Method of Manufacture

Naturally occurring sorbic acid may be extracted as the lactone (parasorbic acid) from the berries of the mountain ash Sorbus aucuparia L. (Fam. Rosaceae). Synthetically, sorbic acid may be prepared by the condensation of crotonaldehyde and ketene in the presence of boron trifluoride; by the condensation of crotonaldehyde and malonic acid in pyridine solution; or from 1,1,3,5-tetraalkoxyhexane. Fermentation of sorbaldehyde or sorbitol with bacteria in a culture medium has also been used.

Safety

Sorbic acid is used as an antimicrobial preservative in oral and topical pharmaceutical formulations and is generally regarded as a nontoxic material. However, adverse reactions to sorbic acid and potassium sorbate, including irritant skin reac- tions(8–11) and allergic hypersensitivity skin reactions (which are less frequent), have been reported.(12–14)

Other adverse reactions that have been reported include exfoliative dermatitis due to ointments that contain sorbic acid,(15) and allergic conjunctivitis caused by contact lens solutions preserved with sorbic acid.(16)

No adverse reactions have been described after systemic administration of sorbic acid, and it has been reported that it can be ingested safely by patients who are allergic to sorbic acid.(17) However, perioral contact urticaria has been reported.(11)

The WHO has set an estimated total acceptable daily intake for sorbic acid, calcium sorbate, potassium sorbate, and sodium sorbate, expressed as sorbic acid, at up to 25 mg/kg body- weight.(18,19)

Animal toxicological studies have shown no mammalian carcinogenicity or teratogenicity for sorbic acid consumed at up to 10% of the diet.(20)

LD50 (mouse, IP): 2.82 g/kg(21) LD50 (mouse, oral): 3.20 g/kg LD50 (mouse, SC): 2.82 g/kg LD50 (rat, oral): 7.36 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sorbic acid can be irritant to the skin, eyes, and respiratory system. Eye protection, gloves, and a dust mask or respirator are recommended.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (ophthalmic solutions; oral capsules, solutions, syrups, tablets, topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

712 Sorbic Acid

Related Substances

Calcium sorbate; potassium sorbate; sodium sorbate.

Calcium sorbate

Empirical formula: C12H14O4Ca

Synonyms: E203

Molecular weight: 262.33

CAS number: [7492-55-9]

Appearance: white, odorless, tasteless, crystalline powder.

Solubility: soluble 1 in 83 parts of water; practically insoluble in fats.

Comments: the EINECS number for calcium sorbate is 231- 321-6.

Sodium sorbate

Empirical formula: C6H7O2Na

Synonyms: E201; sodium (E,E)-hexa-2,4-dienoate.

Molecular weight: 134.12

CAS number: [42788-83-0]

Appearance: light, white, crystalline powder.

Solubility: soluble 1 in 3 parts of water.

Comments: the EINECS number for sodium sorbate is 231- 819-3.

Comments

The trans,trans-isomer of sorbic acid is the commercial product. A specification for sorbic acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for sorbic acid is 203-768-7.

Specific References

Charvalos E, Tzatzarakis M, Tsatsakis A, Petrikkos G. Controlled release of water-soluble polymeric complexes of sorbic acid with antifungal activities. Appl Microbiol Biotechnol 2001; 57(5–6): 770–775.

Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989: 179.

Van-Doorne H, Leijen JB. Preservation of some oral liquid preparations: replacement of chloroform by other preservatives. Pharm World Sci 1994; 16(Feb 18): 18–21.

Golightly LK, Smolinske SS, Bennett ML, et al. Adverse effects associated with inactive ingredients in drug products (part I). Med Toxicol 1988; 3: 128–165.

Eklund T. The antimicrobial effect of dissociated and undissociated sorbic acid at different pH levels. J Appl Bacteriol 1983; 54: 383– 389.

Woodford R, Adams E. Sorbic acid. Am Perfum Cosmet 1970;

85(3): 25–30.

Wallha¨ usser KH. Sorbic acid. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 668–670.

�Soschin D, Leyden JJ. Sorbic acid-induced erythema and edema. J Am Acad Dermatol 1986; 14: 234–241.

Fisher AA. Erythema limited to the face due to sorbic acid. Cutis

1987; 40: 395–397.

Clemmensen OJ, Schiodt M. Patch test reaction of the buccal mucosa to sorbic acid. Contact Dermatitis 1982; 8(5): 341–342.

Clemmensen O, Hjorth N. Perioral contact urticaria from sorbic acid and benzoic acid in a salad dressing. Contact Dermatitis 1982; 3: 1–6.

Saihan EM, Harman RRM. Contact sensitivity to sorbic acid in ‘Unguentum Merck’. Br J Dermatol 1978; 99: 583–584.

Fisher AA. Cutaneous reactions to sorbic acid and potassium sorbate. Cutis 1980; 25: 350, 352, 423.

Fisher AA. Allergic reactions to the preservatives in over-the- counter hydrocortisone topical creams and lotions. Cutis 1983; 32: 222, 224, 230.

