med 10: 2024-11-03

Wednesday, November 6, 2024

Propylene glycol has become widely used as a solvent, extractant, and preservative in a variety of parenteral and nonparenteral pharmaceutical formulations. It is a better general solvent than glycerin and dissolves a wide variety of materials, such as corticosteroids, phenols, sulfa drugs, barbiturates, vitamins (A and D), most alkaloids, and many local anesthetics.

As an antiseptic it is similar to ethanol, and against molds it is similar to glycerin and only slightly less effective than ethanol.

Propylene glycol is commonly used as a plasticizer in aqueous film-coating formulations.

Propylene glycol is also used in cosmetics and in the food industry as a carrier for emulsifiers and as a vehicle for flavors in preference to ethanol, since its lack of volatility provides a more uniform flavor. See Table I.

Table I: Uses of propylene glycol.

Use Dosage form Concentration (%)

Humectant Topicals ≈15

Preservative Solutions, semisolids 15–30

Solvent or cosolvent Aerosol solutions 10–30

Propylene glycol is a clear, colorless, viscous, practically odorless liquid with a sweet, slightly acrid taste resembling that of glycerin.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for propylene glycol.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Appearance — + —

Specific gravity 1.035–1.040 1.035–1.040 1.035–1.037

Acidity + + +

Water 40.5% 40.2% 40.2%

Residue on ignition 40.005% — 43.5 mg

Sulfated ash — 40.01% —

Chloride 40.007% — 40.007%

Sulfate 40.002% — 40.006%

Heavy metals 45 ppm 45 ppm 45 ppm

Organic volatile — — +

impurities

Refractive index — 1.431–1.433 —

Distilling range 184–1898C — —

Assay — — 599.5%

Typical Properties

Autoignition temperature: 3718C

Boiling point: 1888C

Density: 1.038 g/cm3 at 208C

Flammability: upper limit, 12.6% v/v in air; lower limit, 2.6% v/v in air.

Flash point: 998C (open cup)

Heat of combustion: 1803.3 kJ/mol (431.0 kcal/mol) Heat of vaporization: 705.4 J/g (168.6 cal/g) at b.p. Melting point: —598C

Propylene Glycol 625

Osmolarity: a 2.0% v/v aqueous solution is iso-osmotic with serum.

Refractive index: n20 = 1.4324

Specific rotation [a]20:

—15.08 (neat) for (R)-form;

+15.88 (neat) for (S)-form.

Solubility: miscible with acetone, chloroform, ethanol (95%), glycerin, and water; soluble at 1 in 6 parts of ether; not miscible with light mineral oil or fixed oils, but will dissolve some essential oils.

Specific heat: 2.47 J/g (0.590 cal/g) at 208C

Surface tension: 40.1 mN/m (40.1 dynes/cm) at 258C

Vapor density (relative): 2.62 (air = 1)

Vapor pressure: 9.33 Pa (0.07 mmHg) at 208C

Viscosity (dynamic): 58.1 mPa s (58.1 cP) at 208C

Stability and Storage Conditions

At cool temperatures, propylene glycol is stable in a well-closed container, but at high temperatures, in the open, it tends to oxidize, giving rise to products such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene glycol is chemically stable when mixed with ethanol (95%), glycerin, or water; aqueous solutions may be sterilized by autoclaving.

Propylene glycol is hygroscopic and should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Propylene glycol is incompatible with oxidizing reagents such as potassium permanganate.

Method of Manufacture

Propylene is converted to chlorohydrin by chlorine water and hydrolyzed to 1,2-propylene oxide. With further hydrolysis, 1,2-propylene oxide is converted to propylene glycol.

Safety

Propylene glycol is used in a wide variety of pharmaceutical formulations and is generally regarded as a relatively nontoxic material. It is also used extensively in foods and cosmetics. Probably as a consequence of its metabolism and excretion, propylene glycol is less toxic than other glycols. Propylene glycol is rapidly absorbed from the gastrointestinal tract; there is also evidence that it is absorbed topically when applied to damaged skin. It is extensively metabolized in the liver, mainly to lactic and pyruvic acids and is also excreted unchanged in the urine.(1,2)

In topical preparations, propylene glycol is regarded as minimally irritant, although it is more irritant than glycerin. Some local irritation is produced upon application to mucous membranes or when it is used under occlusive conditions.(3) Parenteral administration may cause pain or irritation when used in high concentration.

