kywods

Applications in Pharmaceutical Formulation or Technology

Light mineral oil is used in applications similar to those of mineral oil. It is used primarily as an excipient in topical pharmaceutical formulations where its emollient properties are exploited in ointment bases;(1–3) see Table I. It is also used in ophthalmic formulations.(4,5) Light mineral oil is additionally used in oil-in-water and polyethlylene glycol/gylcerol emul- sions;(6–9) as a solvent and lubricant in capsules and tablets; as a solvent and penetration enhancer in transdermal prepara- tions;(10) and as the oily medium used in the microencapsula- tion of many drugs.(11–20)

Light mineral oil is also used in cosmetics and certain food products.

Table I: Uses of light mineral oil.

Use Concentration (%)

Ophthalmic ointments 415.0

Otic preparations 450.0

Topical emulsions 1.0–20.0

Topical lotions 7.0–16.0

Topical ointments 0.2–23.0

Typical Properties

Solubility: soluble in chloroform, ether, and hydrocarbons; sparingly soluble in ethanol (95%); practically insoluble in water.

Stability and Storage Conditions

Light mineral oil undergoes oxidation when exposed to heat and light. Oxidation begins with the formation of peroxides, exhibiting an ‘induction period’. Under typical storage condi- tions, the induction period may take months or years. However, once a trace of peroxide is formed, further oxidation is autocatalytic and proceeds very rapidly. Oxidation results in the formation of aldehydes and organic acids, which impart taste and odor. The USPNF 23 permits the addition of suitable stabilizers to retard oxidation, butylated hydroxyanisole, butylated hydroxytoluene, and alpha tocopherol being the most commonly used antioxidants.

Light mineral oil may be sterilized by dry heat.

Light mineral oil should be stored in an airtight container in a cool, dry place and protected from light.

Mineral Oil, Light 475

Incompatibilities

Incompatible with strong oxidizing agents.

Method of Manufacture

Light mineral oil is obtained by the distillation of petroleum. A suitable stabilizer may be added to the oil; see Section 11.

See also Mineral Oil for further information.

Safety

Light mineral oil is used in applications similar to those of mineral oil. Mineral oil is considered safe by the FDA for direct use in foods. However, oral ingestion of large doses of light mineral oil or chronic consumption may be harmful. Chronic use may impair appetite and interfere with the absorption of fat-soluble vitamins. It is absorbed to some extent when emulsified, leading to granulomatous reactions. Oral and intranasal use of mineral oil or products containing mineral oil by infants or children is not recommended because of the possible danger of causing lipoid pneumonia.

See Mineral Oil for further information.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Since light mineral oil is combustible, it should not be handled or stored near heat, sparks, or flame. Light mineral oil should not be mixed with or stored with strong oxidants. Inhalation of mineral oil vapors may be harmful.

Regulatory Status

GRAS listed. Accepted in the UK for use in certain food applications. Light mineral oil is included in the FDA Inactive Ingredients Guide (ophthalmic preparations, oral capsules and tablets, otic, rectal, topical, and transdermal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Mineral oil; mineral oil and lanolin alcohols; paraffin; petrolatum.

Comments

—

Specific References

Jolly ER. Clinical evaluation of baby oil as a dermal moisturizer.

Cosmet Toilet 1976; 91: 51–52.

Magdassi S, Frenkel M, Garti N. Correlation between nature of emulsifier and multiple emulsion stability. Drug Dev Ind Pharm 1985; 11: 791–798.

Tanaka S, Takashima Y, Murayama H, Tsuchiya S. Solubility and distribution of dexamethasone acetate in oil-in-water creams and its release from the creams. Chem Pharm Bull 1985; 33: 3929– 3934.

Merritt JC, Perry DD, Russell DN, Jones BF. Topical ∆9- tetrahydrocannabinol and aqueous dynamics in glaucoma. J Clin Pharmacol 1981; 21: 467S–471S.

Jay WM, Green K. Multiple-drop study of topically applied 1% delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 1983; 101: 591–593.

Hallworth GW, Carless JE. Stablization of oil-in-water emulsions by alkyl sulfates: influence of the nature of the oil on stability. J Pharm Pharmacol 1972; 24: 71–83.