Coyle HE, Miller E, Chapman RS. Sorbic acid sensitivity from Unguentum Merck. Contact Dermatitis 1981; 7: 56–57.

Fisher AA. Allergic reactions to contact lens solutions. Cutis 1985;

36: 209–211.

Klaschka F, Beiersdorff HU. Allergic eczematous reaction from sorbic acid used as a preservative in external medicaments. Munch Med Wschr 1965; 107: 185–187.

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.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1986; No. 733.

Walker R. Toxicology of sorbic acid and sorbates. Food Addit Contam 1990; 7(5): 671–676.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3291.

General References

Radus TP, Gyr G. Determination of antimicrobial preservatives in pharmaceutical formulations using reverse-phase liquid chromato- graphy. J Pharm Sci 1983; 72: 221–224.

Sofos JN, Busta FF. Sorbates. In: Branen AL, Davidson PM, eds. Antimicrobials in Foods. New York: Marcel Dekker, 1983: 141– 175.

Warth A. Mechanism of resistance of Saccharomyces bailii to benzoic, sorbic and other weak acids used as food preservatives. J Appl Bacteriol 1977; 43: 215–230.

Authors

W Cook.

Date of Revision

4 August 2005.

Sorbitan Esters (Sorbitan Fatty Acid Esters)

Nonproprietary Names

BP: Sorbitan laurate Sorbitan oleate Sorbitan palmitate Sorbitan stearate

�Table II: Chemical name and CAS Registry Number of selected sorbitan esters.

Name Chemical name CAS number

Sorbitan diisostearate Sorbitan diisooctadecanoate [68238-87-9]

Sorbitan trioleate

JP: Sorbitan sesquioleate

�Sorbitan dioleate (Z,Z)-Sorbitan di-9-

octadecanoate

�[29116-98-1]

PhEur: Sorbitani lauras Sorbitan monolaurate Sorbitan monododecanoate [1338-39-2]

Sorbitani oleas Sorbitani palmitas Sorbitani sesquioleas Sorbitani stearas

�Sorbitan monoisostearate Sorbitan

monoisooctadecanoate Sorbitan monooleate (Z)-Sorbitan mono-9-

octadecenoate

�[71902-01-7]

[1338-43-8]

Sorbitani trioleas

USPNF: Sorbitan  monolaurate  (sorbitan,  esters  mono-

�Sorbitan monopalmitate Sorbitan monohexadecanoate[26266-57-9] Sorbitan monostearate Sorbitan mono-octadecanoate [1338-41-6]

decanoate)

Sorbitan monooleate Sorbitan monopalmitate Sorbitan monostearate

�Sorbitan sesquiisostearateSorbitan

sesquiisooctadecanoate Sorbitan sesquioleate (Z)-Sorbitan sesqui-9-

octadecenoate

�[71812-38-9]

[8007-43-0]

Sorbitan sesquioleate Sorbitan trioleate

�Sorbitan sesquistearate Sorbitan sesqui-octadecanoate[51938-44-4] Sorbitan triisostearate Sorbitan triisooctadecanoate [54392-27-7]

Sorbitan trioleate (Z,Z,Z)-Sorbitan tri-9-

octadecenoate

�[26266-58-0]

Synonyms

See Table I.

Chemical Names and CAS Registry Numbers

See Table II.

�Sorbitan tristearate Sorbitan tri-octadecanoate [26658-19-5]

Empirical Formula and Molecular Weight

See Table III.

Table I: Synonyms of selected sorbitan esters.

Name Synonym

Sorbitan monoisostearate 1,4-Anhydro-D-glucitol, 6-isooctadecanoate; anhydrosorbitol monoisostearate; Arlacel 987; Crill 6; sorbitan isostearate. Sorbitan monolaurate Arlacel 20; Armotan ML; Crill 1; Dehymuls SML; E493; Glycomul L; Hodag SML; Liposorb L; Montane 20; Protachem

SML; Sorbester P12; Sorbirol L; sorbitan laurate; Span 20; Tego SML.

Sorbitan monooleate Ablunol S-80; Arlacel 80; Armotan MO; Capmul O; Crill 4; Crill 50; Dehymuls SMO; Drewmulse SMO; Drewsorb 80K; E494; Glycomul O; Hodag SMO; Lamesorb SMO; Liposorb O; Montane 80; Nikkol SO-10; Nissan Nonion OP- 80R; Norfox Sorbo S-80; Polycon S80 K; Proto-sorb SMO; Protachem SMO; S-Maz 80K; Sorbester P17; Sorbirol O; sorbitan oleate; Sorgen 40; Sorgon S-40-H; Span 80; Tego SMO.

Sorbitan monopalmitate 1,4-Anhydro-D-glucitol, 6-hexadecanoate; Ablunol S-40; Arlacel 40; Armotan MP; Crill 2; Dehymuls SMP; E495; Glycomul P; Hodag SMP; Lamesorb SMP; Liposorb P; Montane 40; Nikkol SP-10; Nissan Nonion PP-40R; Protachem SMP; Proto-sorb SMP; Sorbester P16; Sorbirol P; sorbitan palmitate; Span 40.