Propylene glycol is estimated to be one-third as intoxicating as ethanol, with administration of large volumes being associated with adverse effects most commonly on the central nervous system, especially in neonates and children.(4–6) Other adverse reactions reported, though generally isolated, include: ototoxicity;(7) cardiovascular effects; seizures; and hyperosmo- larity(8) and lactic acidosis, both of which occur most frequently in patients with renal impairment. Adverse effects are more likely to occur following consumption of large quantities of propylene glycol or on adminstration to neonates, children

under 4 years of age, pregnant women, and patients with hepatic or renal failure. Adverse events may also occur in patients treated with disulfiram or metronidazole.(9)

On the basis of metabolic and toxicological data, the WHO has set an acceptable daily intake of propylene glycol at up to 25 mg/kg body-weight.(10) Formulations containing 35% pro- pylene glycol can cause hemolysis in humans.

In animal studies, there has been no evidence that propylene glycol is teratogenic or mutagenic. Rats can tolerate a repeated oral daily dose of up to 30 mL/kg in the diet over 6 months, while the dog is unaffected by a repeated oral daily dose of 2 g/kg in the diet for 2 years.(11)

LD50 (mouse, IP): 9.72 g/kg(12) LD50 (mouse, IV): 6.63 g/kg LD50 (mouse, oral): 22.0 g/kg LD50 (mouse, SC): 17.34 g/kg LD50 (rat, IM): 0.01 g/kg

LD50 (rat, IP): 6.66 g/kg LD50 (rat, IV): 6.42 g/kg LD50 (rat, oral): 0.02 g/kg LD50 (rat, SC): 22.5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Propylene glycol should be handled in a well-ventilated environment; eye protection is recommended. In the UK, the long-term (8-hour TWA) occupational exposure limit for propylene glycol vapor and particulates is 474 mg/m3 (150 ppm) and 10 mg/m3 for particulates.(13)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (dental preparations, IM and IV injections, inhalations, ophthalmic, oral, otic, percutaneous, rectal, topical, and vaginal prepara- tions). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Propylene glycol alginate.

Comments

In addition to its uses as an excipient, propylene glycol is used in veterinary medicine as an oral glucogenic in ruminants.(14) A specification for potassium glycol is contained in the Food Chemicals Codex (FCC). The EINECS number for propylene glycol is 200-338-0.

Specific References

Yu DK, Elmquist WF, Sawchuk RJ. Pharmacokinetics of propylene glycol in humans during multiple dosing regimens. J Pharm Sci 1985; 74: 876–879.

Speth PAJ, Vree TB, Neilen NF, et al. Propylene glycol pharmacokinetics and effects after intravenous infusion in humans. Ther Drug Monit 1987; 9: 255–258.

Motoyoshi K, Nozawa S, Yoshimura M, Matsuda K. The safety of propylene glycol and other humectants. Cosmet Toilet 1984; 99(10): 83–91.

626 Propylene Glycol

Arulanantham K, Genel M. Central nervous system toxicity associated with ingestion of propylene glycol. J Pediatr 1978; 93: 515–516.

MacDonald MG, Getson PR, Glasgow AM, et al. Propylene glycol: increased incidence of seizures in low birth weight infants. Pediatrics 1987; 79: 622–625.

Martin G, Finberg L. Propylene glycol: a potentially toxic vehicle in liquid dosage form. J Pediatr 1970; 77: 877–878.

Morizono T, Johnstone BM. Ototoxicity of chloramphenicol ear drops with propylene glycol as solvent. Med J Aust 1975; 2: 634– 638.

Fligner CL, Jack R, Twiggs GA, Raisys VA. Hyperosmolality induced by propylene glycol: a complication of silver sulfadiazine therapy. J Am Med Assoc 1985; 253: 1606–1609.

Anonymous. US warning on HIV drug excipient. Pharm J 2000;

264: 685.

