitan [9005-67-8] oxide for each mole of sorbitol and its anhydrides. The resulting monostearate product is therefore a mixture of molecules of varying sizes rather Polysorbate 65 Polyoxyethylene 20 sorbitan tristearate [9005-71-4] than a single uniform compound. Polysorbate 80 Polyoxyethylene 20 sorbitan [9005-65-6] Polysorbates containing 20 units of oxyethylene are hydrophilic monooleate nonionic that are used widely as emulsifying agents in Polysorbate 81 Polyoxyethylene (5) sorbitan [9005-65-6] the preparation of stable oil-in-water pharmaceutical emulsions. monooleate Polysorbate 85 Polyoxyethylene 20 sorbitan trioleate [9005-70-3] They may also be used as solubilizing agents for a variety of Polysorbate 120Polyoxyethylene 20 sorbitan [66794-58-9] substances including essential oils and oil-soluble vitamins, and as monoisostearate wetting agents in the formulation of oral and parenteral suspen- sions. They have been found to be useful in improving the oral bioavailability of drug molecules that are substrates for P- glycoprotein.(1,2) Polysorbates are also widely used in cosmetics and food products. See Table IV. Table IV: Uses of polysorbates. Use Concentration (%) 8 Description Emulsifying agent Polysorbates have a characteristic odor and a warm, somewhat Used alone in oil-in-water emulsions 1–15 8 Used in combination with hydrophilic emulsifiers in 1–10 bitter taste. Their colors and physical forms at 25 C are shown in oil-in-water emulsions Table V, although it should be noted that the absolute color intensity Used to increase the water-holding properties of 1–10 of the products may vary from batch to batch and from ointments manufacturer to manufacturer. Solubilizing agent For poorly soluble active constituents in lipophilic 1–15 bases Wetting agent 9 Pharmacopeial Specifications For insoluble active constituents in lipophilic bases 0.1–3 See Tables VI and VII. See also Section 18. Polyoxyethylene Sorbitan Fatty Acid Esters 551

Table V: Colors and physical forms of selected polysorbates at 258C. Table IX: Typical properties of selected polysorbates. Polysorbate Color and form at 258C Polysorbate HLB value Specific gravity at 258C Viscosity (mPa s) Polysorbate 20 Yellow oily liquid Polysorbate 20 16.7 1.1 400 Polysorbate 21 Yellow oily liquid Polysorbate 21 13.3 1.1 500 Polysorbate 40 Yellow oily liquid Polysorbate 40 15.6 1.08 500 Polysorbate 60 Yellow oily liquid Polysorbate 60 14.9 1.1 600 Polysorbate 61 Tan solid Polysorbate 61 9.6 1.06 Solid Polysorbate 65 Tan solid Polysorbate 65 10.5 1.05 Solid Polysorbate 80 Yellow oily liquid Polysorbate 80 15.0 1.08 425 Polysorbate 81 Amber liquid Polysorbate 81 10.0 — 450 Polysorbate 85 Amber liquid Polysorbate 85 11.0 1.00 300 Polysorbate 120 Yellow liquid Polysorbate 120 14.9 — —