Sorbitan monostearate Ablunol S-60; Alkamuls SMS; 1,4-Anhydro-D-glucitol, 6-octadecanoate; anhydrosorbitol monostearate; Arlacel 60; Armotan MS; Atlas 110K; Capmul S; Crill 3; Dehymuls SMS; Drewmulse SMS; Drewsorb 60K; Durtan 6O; Durtan 60K; E491; Famodan MS Kosher; Glycomul S FG; Glycomul S KFG; Hodag SMS; Lamesorb SMS; Liposorb S; Liposorb SC; Liposorb S-K; Montane 60; Nissan Nonion SP-60R; Norfox Sorbo S-60FG; Polycon S60K; Protachem SMS; Prote-sorb SMS; S-Maz 60K; S-Maz 60KHS; Sorbester P18; Sorbirol S; sorbitan stearate; Sorgen 50; Span 60; Span 60K; Span 60 VS; Tego SMS.

Sorbitan sesquiisostearate Protachem SQI.

Sorbitan sesquioleate Arlacel C; Arlacel 83; Crill 43; Glycomul SOC; Hodag SSO; Liposorb SQO; Montane 83; Nikkol SO-15; Nissan Nonion OP-83RAT; Protachem SOC; Sorgen 30; Sorgen S-30-H.

Sorbitan trilaurate Span 25.

Sorbitan trioleate Ablunol S-85; Arlacel 85; Crill 45; Glycomul TO; Hodag STO; Liposorb TO; Montane 85; Nissan Nonion OP-85R; Protachem STO; Prote- sorb STO; S-Maz 85K; Sorbester P37; Span 85; Tego STO.

Sorbitan tristearate Alkamuls STS; Crill 35; Crill 41; Drewsorb 65K; E492; Famodan TS Kosher; Glycomul TS KFG; Hodag STS; Lamesorb STS; Liposorb TS; Liposorb TS-K; Montane 65; Protachem STS; Proteo-sorb STS; Sorbester P38; Span 65; Span 65K.

714 Sorbitan Esters (Sorbitan Fatty Acid Esters)

Table III: Empirical formula and molecular weight of selected sorbitan esters.

Name Formula Molecular weight

Sorbitan diisostearate C42H80O7 697

Sorbitan dioleate C42H76O7 693

Sorbitan monoisostearate C24H46O6 431

�proportions of a polysorbate to produce water-in-oil or oil-in- water emulsions or creams of varying consistencies.

Sorbitan monolaurate, sorbitan monopalmitate and sorbi- tan trioleate have also been used at concentrations of 0.01–0.05% w/v in the preparation of an emulsion for intramuscular administration. See Table IV.

Table IV:  Uses of sorbitan esters.

Sorbitan monolaurate C18H34O6 346

Sorbitan monooleate C24H44O6 429

Sorbitan monopalmitate C22H42O6 403

Sorbitan monostearate C24H46O6 431

Sorbitan sesquiisostearate C33H63O6.5 564

�Use Concentration (%)

Emulsifying agent

Used alone in water-in-oil emulsions 1–15

Sorbitan sesquioleate C33H60O6.5  561

Sorbitan sesquistearate C33H63O6.5  564

Sorbitan triisostearate C60H114O8   964

Sorbitan trioleate C60H108O8  958

Sorbitan tristearate C60H114O8  964

Structural Formula

�Used in combination with hydrophilic emulsifiers in oil-in-water emulsions Used to increase the water-holding properties of ointments

Solubilizing agent

For poorly soluble, active constituents in lipophilic bases

Wetting agent

For insoluble, active constituents in lipophilic bases

�1–10

1–10

1–10

0.1–3

 Description

Sorbitan esters occur as cream- to amber-colored liquids or solids with a distinctive odor and taste; see Table V.

R1 = R2 = OH, R3 = R (see below) for sorbitan monoesters R1 = OH, R2 = R3 = R for sorbitan diesters

R1 = R2 = R3 = R for sorbitan triesters where R =

(C17H35)COO for isostearate (C11H23)COO for laurate (C17H33)COO for oleate

(C15H31)COO for palmitate (C17H35)COO for stearate

The sesquiesters are equimolar mixtures of monoesters and diesters.

Functional Category

Emulsifying agent; nonionic surfactant; solubilizing agent; wetting and dispersing/suspending agent.

Applications in Pharmaceutical Formulation or Technology

Sorbitan monoesters are a series of mixtures of partial esters of sorbitol and its mono- and dianhydrides with fatty acids. Sorbitan diesters are a series of mixtures of partial esters of sorbitol and its monoanhydride with fatty acids.