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

Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and Toxicology, 3rd edn. Chichester: Wiley, 1987.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3061.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

Bishop Y, ed. The Veterinary Formulary, 6th edn. London: Pharmaceutical Press, 2005: 420.

General References

Doenicke A, Nebauer AE, Hoernecke R, et al. Osmolalities of propylene glycol-containing drug formulations for parenteral use: should propylene glycol be used as a solvent? Anesth Analg 1992; 75(3): 431–435.

Krzyzaniak JF, Raymond DM, Yalkowsky SH. Lysis of human red blood cells 2: effect of contact time on cosolvent induced hemolysis. Int J Pharm 1997; 152: 193–200.

Strickley RG. Solubilizing excipients in oral and injectable formula- tions. Pharm Res 2004; 21(2): 201–230.

Wells JI, Bhatt DA, Khan KA. Improved wet massed tableting using plasticized binder. J Pharm Pharmacol 1982; 34 (Suppl.): 46P. Williams AC, Barry BW. Penetration enhancers. Adv Drug Delivery

Rev 2004; 56(5): 603–618.

Yu CD, Kent JS. Effect of propylene glycol on subcutaneous absorption of a benzimidazole hydrochloride. J Pharm Sci 1982; 71: 476–478.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for propionic acid.

Test USPNF 23

Specific gravity 0.988–0.993

Distilling range 138.5–142.58C

Heavy metals 40.001%

Limit of nonvolatile residue 40.01%

Readily oxidizable substances +

Limit of aldehydes +

Organic volatile impurities +

Assay 99.5–100.5%

Typical Properties

Antimicrobial activity: see Table II.

Table II: Typical minimum inhibitory concentrations (MICs) for propionic acid at pH 3.9.(1)

Microorganism MIC (mg/mL)

Aspergillus niger 2000

Candida albicans 2000

Escherichia coli 2000

Klebsiella pneumoniae 1250

Penicillium notatum 2000

Pseudomonas aeruginosa 3000

Pseudomonas cepacia 3000

Pseudomonas fluorescens 1250

Staphylococcus aureus 2000

Autoignition temperature: 9558C Boiling point: 141.18C Dissociation constant: pKa = 4.874 Flash point: 52–588C (open cup) Melting point: —21.58C

Partition coefficients: Octanol : water = 0.33.

Refractive index: n25 = 1.3848

Solubility: miscible with chloroform, ethanol (95%), ether, and water.

Specific gravity: 0.9934

Surface tension: 27.21 mN/m (27.21 dynes/cm) at 158C

Vapor density (relative): 2.56 (air = 1) Vapor pressure: 320 Pa (2.4 mmHg) at 208C Viscosity (dynamic): see Table III.

Table III: Dynamic viscosity of propionic acid.

Viscosity (dynamic)/mPa s Temperature

Stability and Storage Conditions

Although stable, propionic acid is flammable. It should be stored in an airtight container away from heat and flames.

Incompatibilities

Propionic acid is incompatible with alkalis, ammonia, amines, and halogens. It can be salted out of aqueous solutions by the addition of calcium chloride or other salts.

Method of Manufacture

Propionic acid can be obtained from wood pulp waste liquor by fermentation. It can also be prepared from ethylene, carbon monoxide and steam; from ethanol and carbon monoxide using boron trifluoride catalyst; from natural gas; or as a by-product in the pyrolysis of wood. Very pure propionic acid can be obtained from propionitrile. Propionic acid can be found in dairy products in small amounts.

Safety

Propionic acid is generally regarded as a nontoxic and nonirritant material when used as an excipient. Up to 1% may be used in food applications (up to 0.3% in flour and cheese products). See also Sodium Propionate.

(10 ppm) long-term (8-hour TWA) and 46 mg/m3 (15 ppm) short-term.(3)

Regulatory Status

GRAS listed. Accepted for use in Europe as a food additive. In Japan, propionic acid is restricted to use as a flavoring agent.

Related Substances

Sodium propionate.

Comments

A specification for propionic acid is contained in the Food Chemicals Codex (FCC). The EINECS number for propionic acid is 201-176-3.

