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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.

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