Sorbitan esters are widely used in cosmetics, food products, and pharmaceutical formulations as lipophilic nonionic surfac- tants. They are mainly used in pharmaceutical formulations as emulsifying agents in the preparation of creams, emulsions, and ointments for topical application. When used alone, sorbitan esters produce stable water-in-oil emulsions and microemul- sions but are frequently used in combination with varying

�Table V: Appearance of selected sorbitan esters.

Name Appearance

Sorbitan monoisostearate Yellow viscous liquid

Sorbitan monolaurate Yellow viscous liquid

Sorbitan monooleate Yellow viscous liquid

Sorbitan monopalmitate Cream solid

Sorbitan monostearate Cream solid

Sorbitan sesquioleate Amber viscous liquid

Sorbitan trioleate Amber viscous liquid

Sorbitan tristearate Cream/yellow solid

Pharmacopeial Specifications

See Table VI.

Typical Properties

Acid value: see Table VII. Density: see Table VII. Flash point: >1498C HLB value: see Table VII.

Hydroxyl value: see Table VII. Iodine number: see Table VII. Melting point: see Table VII. Moisture content: see Table VIII. Pour point: see Table VII. Saponification value: see Table VIII.

Solubility: sorbitan esters are generally soluble or dispersible in oils; they are also soluble in most organic solvents. In water, although insoluble, they are generally dispersible.

Surface tension: see Table VIII.

Viscosity (dynamic): see Table VIII.

Sorbitan Esters (Sorbitan Fatty Acid Esters) 715

Table VI: Pharmacopeial specifications for sorbitan esters.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +    

Characters — + —    

Acid value    

Sorbitan monolaurate — 47.0 48    

Sorbitan monooleate — 48.0 48    

Sorbitan monopalmitate — 48.0 48    

Sorbitan monostearate — 410.0 410    

Sorbitan sesquioleate — 416.0 414    

Sorbitan trioleate — 416.0 417    

Hydroxyl value    

Sorbitan monolaurate — 330–358 330–358    

Sorbitan monooleate — 190–210 190–215    

Sorbitan monopalmitate — 270–305 275–305    

Sorbitan monostearate — 235–260 235–260    

Sorbitan sesquioleate — 180–215 182–220    

Sorbitan trioleate — 55–75 50–75    

Iodine value    

Sobitan monolaurate — 410.0 —    

Sorbitan monooleate — 62–76 62–76    

Sorbitan sesquioleate — 70–95 65–75    

Sorbitan trioleate — 76–90 77–85    

Peroxide value

Sorbitan monolaurate

—

45.0

—    

Sorbitan monooleate — 410.0 —    

Sorbitan monopalmitate — 45.0 —    

Sorbitan monostearate — 45.0 —    

Sorbitan sesquioleate — 410.0 —    

Sorbitan trioleate — 410.0 —    

Saponification value    

Sorbitan monolaurate — 158–170 158–170    

Sorbitan monooleate — 145–160 145–160    

Sorbitan monopalmitate — 140–155 140–150    

Sorbitan monostearate — 147–157 147–157    

Sorbitan sesquioleate 150–168 145–166 143–165    

Sorbitan trioleate — 170–190 169–183    

Water

Sorbitan monolaurate

—

41.5%

41.5%    

Sorbitan monooleate — 41.5% 41.0%    

Sorbitan monopalmitate — 41.5% 41.5%    

Sorbitan monostearate — 41.5% 41.5%    

Sorbitan sesquioleate 43.0% 41.5% 41.0%    

Sorbitan trioleate — 41.5% 40.7%    

Residue on ignition

Sorbitan monolaurate

—

—

40.5%    

Sorbitan monooleate — — 40.5%    

Sorbitan monopalmitate — — 40.5%    

Sorbitan monostearate — — 40.5%    

Sorbitan sesquioleate 41.0% — 41.4%    

Sorbitan trioleate — — 40.25%    

Total ash — 40.5% —    

Heavy metals 420 ppm 410 ppm 40.001%    

Arsenic 42 ppm — —    

Specific gravity    

Sorbitan laurate — ≈0.98 —    

Sorbitan oleate — ≈0.99 —    

Sorbitan sesquioleate 0.960–1.020 ≈0.99 —    

Melting point    

Sorbitan palmitate — 44–518C —    

Sorbitan monostearate — 50–608C —    

Organic volatile impurities — — +    

Assay for fatty acids    

Sorbitan monolaurate — + 55.0–63.0%    

Continued  

716 Sorbitan Esters (Sorbitan Fatty Acid Esters)

Table VI: Continued

 

Test JP 2001 PhEur 2005 USPNF 23    

Sorbitan monooleate — + 72.0–78.0%    

Sorbitan monopalmitate — + 63.0–71.0%    

Sorbitan monostearate — + 68.0–76.0%    

Sorbitan sesquioleate — + 74.0–80.0%    

Sorbitan trioleate — + 85.5–90.0%    

Assay for polyols    

Sorbitan monolaurate — — 39.0–45.0%    

Sorbitan monooleate — — 25.0–31.0%    

Sorbitan monopalmitate — — 32.0–38.0%    

Sorbitan monostearate — — 27.0–34.0%    

Sorbitan sesquioleate — — 22.0–28.0%    

Sorbitan trioleate — — 13.0–19.0%  

Table VII: Typical properties of selected sorbitan esters.

