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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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