Specific References

Wallha¨ usser KH. Propionic acid. In: Kabara JJ, ed. Cosmetic and Drug Preservation: Principles and Practice. New York: Marcel Dekker, 1984: 665–666.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3069–3070.

Health and Safety Executive. EH40/2002: Occupational Exposure

LD50

(mouse, IV): 0.63 g/kg(2)

Limits 2002. Sudbury: Health and Safety Executive, 2002.

LD50 (rabbit, skin): 0.5 g/kg LD50 (rat, oral): 2.6 g/kg

Handling Precautions

Propionic acid is corrosive and can cause eye and skin burns. It may be harmful if swallowed, inhaled or absorbed through the skin as a result of prolonged or widespread contact. Eye protection, PVC gloves, and suitable protective clothing should be worn. Propionic acid should be handled in a well-ventilated environment away from heat and flames. In the UK, the occupational exposure limits for propionic acid are 31 mg/m3

BP: Propyl gallate PhEur: Propylis gallas USPNF: Propyl gallate

Synonyms

E310; gallic acid propyl ester; n-propyl gallate; Progallin P; propyl 3,4,5-trihydroxybenzoate; Tenox PG.

Chemical Name and CAS Registry Number

3,4,5-Trihydroxybenzoic acid propyl ester [121-79-9]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Propyl gallate has become widely used as an antioxidant in cosmetics, perfumes, foods, and pharmaceuticals since its use in preventing autoxidation of oils was first described in 1943.(1,2) It is primarily used, in concentrations up to 0.1% w/v, to prevent the rancidity of oils and fats;(3) it may also be used at concentrations of 0.002% w/v to prevent peroxide formation in ether, and at 0.01% w/v to prevent the oxidation of paraldehyde. Synergistic effects with other antioxidants such as butylated hydroxyanisole and butylated hydroxytoluene have been reported. Propyl gallate is also said to possess some antimicrobial properties; see Section 10.

Studies have shown that, when added to powder blends containing ketorolac, propyl gallate significantly increases the drug stability in the preparation.(4)

Other alkyl gallates are also used as antioxidants and have approximately equivalent antioxidant properties when used in equimolar concentration; however, solubilities vary, see Section 17.

Description

Propyl gallate is a white, odorless or almost odorless crystalline powder, with a bitter astringent taste that is not normally noticeable at the concentrations employed as an antioxidant.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for propyl gallate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Melting range — 146–1508C

Appearance of solution + —

Gallic acid + —

Loss on drying 40.5% 40.5%

Residue on ignition — 40.1%

Sulfated ash 40.1% 40.1%

Total chlorine 4200 ppm —

Chloride 4100 ppm —

Heavy metals 410 ppm 40.001%

Zinc 425 ppm —

Organic volatile impurities — +

Assay (dried basis) 97.0–103.0% 98.0–102.0%

Typical Properties

Acidity/alkalinity: pH = 5.9 (0.1% w/v aqueous solution)

Antimicrobial activity: propyl gallate has been reported to possess some antimicrobial activity against Gram-negative, Gram-positive, and fungal species.(5) Its effectiveness as a preservative may be improved when used in combination with zinc salts, such as zinc sulfate, owing to synergistic effects.(6) For reported minimum inhibitory concentrations (MICs) for aqueous solutions containing 4% v/v ethanol as cosolvent, see Table II.(5)

Table II: Minimum inhibitory concentrations (MICs) for aqueous solutions containing propyl gallate and 4% v/v ethanol.

Microorganism MIC (mg/mL)

Candida albicans 1500

Escherichia coli 330

Staphylococcus aureus 600

Dissociation constant: pKa = 8.11

Melting point: 1508C

Partition coefficients:

Octanol : water = 32; Oleyl alcohol : water = 17.

Solubility: see Table III.

620 Propyl Gallate

Table III: Solubility of propyl gallate.