Name Acid value Density (g/cm3) HLB value Hydroxyl value Iodine number Melting point (8C) Pour point (8C)

 

Sorbitan monoisostearate 48 — 4.7 220–250 — — —    

Sorbitan monolaurate 47 1.01 8.6 159–169 47 — 16–20    

Sorbitan monooleate 48 1.01 4.3 193–209 — — —12    

Sorbitan monopalmitate 3–7 1.0 6.7 270–303 41 43–48 —    

Sorbitan monostearate 5–10 — 4.7 235–260 41 53–57 —    

Sorbitan sesquioleate 8.5–13 1.0 3.7 188–210 — — —    

Sorbitan trioleate 10–14 0.95 1.8 55–70 — — —    

Sorbitan tristearate 47 — 2.1 60–80 — — —  

Table VIII: Typical properties of selected sorbitan esters.

 

Name Saponification value Surface tension of 1% aqueous solution (mN/m) Viscosity at 258C (mPa s) Water content (%)    

Sorbitan monoisostearate 143–153 — — 41.0    

Sorbitan monolaurate 159–169 28 3900–4900 40.5    

Sorbitan monooleate 149–160 30 970–1080 40.5    

Sorbitan monopalmitate 142–152 36 Solid 41.0    

Sorbitan monostearate 147–157 46 Solid 41.0    

Sorbitan sesquioleate 149–160 — 1500 41.0    

Sorbitan trioleate 170–190 32 200–250 41.0    

Sorbitan tristearate 172–185 48 Solid 41.0  

Stability and Storage Conditions

Gradual soap formation occurs with strong acids or bases; sorbitan esters are stable in weak acids or bases.

Sorbitan esters should be stored in a well-closed container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Sorbitol is dehydrated to form a hexitan (1,4-sorbitan), which is then esterified with the desired fatty acid.

Safety

Sorbitan esters are widely used in cosmetics, food products, and oral and topical pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. However, there

�have been occasional reports of hypersensitive skin reactions following the topical application of products containing sorbitan esters.(1–4) When heated to decomposition, the sorbitan esters emit acrid smoke and irritating fumes.

The WHO has set an estimated acceptable daily intake of sorbitan monopalmitate, monostearate, and tristearate,(5) and of sorbitan monolaurate and monooleate(6) at up to 25 mg/kg body-weight calculated as total sorbitan esters.

Sorbitan monolaurate: LD50 (rat, oral): 33.6 g/kg.(7) Experimental neoplastigen.

Sorbitan monostearate: LD50 (rat, oral): 31 g/kg.(7) Very mildly toxic by ingestion. Experimental reproductive effects.

Handling Precautions

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

Sorbitan Esters (Sorbitan Fatty Acid Esters) 717

Regulatory Status

Certain sorbitan esters are accepted as food additives in the UK. Sorbitan esters are included in the FDA Inactive Ingredients Guide (inhalations; IM injections; ophthalmic, oral, topical, and vaginal preparations). Sorbitan esters are used in non- parenteral medicines licensed in the UK. Sorbitan esters are included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Polyoxyethylene sorbitan fatty acid esters.

Comments

EINECS numbers

Sorbitan diisostearate [269-410-7]

Sorbitan dioleate [249-448-0]

Sorbitan laurate [215-663-3]

Sorbitan oleate [215-665-4]

Sorbitan palmitate [247-568-8]

Sorbitan sesquiolate [232-360-1]

Sorbitan sesquistearate [257-529-7]

Sorbitan stearate [215-664-9]

Sorbitan triisostearate [259-141-3]

Sorbitan trioleate [247-569-3]

Sorbitan tristearate 247-891-4

Specific References

Finn OA, Forsyth A. Contact dermatitis due to sorbitan mono- laurate. Contact Dermatitis 1975; 1: 318.

Hannuksela M, Kousa M, Pirila V. Allergy to ingredients of vehicles. Contact Dermatitis 1976; 2: 105–110.

Austad J. Allergic contact dermatitis to sorbitan monooleate (Span 80). Contact Dermatitis 1982; 8: 426–427.

�

Boyle J, Kennedy CTC. Contact urticaria and dermatitis to Alphaderm. Contact Dermatitis 1984; 10: 178.

FAO/WHO. Toxicological evaluations 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.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1982; No. 683.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3291.

General References

Konno K, Jinno T, Kitahara A. Solubility, critical aggregating or micellar concentration and aggregate formation of non-ionic surfactants in non-aqueous solutions. J Colloid Interface Sci 1974; 49: 383.

Mittal KL, ed. Micellization, Solubilization and Microemulsions, vol. 1.

New York: Plenum Press, 1977.

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

Boca Raton, FL: CRC Press, 1992: 369–370.