Table VII: Fatty acid composition of polysorbate 20, 40, 60 from PhEur Table X: Solubilities of selected polysorbates in various solvents. 6.3 and polysorbate 80 from PhEur 6.5. Polysorbate Solvent Fatty acid Polysorbate Polysorbate Polysorbate Polysorbate 20 40 60 80 Ethanol Mineral oil Vegetable oil Water 4 Caproic acid 1.0% — — — Polysorbate 20 S I I S 4 Caprylic 10.0% — — — Polysorbate 21 S I I D acid Polysorbate 40 S I I S 4 Capric acid 10.0% — — — Polysorbate 60 S I I S Lauric acid 40.0–60.0% — — — Polysorbate 61 SW SW SWT D 4 Myristic acid 14.0–25.0% — — 5.0% Polysorbate 65 SW SW DW D 5 þ(a) 4 Palmitic acid 7.0–15.0% 92.0% 16.0% Polysorbate 80 S I I S 4 Palmitoleic ——— 8.0% Polysorbate 81 S S ST D acid Polysorbate 85 S I ST D 4 4 Stearic acid 7.0% — 40.0–60.0% 6.0% Polysorbate 120 S I I S Oleic acid 411.0% — — 58.0% Linolenic ——— 44.0% D = dispersible; I = insoluble; S = soluble; T = turbid; W = on warming. acid Linoleic acid 43.0% — — 418.0% Table XI: Surface tension of related polysorbates. (a) Sum of the contents of palmitic and stearic acids 590.0%. Polysorbate Surface tension at 208C (mN/m) Polysorbate 21 34.7 10 Typical Properties Polysorbate 40 41.5 Acid value see Table VIII. Polysorbate 60 42.5 P Acidity/alkalinity pH = 6.0–8.0 for a 5% w/v aqueous solution. Polysorbate 61 41.5 Flash point 1498C Polysorbate 80 42.5 HLB value see Table IX. Polysorbate 85 41.0 Hydroxyl value see Table VIII. Moisture content see Table VIII. acid esters are sensitive to oxidation. Polysorbates are hygroscopic Saponification value see Table VIII. and should be examined for water content prior to use and dried if Solubility see Table X. necessary. Also, in common with other polyoxyethylene surfactants, Specific gravity see Table IX. prolonged storage can lead to the formation of peroxides. Surface tension For 0.1% w/v solutions, see Table XI. Viscosity (dynamic) see Table IX. Polysorbates should be stored in a well-closed container, protected from light, in a cool, dry place. Table VIII: Typical properties of selected polysorbates. 12 Incompatibilities Polysorbate Acid value (%) Hydroxyl Moisture Saponification Discoloration and/or precipitation occur with various substances, value content value especially phenols, tannins, tars, and tarlike materials. The Polysorbate 20 2.0 96–108 3.0 40–50 antimicrobial activity of paraben preservatives is reduced in the Polysorbate 21 3.0 225–255 3.0 100–115 presence of polysorbates.(3) See Methylparaben. 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 13 Method of Manufacture Polysorbate 65 2.0 44–60 3.0 88–98 Polysorbates are prepared from sorbitol in a three-step process. Polysorbate 80 2.0 65–80 3.0 45–55 Water is initially removed from the sorbitol to form a sorbitan (a Polysorbate 81 2.0 134–150 3.0 96–104 cyclic sorbitol anhydride). The sorbitan is then partially esterified Polysorbate 85 2.0 39–52 3.0 80–95 with a fatty acid, such as oleic or stearic acid, to yield a hexitan ester. Polysorbate 120 2.0 65–85 5.0 40–50 Finally, ethylene oxide is chemically added in the presence of a catalyst to yield the polysorbate.

11 Stability and Storage Conditions 14 Safety Polysorbates are stable to electrolytes and weak acids and bases; Polysorbates are widely used in cosmetics, food products, and oral, gradual saponification occurs with strong acids and bases. The oleic parenteral and topical pharmaceutical formulations, and are 552 Polyoxyethylene Sorbitan Fatty Acid Esters

Table VI: Pharmacopeial specifications for polysorbates. Test JP XV PhEur 6.3 and 6.5(a) USP32–NF27 Identification Polysorbate 20 — þþ Polysorbate 40 — þþ Polysorbate 60 — þþ Polysorbate 80 þþþ Characters — þ — 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 40.1% 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 P 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/s 400 mPa s 300–500 mm2/s 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 Polysorbate 20 — 410 ppm — Polysorbate 40 — 410 ppm — Polysorbate 60 — 410 ppm — Polysorbate 80 — 410 ppm —