Solvent Solubility at 208C unless otherwise stated

Almond oil 1 in 44

Castor oil 1 in 4.5

Cottonseed oil 1 in 81 at 308C

Lanolin 1 in 16.7 at 258C

Lard 1 in 88 at 458C

Mineral oil 1 in 200

Peanut oil 1 in 2000

Propylene glycol 1 in 2.5 at 258C

Soybean oil 1 in 100 at 258C

Water 1 in 1000

1 in 286 at 258C

Stability and Storage Conditions

Propyl gallate is unstable at high temperatures and is rapidly destroyed in oils that are used for frying purposes.

The bulk material should be stored in a well-closed, nonmetallic container, protected from light, in a cool, dry place.

Incompatibilities

The alkyl gallates are incompatible with metals, e.g. sodium, potassium, and iron, forming intensely colored complexes. Complex formation may be prevented, under some circum- stances, by the addition of a sequestering agent, typically citric acid. Propyl gallate may also react with oxidizing materials.

Method of Manufacture

Propyl gallate is prepared by the esterification of 3,4,5- trihydroxybenzoic acid (gallic acid) with n-propanol. Other alkyl gallates are prepared similarly using an appropriate alcohol of the desired alkyl chain length.

Safety

It has been reported, following animal studies, that propyl gallate has a strong contact sensitization potential.(7) Propyl gallate has also produced cytogenic effects in CHO-K1 cells.(8) However, despite this, there have been few reports of adverse reactions to propyl gallate.(9) Those that have been described include contact dermatitis; allergic contact dermatitis;(9–11) and methemoglobinemia in neonates.(12)

The WHO has set an estimated acceptable daily intake for propyl gallate at up to 1.4 mg/kg body-weight.(13)

LD50 (cat, oral): 0.4 g/kg(14) LD50 (mouse, oral): 1.7 g/kg LD50 (rat, oral): 2.1 g/kg LD50 (rat, IP): 0.38 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. When heated to decomposition, propyl gallate may emit toxic fumes and smoke.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM injections, oral, and topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Dodecyl gallate; ethyl gallate; octyl gallate.

Dodecyl gallate

Empirical formula: C19H30O5

Molecular weight: 338.44

CAS number: [1166-52-5]

Synonyms: dodecyl 3,4,5-trihydroxybenzoate; dodecylis gallas; E312; lauryl gallate.

Appearance: white, odorless or almost odorless, crystalline powder.

Melting point: 96–97.58C

Solubility: see Table IV.

Table IV: Solubility of dodecyl gallate.

Solvent Solubility at 208C

Acetone 1 in 2

Chloroform 1 in 60

Ethanol (95%) 1 in 3.5

Ether 1 in 4

Methanol 1 in 1.5

Peanut oil 1 in 30

Propylene glycol 1 in 60

Water Practically insoluble

Safety: the WHO has established a temporary estimated acceptable daily intake for dodecyl gallate at up to

0.05 mg/kg body-weight.(13)

Comments: the EINECS number for dodecyl gallate is 214- 620-6.

Ethyl gallate

Empirical formula: C9H10O5

Molecular weight: 198.17

CAS number: [831-61-8]

Synonyms: ethyl 3,4,5-trihydroxybenzoate.

Appearance: white, odorless or almost odorless, crystalline powder.

Melting point: 151–1548C

Solubility: see Table V.

Table V: Solubility of ethyl gallate.

Solvent Solubility at 208C

Ethanol (95%) 1 in 3

Ether 1 in 3

Peanut oil Practically insoluble

Water Slightly soluble

Octyl gallate

Empirical formula: C15H22O5

Molecular weight: 282.34

CAS number: [1034-01-1]

Propyl Gallate 621

Synonyms: E311; octyl 3,4,5-trihydroxybenzoate.

Appearance: white, odorless or almost odorless, crystalline powder.

Melting point: 100–1028C

Solubility: see Table VI.

Table VI: Solubility of octyl gallate.

Solvent Solubility at 208C

Acetone 1 in 1

Chloroform 1 in 30

Ethanol (95%) 1 in 2.5

Ether 1 in 3

Methanol 1 in 0.7

Peanut oil 1 in 33

Propylene glycol 1 in 7

Water Practically insoluble

Safety: the WHO has established a temporary estimated acceptable daily intake for octyl gallate at up to 0.1 mg/kg body-weight.(13)

Comments: the EINECS number for octyl gallate is 252-073-5.