Suzuki E, Shirotani KI, Tsuda Y, Sekiguchi K. Studies on methods of particle size reduction of medicinal compounds VIII: size reduction by freeze-drying and the influence of pharmaceutical adjuvants on the micromeritic properties of freeze-dried powders. Chem Pharm Bull 1979; 27: 1214–1222.

Whitworth CW, Pongpaibul Y. The influence of some additives on the stability of aspirin in an oleaginous suppository base. Can J Pharm Sci 1979; 14: 36–38.

Authors

MJ Lawrence.

Date of Revision

22 August 2005.

Sorbitol

Nonproprietary Names

BP: Sorbitol JP: D-Sorbitol

PhEur: Sorbitolum USPNF: Sorbitol

Synonyms

C*PharmSorbidex; E420; 1,2,3,4,5,6-hexanehexol; Liponic 70-NC; Liponic 76-NC; Meritol; Neosorb; sorbite; D-sorbitol; Sorbitol Instant; Sorbogem.

Chemical Name and CAS Registry Number

D-Glucitol [50-70-4]

Empirical Formula and Molecular Weight

C6H14O6 182.17

Structural Formula

 

Functional Category

Humectant; plasticizer; sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Sorbitol is widely used as an excipient in pharmaceutical formulations. It is also used extensively in cosmetics and food products; see Table I.

Sorbitol is used as a diluent in tablet formulations pre- pared by either wet granulation or direct compression.(1–5) It is particularly useful in chewable tablets owing to its pleasant, sweet taste and cooling sensation. In capsule formulations it is used as a plasticizer for gelatin. Sorbitol has been used as a plasticizer in film formulations.(6,7)

In liquid preparations(8) sorbitol is used as a vehicle in sugar- free formulations and as a stabilizer for drug,(9) vitamin,(10,11) and antacid suspensions. It has also been shown to be a suitable carrier to enhance the in vitro dissolution rate of indometa- cin.(12) In syrups it is effective in preventing crystallization around the cap of bottles. Sorbitol is additionally used in injectable(13) and topical preparations and therapeutically as an osmotic laxative.

Sorbitol may also be used analytically as a marker for assessing liver blood flow.(14)

�Table I: Uses of sorbitol.

Use Concentration (%)

Humectant 3–15

IM injections 10–25

Moisture control agent in tablets 3–10

Oral solutions 20–35

Oral suspensions 70

Plasticizer for gelatin and cellulose 5–20

Prevention of ‘cap locking’ in syrups and elixirs 15–30

Substitute for glycerin and propylene glycol 25–90

Tablet binder and filler 25–90

Toothpastes 20–60

Topical emulsions 2–18

Description

Sorbitol is D-glucitol. It is a hexahydric alcohol related to mannose and is isomeric with mannitol.

Sorbitol occurs as an odorless, white or almost colorless, crystalline, hygroscopic powder. Four crystalline polymorphs and one amorphous form of sorbitol have been identified that have slightly different physical properties, e.g., melting point.(3) Sorbitol is available in a wide range of grades and polymorphic forms such as granules, flakes, or pellets that tend to cake less than the powdered form and have more desirable compression characteristics. Sorbitol has a pleasant, cooling, sweet taste and has approximately 50–60% of the sweetness of sucrose.

SEM: 1

Excipient: Sorbitol Manufacturer: SPI Pharma Lot No.: 5224F8

Magnification: 100×

 

Pharmacopeial Specifications

See Table II.

Sorbitol 719

Typical Properties

Acidity/alkalinity: pH = 4.5–7.0 for a 10% w/v aqueous solution.

Compressibility: compression characteristics and the degree of lubrication required vary, depending upon the particle size and grade of sorbitol used.

Density: 1.49 g/cm3

Density (bulk): 0.448 g/cm3 Density (tapped): 0.400 g/cm3 Density (true): 1.507 g/cm3

Flowability: flow characteristics vary depending upon the particle size and grade of sorbitol used. Fine powder grades tend to be poorly flowing, while granular grades have good flow properties.

Heat of solution: —110.9 J/g (–26.5 cal/g)

Melting point:

Anhydrous form: 110–1128C; Gamma polymorph: 97.78C; Metastable form: 938C.

Moisture content: sorbitol is a very hygroscopic powder and relative humidities greater than 60% at 258C should be avoided when sorbitol is added to direct-compression tablet formulas. See also Figure 1.

Table II: Pharmacopeial specifications for sorbitol.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +    

Characters + + —    

Acidity or alkalinity + — —    

pH — — 3.5–7.0    

Appearance of solution + + +    

Arsenic 41.3 ppm — —    

Chloride 40.005% — 40.005%    

Sulfate 40.006% — 40.01%    

Conductivity — 420 mS·cm—1 —    

Glucose + — —    

Heavy metals 45 ppm — —    

Lead — 40.5 ppm —    

Microbial contamination — + —    

Bacterial — 4102/g 4103/g    

Fungi — 4102/g 4102/g    

Bacterial endotoxins — + +    

Nickel + 41 ppm 41 mg/g    

Organic volatile — — +    

impurities    

Reducing sugars — 40.2% 40.3%    

Related products — 40.1% —    

Residue on ignition 40.02% — 40.1%    

Total sugars + — —    

Water 42.0% 41.5% 41.5%    

Assay (anhydrous basis) 597.0% 97.0–102.0% 91.0–100.5%  

Osmolarity: a 5.48% w/v aqueous solution of sorbitol hemihydrate is isoosmotic with serum.