Magdassi S. Formation of oil-in-polyethylene glycol/water emul- sions. J Disper Sci Technol 1988; 9: 391–399.

Magdassi S, Frank SG. Formation of oil in glycerol/water emulsions: effect of surfactant ethylene oxide content. J Disper Sci Technol 1990; 11: 519–528.

Moaddel T, Frierg SE. Phase equilibria and evaporation rates in a four component emulsion. J Disper Sci Technol 1995; 16: 69–97.

Pfister WR, Hsieh DST. Permeation enhancers compatible with transdermal drug delivery systems part II: system design con- siderations. Pharm Technol 1990; 14(10): 54, 56–58, 60.

Beyger JW, Nairn JG. Some factors affecting the microencapsula- tion of pharmaceuticals with cellulose acetate phthalate. J Pharm Sci 1986; 75: 573–578.

Pongpaibul Y, Whitworth CW. Preparation and in vitro dissolution characteristics of propranolol microcapsules. Int J Pharm 1986; 33: 243–248.

Sheu M-T, Sokoloski TD. Entrapment of bioactive compounds within native albumin beads III: evaluation of parameters affecting drug release. J Parenter Sci Technol 1986; 40: 259–265.

D’Onofrio GP, Oppenheim RC, Bateman NE. Encapsulated microcapsules. Int J Pharm 1979; 2: 91–99.

Huang HP, Ghebre Sellassie I. Preparation of microspheres of water-soluble pharmaceuticals. J Microencapsul 1989; 6(2): 219–

225.

Ghorab MM, Zia H, Luzzi LA. Preparation of controlled release anticancer agents I: 5-fluorouracil–ethyl cellulose microspheres. J Microencapsul 1990; 7(4): 447–454.

Ruiz R, Sakr A, Sprockel OL. A study on the manufacture and in vitro dissolution of terbutaline sulfate microcapsules and their tablets. Drug Dev Ind Pharm 1990; 16: 1829–1842.

Sanghvi SP, Nairn JG. Phase diagram studies for microencapsula- tion of pharmaceuticals using cellulose acetate trimellitate. J Pharm Sci 1991; 80: 394–398.

Iwata M, McGinity JW. Preparation of multi-phase microspheres of poly(D,L-lactic acid) and poly(D,L-lactic co-glycolic acid) containing a w/o emulsion by a multiple emulsion solvent evaporation technique. J Microencapsul 1992; 9(2): 201–214.

Sanghvi SP, Nairn JG. Effect of viscosity and interfacial tension on particle size of cellulose acetate trimellitate microspheres. J Microencapsul 1992; 9(2): 215–227.

General References

Allen LV. Featured excipient: capsule and tablet lubricants. Int J Pharm Compound 2000; 4(5): 390–392.

Allen LV. Featured excipient: oleaginous vehicles. Int J Pharm Compound 2000; 4(6): 470–473, 484–485.

See also Mineral Oil.

Mineral Oil and Lanolin Alcohols

Nonproprietary Names

None adopted.

Synonyms

Amerchol L-101; liquid paraffin and lanolin alcohols; Protalan M-16; Protalan M-26.

Chemical Name and CAS Registry Number

Mineral oil [8012-95-1]

Lanolin alcohols [8027-33-6]

Empirical Formula and Molecular Weight

A mixture of mineral oil and lanolin alcohols.

Structural Formula

See Section 4.

Functional Category

Emollient; emulsifying agent; plasticizer.

Applications in Pharmaceutical Formulation or Technology

Mineral oil and lanolin alcohols is an oily liquid used in topical pharmaceutical formulations and cosmetics as an emulsifying agent with emollient properties; see Table I. It is used as a primary emulsifier in the preparation of water-in-oil creams and lotions and as an auxiliary emulsifier and stabilizing agent in oil-in-water creams and lotions.

Table I: Uses of mineral oil and lanolin alcohols.

Use Concentration (%)

Emollient 3.0–6.0

Emulsifier in w/o creams and lotions 5.0–15.0

Emulsifier in o/w creams and lotions 0.5–6.0

Description

A pale yellow-colored, oily liquid with a faint characteristic sterol odor.