Comments

Propyl gallate has been reported to impart an ‘off’ flavor to corn and cottonseed oils when used as an antioxidant.(15) A specification for propyl gallate is contained in the Food Chemicals Codex (FCC). The EINECS number for propyl gallate is 204-498-2.

Specific References

Boehm E, Williams R. The action of propyl gallate on the autoxidation of oils. Pharm J 1943; 151: 53.

Boehm E, Williams R. A study of the inhibiting actions of propyl gallate (normal propyl trihydroxy benzoate) and certain other trihydric phenols on the autoxidation of animal and vegetable oils. Chemist Drug 1943; 140: 146–147.

Okide GB, Adikwu MU. Kinetic study of the auto-oxidation of arachis oil. Boll Chim Farm 1998; 137: 277–280.

Brandl M, Magill A, Rudrarajn V, Gordon MS. Approaches for improving the stability of ketorolac in powder blends. J Pharm Sci 1995; 84: 1151–1153.

Zeelie JJ, McCarthy TJ. The potential antimicrobial properties of antioxidants in pharmaceutical systems. S Afr Pharm J 1982; 49: 552–554.

McCarthy TJ, Zeelie JJ, Krause DJ. The antimicrobial action of zinc ion/antioxidant combinations. J Clin Pharm Ther 1992; 17: 51–54.

Kahn G, Phanuphak P, Claman HN. Propyl gallate contact sensitization and orally induced tolerance. Arch Dermatol 1974; 109: 506–509.

Tayama S, Nakagawa Y. Cytogenetic effects of propyl gallate in CHO-K1 cells. Mutat Res 2001; 498(1–2): 117–127.

Golightly LK, Smolinske SS, Bennett ML, Sutherland EW, Rumack BH. Pharmaceutical excipients: adverse effects associated with ‘inactive’ ingredients in drug products (part II). Med Toxicol 1988; 3: 209–240.

Cusano F, Capozzi M, Errico G. Safety of propyl gallate in topical products. J Am Acad Dermatol 1987; 17: 308–309.

Bojs G, Nicklasson B, Svensson A. Allergic contact dermatitis to propyl gallate. Contact Dermatitis 1987; 17: 294–298.

Nitzan M, Volovitz B, Topper E. Infantile methemoglobinemia caused by food additives. Clin Toxicol 1979; 15(3): 273–280.

FAO/WHO. Evaluation of certain food additives and contami- nants. Forty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1997; No. 868.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3084.

McConnell JEW, Esselen WB. Effect of storage conditions and antioxidants on the keeping quality of packaged oils. J Am Oil Chem Soc 1947; 24: 6–14.

General References

Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, volume 1. New York: Marcel Dekker, 1988: 415–449.

USPNF: Propylene carbonate

Synonyms

Carbonic acid, cyclic propylene ester; cyclic methylethylene carbonate; cyclic propylene carbonate; 4-methyl-2-oxo-1,3- dioxolane; 1,2-propanediol cyclic carbonate; 1,2-propylene carbonate.

Chemical Name and CAS Registry Number

-4-Methyl-1,3-dioxolan-2-one [108-32-7]

Empirical Formula and Molecular Weight

C4H6O3 102.09

Structural Formula

Functional Category

Gelling agent; solvent.

Applications in Pharmaceutical Formulation or Technology

Propylene carbonate is used mainly as a solvent in oral and topical pharmaceutical formulations.

In topical applications, propylene carbonate has been used in combination with propylene glycol as a solvent for corticosteroids. The corticosteroid is dissolved in the solvent mixture to yield microdroplets that can then be dispersed in petrolatum.(1) Propylene carbonate has been used as a dispensing solvent in topical preparations.(2)

Propylene carbonate has also been used in hard gelatin capsules as a nonvolatile, stabilizing, liquid carrier. For formulations with a low dosage of active drug, a uniform drug content may be obtained by dissolving the drug in propylene carbonate then spraying this solution on to a solid carrier such as compressible sugar; the sugar may then be filled into hard gelatin capsules.(3)

Propylene carbonate may additionally be used as a solvent, at room and elevated temperatures, for many cellulose-based polymers and plasticizers. Propylene carbonate is also used in cosmetics.