Particle size distribution: particle size distribution varies depending upon the grade of sorbitol. For fine powder grades, typically 87% <125 mm in size; for granular grades,

22% <125 mm, 45% between 125 and 250 mm, and 33%

between 250 and 590 mm. Individual suppliers’ literature

should be consulted for further information.

Solubility: see Table III.

See also Section 17.

�

Table III: Solubility of sorbitol.

Solvent Solubility at 208C

Chloroform Practically insoluble

Ethanol (95%) 1 in 25

Ethanol (82%) 1 in 8.3

Ethanol (62%) 1 in 2.1

Ethanol (41%) 1 in 1.4

Ethanol (20%) 1 in 1.2

Ethanol (11%) 1 in 1.14

Ether Practically insoluble

Methanol Slightly soluble

Water 1 in 0.5

 

Figure 1: Equilibrium moisture content of sorbitol USPNF.

Stability and Storage Conditions

Sorbitol is chemically relatively inert and is compatible with most excipients. It is stable in air in the absence of catalysts and in cold, dilute acids and alkalis. Sorbitol does not darken or decompose at elevated temperatures or in the presence of amines. It is nonflammable, noncorrosive, and nonvolatile.

Although sorbitol is resistant to fermentation by many microorganisms, a preservative should be added to sorbitol solutions. Solutions may be stored in glass, plastic, aluminum, and stainless steel containers. Solutions for injection may be sterilized by autoclaving.

The bulk material is hygroscopic and should be stored in an airtight container in a cool, dry place.

Incompatibilities

Sorbitol will form water-soluble chelates with many divalent and trivalent metal ions in strongly acidic and alkaline conditions. Addition of liquid polyethylene glycols to sorbitol solution, with vigorous agitation, produces a waxy, water- soluble gel with a melting point of 35–408C. Sorbitol solutions also react with iron oxide to become discolored.

720 Sorbitol

Sorbitol increases the degradation rate of penicillins in neutral and aqueous solutions.(15)

Method of Manufacture

�Comments: sorbitol solution is an aqueous solution of hydrogenated, partly hydrolyzed starch. For physical properties, see Table IV.

Table IV: Physical properties of sorbitol in water solutions.

Sorbitol occurs naturally in the ripe berries of many trees and plants. It was first isolated in 1872 from the berries of the Mountain Ash (Sorbus americana).

Industrially, sorbitol is prepared by high-pressure hydro- genation with a copper–chromium or nickel catalyst, or by electrolytic reduction of glucose and corn syrup. If cane or beet sugars are used as a source, the disaccharide is hydrolyzed to dextrose and fructose prior to hydrogenation.

�Concentration

�Density

�Viscosity

�Refractive

�Freezing

Safety

Sorbitol is widely used in a number of pharmaceutical products and occurs naturally in many edible fruits and berries. It is absorbed more slowly from the gastrointestinal tract than sucrose and is metabolized in the liver to fructose and glucose. Its caloric value is approximately 16.7 J/g (4 cal/g). Sorbitol is better tolerated by diabetics than sucrose and is widely used in many sugar-free liquid vehicles. However, it is not considered to be unconditionally safe for diabetics.

Reports of adverse reactions to sorbitol are largely due to its action as an osmotic laxative when ingested orally,(16–18) which may be exploited therapeutically. Ingestion of large quantities of sorbitol (>20 g/day in adults) should therefore be avoided. Sorbitol is not readily fermented by oral microorganisms

and has little effect on dental plaque pH; hence, it is generally considered to be noncariogenic.(19)

Sorbitol is generally considered to be more irritating than mannitol.

LD50 (mouse, IV): 9.48 g/kg(20) LD50 (mouse, oral): 17.8 g/kg LD50 (rat, IV): 7.1 g/kg

LD50 (rat, SC): 29.6 g/kg

Handling Precautions

Sorbitol may be harmful if ingested in great quantities. It may be irritant to the eyes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask or respirator are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (intra-articular and IM injections; nasal; oral capsules, solutions, suspensions, syrups and tablets; rectal, topical, and vaginal preparations). Included in parenteral and nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Maltitol solution; mannitol; sorbitol solution 70%; xylitol.

Sorbitol solution 70%

Synonyms: sorbitol liquid; Sorbo.

Appearance: a clear, colorless and odorless, viscous liquid.

�

Comments

Sorbitol may be substituted for sucrose to prepare 70–90% w/v syrups.

Several different grades of sorbitol, with different poly- morphic form, particle size, and other physical characteristics are commercially available, e.g., Neosorb (Roquette Fre`res). Pyrogen-free grades are also available from some suppliers.