Pharmacopeial Specifications

Heavy metals: 420 ppm

HLB value: ≈8

Hydroxyl value: 10–15

Iodine number: 412

Microbiological count: the total bacterial count, when pack- aged, is less than 10 per gram of sample.

Moisture content: 40.2%

Saponification value: 42

Solubility: soluble 1 in 2 parts of chloroform, 1 in 4 parts of castor oil, and 1 in 4 parts of corn oil. Practically insoluble in ethanol (95%) and water. Precipitation occurs in hexane.

Specific gravity: 0.840–0.860 at 258C

Stability and Storage Conditions

Mineral oil and lanolin alcohols is stable and should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Lanolin alcohols is incompatible with coal tar, ichthammol, phenol, and resorcinol.

Method of Manufacture

Lanolin alcohols is dissolved in mineral oil.

Safety

Mineral oil and lanolin alcohols is generally regarded as an essentially nontoxic and nonirritant material. However, lanolin alcohols may be irritant to the skin and causes hypersensitivity in some individuals.(1)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

Accepted for use in topical pharmaceutical formulations and cosmetics. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Lanolin alcohols; mineral oil; petrolatum and lanolin alcohols.

Comments

See Lanolin Alcohols and Mineral Oil for further information.

Mineral Oil and Lanolin Alcohols 477

Specific References

1 Wakelin SH, Smith H, White IR, et al. A retrospective analysis of contact allergy to lanolin. Br J Dermatol 2001; 145(1): 28–31.

General References

Davis SS. Viscoelastic properties of pharmaceutical semisolids I: ointment bases. J Pharm Sci 1969; 58: 412–418.

Prosperio G, Gatti S, Genesi P. Lanolin and its derivatives for cosmetic creams and lotions. Cosmet Toilet 1980; 95(4): 81–85.

USPNF: Monoethanolamine

Synonyms

b-Aminoethyl alcohol; colamine; ethylolamine; b-hydroxy- ethylamine; 2-hydroxyethylamine.

Chemical Name and CAS Registry Number

2-Aminoethanol [141-43-5]

Empirical Formula and Molecular Weight

C2H7NO 61.08

Structural Formula

Functional Category

Alkalizing agent; emulsifying agent.

Applications in Pharmaceutical Formulation or Technology

Monoethanolamine is used primarily in pharmaceutical for- mulations for buffering purposes and in the preparation of emulsions. Other uses include as a solvent for fats and oils and as a stabilizing agent in an injectable dextrose solution of phenytoin sodium.

Monoethanolamine is also used to produce a variety of salts with therapeutic uses. For example, a salt of monoethanola- mine with vitamin C is used for intramuscular injection, while the salicylate and undecenoate monoethanolamine salts are utilized respectively in the treatment of rheumatism and as an antifungal agent. However, the most common therapeutic use of monoethanolamine is in the production of ethanolamine oleate injection, which is used as a sclerosing agent.(1)

Description

Monoethanolamine is a clear, colorless or pale yellow-colored, moderately viscous liquid with a mild, ammoniacal odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for monoethanolamine.

Test BP 2004 USPNF 23

Identification + —

Characters + —

Specific gravity 1.014–1.023 1.013–1.016

Refractive index 1.453–1.459 —

Related substances 42.0% —

Distilling range — 167–1738C

Residue on ignition — 40.1%

Organic volatile impurities — +

Assay 98.0–100.5% 98.0–100.5%

10 Typical Properties

Acidity/alkalinity: pH = 12.1 for a 0.1 N aqueous solution.

Boiling point: 170.88C Critical temperature: 3418C Density:

1.0117 g/cm3 at 258C;

0.9998 g/cm3 at 408C;

0.9844 g/cm3 at 608C.

Dissociation constant: pKa = 9.4 at 258C Flash point (open cup): 938C Hygroscopicity: very hygroscopic.

Melting point: 10.38C Refractive index: n20 = 1.4539 Solubility: see Table II.

Table II: Solubility of monoethanolamine.

Solvent Solubility at 208C

Acetone Miscible

Benzene 1 in 72

Chloroform Miscible

Ethanol (95%) Miscible

Surface tension: 48.8 mN/m at 208C

Vapor density (relative): 2.1 (air = 1)

Vapor pressure: 53.3 Pa (0.4 mmHg) at 208C

Viscosity (dynamic):

18.95 mPa s (18.95 cP) at 258C;

5.03 mPa s (5.03 cP) at 608C.