(a) Polysorbate 80 is PhEur 6.5. Polyoxyethylene Sorbitan Fatty Acid Esters 553 generally regarded as nontoxic and nonirritant materials. There 18 Comments have, however, been occasional reports of hypersensitivity to (4) Polysorbate 80 is one of the materials that have been selected for polysorbates following their topical and intramuscular use. harmonization by the Pharmacopeial Discussion Group. For further Polysorbates have also been associated with serious adverse effects, information see the General Information Chapter <1196> in the including some deaths, in low-birthweight infants intravenously USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the administered a vitamin E preparation containing a mixture of ‘ ’ (5,6) State of Work document on the PhEur EDQM website, and also polysorbates 20 and 80. When heated to decomposition, the the General Information Chapter 8 in the JP XV. polysorbates emit acrid smoke and irritating fumes. The PubChem Compound ID (CID) for polysorbates includes The WHO has set an estimated acceptable daily intake for 443314 and 5281955. polysorbates 20, 40, 60, 65, and 80, calculated as total polysorbate esters, at up to 25 mg/kg body-weight.(7) 19 Specific References Polysorbate 20 Moderate toxicity by IP and IV routes. Moder- ately toxic by ingestion. Human skin irritant. 1 Nerurkar MM et al. The use of surfactants to enhance the permeability (8) of peptides through Caco-2 cells by inhibition of an apically polarized LD50 (hamster, oral): 18 g/kg efflux system. Pharm Res 1996; 13(4): 528–534. LD50 (mouse, IV): 1.42 g/kg 2 Zhang H et al. Commonly used surfactant, Tween 80, improves LD (rat, oral): 37 g/kg absorption of P-glycoprotein substrate, digoxin, in rats. Arch Pharm 50 Res 2003; 26: 768–772. Polysorbate 21 Moderately toxic by IV route. 3 Blanchard J. Effect of polyols on interaction of paraben preservatives Polysorbate 40 Moderately toxic by IV route. with polysorbate 80. J Pharm Sci 1980; 69: 169–173. (8) LD50 (rat, IV): 1.58 g/kg. 4 Shelley WB et al. Polysorbate 80 hypersensitivity [letter]. Lancet 1995; Polysorbate 60 Moderately toxic by IV route. Experimental 345: 1312–1313. tumorigen; reproductive effects. 5 Alade SL et al. Polysorbate 80 and E-Ferol toxicity. Pediatrics 1986; 77: (8) 593–597. LD50 (rat, IV): 1.22 g/kg. Polysorbate 61 Moderately toxic by IV route. 6 Balistreri WF et al. Lessons from the E-Ferol tragedy. Pediatrics 1986; Polysorbate 80 Moderately toxic by IV route. Mildly toxic by 78: 503–506. 7 FAO/WHO. Toxicological evaluation of certain food additives with a ingestion. Eye irritation. Experimental tumorigen, reproduc- review of general principles and of specifications, Seventeenth report of tive effects. Mutagenic data. the joint FAO/WHO expert committee on food additives. World Health (8) LD50 (mouse, IP): 7.6 g/kg Organ Tech Rep Ser 1974; No. 539. LD (mouse, IV): 4.5 g/kg 8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th 50 edn. New York: Wiley, 2004; 3013. LD50 (mouse, oral): 25 g/kg LD50 (rat, IP): 6.8 g/kg 20 General References LD50 (rat, IV): 1.8 g/kg Allen LV et al. Effect of surfactant on tetracycline absorption across everted Polysorbate 85 Skin irritant. rat intestine. J Pharm Sci 1981; 70: 269–271. Chowhan ZT, Pritchard R. Effect of surfactants on percutaneous absorption 15 Handling Precautions of naproxen I: comparisons of rabbit, rat, and human excised skin. J Pharm Sci 1978; 67: 1272–1274. Observe normal precautions appropriate to the circumstances and Donbrow M et al. Autoxidation of polysorbates. J Pharm Sci 1978; 67: quantity of material handled. Eye protection and gloves are 1676–1681. P recommended. European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia – State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edq- 16 Regulatory Status m.eu/site/-614.html (accessed 3 February 2009). Polysorbates 60, 65, and 80 are GRAS listed. Polysorbates 20, 40, Khossravi M et al. Analysis methods of polysorbate 20: a new method to 60, 65, and 80 are accepted as food additives in Europe. assess the stability of polysorbate 20 and established methods that may Polysorbates 20, 40, 60, and 80 are included in the FDA Inactive overlook degraded polysorbate 20. Pharm Res 2002; 19(5): 634–639. Ingredients Database (IM, IV, oral, rectal, topical, and vaginal Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca preparations). Polysorbates are included in parenteral and non- Raton, FL: CRC Press, 1992; 295–301. parenteral medicines licensed in the UK. Polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, and 120 are included in the Canadian List of 21 Author Acceptable Non-medicinal Ingredients. D Zhang.

17 Related Substances 22 Date of Revision Polyethylene glycol; sorbitan esters (sorbitan fatty acid esters). 3 February 2009.