A specification for sorbitol is contained in the Food Chemicals Codex (FCC). The EINECS number for sorbitol is 200-061-5.

Specific References

Molokhia AM, Moustafa MA, Gouda MW. Effect of storage conditions on the hardness, disintegration and drug release from some tablet bases. Drug Dev Ind Pharm 1982; 8: 283–292.

Bolton S, Atluri R. Crystalline sorbitol tablets: effect of mixing time and lubricants on manufacturing. Drug Cosmet Ind 1984; 135(5): 44, 46, 47, 48, 50.

DuRoss JW. Modification of the crystalline structure of sorbitol and its effects on tableting characteristics. Pharm Technol 1984; 8(9): 42–53.

Basedow AM, Mo¨ schl GA. Sorbitol instant – an excipient with unique tableting properties. Drug Dev Ind Pharm 1986; 12: 2061–

2089.

Schmidt PC, Vortisch W. Influence of manufacturing method of fillers and binders on their tableting properties: comparison of 8 commercially available sorbitols [in German]. Pharm Ind 1987; 49: 495–503.

Krogars K, Heinaemaeki J, Karjalainen M, et al. Development and characterization of aqueous amylose-rich maize starch dispersion for film formation. Eur J Pharm Biopharm 2003; 56(2): 215–221.

Cervera MF, Heina¯ ma¯ ki J, Krogars K, et al. Solid state and mechanical properties of aqueous chitosan-amylose starch films plasticized with polyols. AAPS Pharm Sci Tech 2004; 5(1): E15.

Daoust RG, Lynch MJ. Sorbitol in pharmaceutical liquids. Drug Cosmet Ind 1962; 90(6): 689–691, 773, 776, 777, 779, 781–785.

Sabatini GR, Gulesich JJ. Formulation of a stable and palatable oral suspension of procaine penicillin G. J Am Pharm Assoc (Pract Pharm) 1956; 17: 806–808.

Bandelin FJ, Tuschhoff JV. The stability of ascorbic acid in various liquid media. J Am Pharm Assoc (Sci) 1955; 44: 241–244.

Parikh BD, Lofgren FV. A further stability study of an oral multivitamin liquid preparation. Drug Standards 1958; 26: 56–61.

Valizdeh H, Nokhodchi A, Qarakhari N, et al. Physicochemical characterization of solid dispersions of indometacin with PEG 6000, Myri 52, lactose, sorbitol, dextrin, and Eudragit (R) E100. Drug Dev Ind Pharm 2004; 30(3): 303–317.

Sorbitol 721

Lindvall S, Andersson NSE. Studies on a new intramuscular haematinic, iron–sorbitol. Br J Pharmacol 1961; 17: 358–371.

Burggraaf J, Schoemaker RC, Lentjes EGWM, Cohen AF. Sorbitol as a marker for drug-induced decreases of variable duration in liver blood flow in healthy volunteers. Eur J Pharm Sci 2000; 12: 133– 139.

Bundgaard H. Drug allergy: chemical and pharmaceutical aspects. In: Florence AT, Salole EG, eds. Formulation Factors in Adverse Reactions. London: Wright, 1990: 23–55.

Jain NK, Rosenberg DB, Ulahannan MJ, et al. Sorbitol intolerance in adults. Am J Gastroenterol 1985; 80: 678–681.

Brown AM, Masson E. ‘Hidden’ sorbitol in proprietary medicines – a cause for concern? Pharm J 1990; 245: 211.

Greaves RRSH, Brown RL, Farthing MJG. An air stewardess with puzzling diarrhoea. Lancet 1996; 348: 1488.

Ayers CS, Abrams RA. Noncariogenic sweeteners: sugar sub- stitutes for caries control. Dental Hygiene 1987; 61: 162–167.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3292.

General References

Barr M, Kohn SR, Tice LF. The solubility of sorbitol in hydroalcoholic solutions. Am J Pharm 1957; 129: 102–106.

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Blanchard J, Fink WT, Duffy JP. Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80. J Pharm Sci 1977; 66: 1470–1473.

Burgess S. Sorbitol instant: a unique excipient. Manuf Chem 1987;

58(6): 55, 57, 59.

Collins J. Metabolic disease: time for fructose solutions to go. Lancet

1993; 341: 600.

Rabinowitz MP, Reisberg P, Bodin JI. GLC assay of sorbitol as cyclic n- butylboronate. J Pharm Sci 1974; 63: 1601–1604.

Roquette Fre`res. Technical literature: Neosorb, 2000.

Shah DN, White JL, Hem SL. Mechanism of interaction between polyols and aluminum hydroxide gel. J Pharm Sci 1981; 70: 1101– 1104.

Zatz JL, Lue R-Y. Flocculation of suspensions containing nonionic surfactants by sorbitol. J Pharm Sci 1987; 76: 157–160.

Authors

SC Owen.

Date of Revision

17 August 2005.