Stability and Storage Conditions

Monoethanolamine is very hygroscopic and is unstable when exposed to light. Aqueous monoethanolamine solutions may be sterilized by autoclaving.

When monoethanolamine is stored in large quantities, stainless steel is preferable for long-term storage. Copper, copper alloys, zinc, and galvanized iron are corroded by amines

Monoethanolamine 479

and should not be used for construction of storage containers. Ethanolamines readily absorb moisture and carbon dioxide from the air; they also react with carbon dioxide. This can be prevented by sealing the monoethanolamine under an inert gas. Smaller quantities of monoethanolamine should be stored in an airtight container, protected from light, in a cool, dry place.

Incompatibilities

Monoethanolamine contains both a hydroxy group and a primary amine group and will thus undergo reactions characteristic of both alcohols and amines. Ethanolamines will react with acids to form salts and esters. Discoloration and precipitation will take place in the presence of salts of heavy metals. Monoethanolamine reacts with acids, acid anhydrides, acid chlorides, and esters to form amide derivatives, and with propylene carbonate or other cyclic carbonates to give the corresponding carbonates.

As a primary amine, monoethanolamine will react with aldehydes and ketones to yield aldimines and ketimines. Additionally, monoethanolamine will react with aluminum, copper, and copper alloys to form complex salts. A violent reaction will occur with acrolein, acrylonitrile, epichlorohy- drin, propiolactone, and vinyl acetate.

Method of Manufacture

Monoethanolamine is prepared commercially by the ammon- olysis of ethylene oxide. The reaction yields a mixture of monoethanolamine, diethanolamine, and triethanolamine, which is separated to obtain the pure products. Monoethanol- amine is also produced from the reaction between nitromethane and formaldehyde.

Safety

Monoethanolamine is an irritant, caustic material, but when it is used in neutralized parenteral and topical pharmaceutical formulations it is not usually associated with adverse effects, although hypersensitivity reactions have been reported. Mono- ethanolamine salts are generally regarded as being less toxic than monoethanolamine.

LD50 (mouse, IP): 0.05 g/kg(2) LD50 (mouse, oral): 0.7 g/kg LD50 (rabbit, skin): 1.0 g/kg LD50 (rat, IM): 1.75 g/kg LD50 (rat, IP): 0.07 g/kg

LD50 (rat, IV): 0.23 g/kg LD50 (rat, oral): 1.72 g/kg LD50 (rat, SC): 1.5 g/kg

Handling Precautions

When handling concentrated solutions of monoethanolamine, personal protective equipment such as an appropriate respira- tor, chemically resistant gloves, safety goggles, and other protective clothing should be worn. Transfer or prepare monoethanolamine solutions only in a chemical fume hood.

Vapors may flow along surfaces to distant ignition sources and flash back. Closed containers exposed to heat may explode. Contact with strong oxidizers may cause fire.

In the UK, the short-term (15-minute) occupational expo- sure limit for monoethanolamine is 15 mg/m3 (6 ppm) and the long-term exposure limit (8-hour TWA) is 7.6 mg/m3 (3 ppm).(3)

Regulatory Status

Included in parenteral and nonparenteral medicines licensed in the UK and US. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Diethanolamine; triethanolamine.

Comments

The EINECS number for monoethanolamine is 205-483-3.

Specific References

Crotty B, Wood LJ, Willett IR, et al. The management of acutely bleeding varices by injection sclerotherapy. Med J Aust 1986; 145: 130–133.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1607–1608.

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

General References

Kubis A, Jadach W, Malecka K. Studies on the release of solubilized drugs from ointment bases. Pharmazie 1984; 39: 168–170.

USPNF: Monosodium glutamate

Synonyms

Chinese seasoning; E621; glutamic acid monosodium salt; glutamic acid, sodium salt; MSG; monosodium L-glutamate monohydrate; natrii glutamas; sodium L-glutamate; sodium glutamate monohydrate; sodium hydrogen L-(+)-2-amino- glutarate monohydrate.