Description

Propylene carbonate is a clear, colorless, mobile liquid, with a faint odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for propylene carbonate.

Test USPNF 23

Identification +

Specific gravity 1.203–1.210

pH (10% v/v aqueous solution) 6.0–7.5

Residue on ignition 40.01%

Organic volatile impurities +

Assay 99.0–100.5%

Typical Properties

Boiling point: 2428C Flash point: 1328C Freezing point: —49.28C

Heat of combustion: 14.21 kJ/mol (3.40 kcal/mol)

Heat of vaporization: 55.2 kJ/mol (13.2 kcal/mol) at 1508C

Refractive index: n20 = 1.420–1.422

Solubility: practically insoluble in hexane; freely soluble in water. Miscible with acetone, benzene, chloroform, ethanol, ethanol (95%), and ether.

Specific heat: 2.57 J/g/8C (0.62 cal/g/8C) at 208C Vapor pressure: 4 Pa (0.03 mmHg) at 208C. Viscosity (dynamic): 2.5 mPa s (2.5 cP) at 258C.

Stability and Storage Conditions

Propylene carbonate and its aqueous solutions are stable but may degrade in the presence of acids or bases, or upon heating; see also Section 12.

Store in a well-closed container in a cool, dry place.

Incompatibilities

Propylene carbonate hydrolyzes rapidly in the presence of strong acids and bases, forming mainly propylene oxide and carbon dioxide. Propylene carbonate can also react with primary and secondary amines to yield carbamates.

Method of Manufacture

Propylene carbonate may be prepared by the reaction of sodium bicarbonate with propylene chlorohydrin.(4)

Safety

Propylene carbonate is used as a solvent in oral and topical pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material.

Propylene Carbonate 623

In animal studies, propylene carbonate was found to cause tissue necrosis after parenteral administration.(5)

LD50 (mouse, oral): 20.7 g/kg LD50 (mouse, SC): 15.8 g/kg LD50 (rat, oral): 29 g/kg

LD50 (rat, SC): 11.1 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Propylene carbonate may be irritant to the eyes and mucous membranes. Eye protection and gloves are recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical ointments). Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

(S)-Propylene carbonate.

(S)-Propylene carbonate Empirical formula: C4H6O3 Molecular weight: 102.09

CAS number: [51260-39-0]

Specific rotation: [a]25 = —1.78 (0.92% v/v solution in ethanol)

Comments: the (S)-enantiomer of -propylene carbonate.(6)

Comments

The EINECS number for propylene carbonate is 203-572-1.

Specific References

Burdick KH, Haleblian JK, Poulsen BJ, Cobner SE. Corticosteroid ointments: comparison by two human bioassays. Curr Ther Res 1973; 15: 233–242.

Yoshida H, Tamura S, Toyoda T, et al. In vitro release of tacrolimus from tacrolimus ointment and its speculated mechan- ism. Int J Pharm 2004; 270(1–2): 55–64.

Dahl TC, Burke G. Feasibility of manufacturing a solid dosage form using a liquid nonvolatile drug carrier: a physicochemical characterization. Drug Dev Ind Pharm 1990; 16: 1881–1891.

Najer H, Chabrier P, Giudicelli R. Study of organic cyclic carbonates and their derivatives [in French]. Bull Soc Chim Fr 1954: 1142–1148.

Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation evaluation of potential parenteral vehicles. Drug Dev Commun 1974–75 1: 471–477.

Usieli V, Pilersdorf A, Shor S, et al. Chiroptical properties of cyclic esters and ketals derived from (S)-1,2-propylene glycol and (S,S)- and (R,R)-2,3-butylene glycol. J Org Chem 1974; 39: 2073–2079.

General References

Cheng H, Gadde RR. Determination of propylene carbonate in pharmaceutical formulations using liquid chromatography. J Pharm Sci 1985; 74: 695–696.

Ursin C, Hansen CM, Van Dyk JW, et al. Permeability of commercial solvents through living human skin. Am Ind Hyg J 1995; 56: 651– 660.

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