Chemical Name and CAS Registry Number

Glutamic acid monosodium salt monohydrate [142-47-2]

Empirical Formula and Molecular Weight

C5H8NO4Na 169.13 (anhydrous)

C5H8NO4Na·H2O 187.13 (monohydrate)

Table I: Pharmacopeial specifications for monosodium glutamate.

Test USPNF 23

Identification +

Clarity and color of solution +

Specific rotation +24.88 to +25.38

pH (5% solution) 6.7–7.2

Organic volatile impurities +

Assay 99.0–100.5%

Typical Properties

Acidity/alkalinity: pH = 7.0 (0.2% w/v aqueous solution)

Melting point: 2328C

Solubility: soluble in water; sparingly soluble in ethanol (95%).

Specific rotation [a]25 +24.28 to +25.58 at 258C (8.0% w/v in

Structural Formula

Functional Category

Buffering agent; flavor enhancer.

Applications in Pharmaceutical Formulation or Technology

Monosodium glutamate is used in oral pharmaceutical formulations as a buffer and a flavor enhancer. For example, it is used with sugar to improve the palatability of bitter-tasting drugs and can reduce the metallic taste of iron-containing liquids. However, the most widespread use of monosodium glutamate is as a flavor enhancer in food products. Typically, 0.2–0.9% is used in normally salted foods, although products such as soy protein can contain 10–30%. The use of monosodium glutamate in food products has been controver- sial owing to the relatively high number of adverse reactions attributed to the substance, which gives rise to the so-called ‘Chinese Restaurant Syndrome’ (see Section 18).

Description

Monosodium glutamate occurs as white free-flowing crystals or a crystalline powder. It is practically odorless and has a meat- like taste.

Pharmacopeial Specifications

See Table I.

1.0 N HCl)

Stability and Storage Conditions

Aqueous solutions of monosodium glutamate may be sterilized by autoclaving. Monosodium glutamate should be stored in a tight container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Monosodium glutamate is the monosodium salt of the naturally occurring L-form of glutamic acid. It is commonly manufactured by fermentation of carbohydrate sources such as sugar beet molasses. In general, sugar beet products are used in Europe and the USA. Other carbohydrate sources such as sugar cane and tapioca are used in Asia.

Safety

Monosodium glutamate is widely used in foods and oral pharmaceutical formulations. It is generally regarded as moderately toxic on ingestion or intravenous administration. Adverse effects include somnolence, hallucinations and dis- torted perceptions, headache, dyspnea, nausea or vomiting, and dermatitis. The lowest lethal oral dose in humans is reported to be 43 mg/kg.(1) See also Section 18.

LD50 (cat, SC): 8.0 g/kg(1) LD50 (guinea pig, IP): 15 g/kg LD50 (mouse, IP): 3.8 g/kg LD50 (mouse, IV): 30 g/kg LD50 (mouse, oral): 11.4 g/kg LD50 (mouse, SC): 8.2 g/kg LD50 (rat, IP): 4.3 g/kg

Monosodium Glutamate 481

LD50 (rat, IV): 3.3 g/kg LD50 (rat, oral): 16.6 g/kg LD50 (rat, SC): 5.6 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When heated to decomposi- tion, monosodium glutamate emits toxic fumes of NOx and Na2O.

Regulatory Status

GRAS listed. Accepted in Europe for use as a food additive in certain applications. Included in the FDA Inactive Ingredients Guide (oral syrup). Included in nonparenteral medicines licensed in the UK.

Related Substances

—

Comments

Monosodium glutamate has been associated with reports of adverse reactions termed ‘Chinese Restaurant Syndrome’ after it was first self-reported by a physician who regularly experienced numbness and palpitations after consuming Chinese food.(2)

Subsequent to this first report, numerous other anecdotal reports of adverse reactions to monosodium glutamate were made, with symptoms occurring at doses of 1.5–12 g. Reactions include paresthesias or a skin burning sensation, facial pressure or tightness sensation, and substernal chest pressure. Severity of reaction corresponded with increased dose. Reports of ‘Chinese Restaurant Syndrome’ in children are rare. A variety of other adverse reactions to monosodium glutamate have also been reported including flushing, asthma,(3) headache, behavioral abnormalities, and ventricular tachycardia.(4)

Placebo-controlled, blinded, trials of monosodium gluta- mate consumption have, however, largely failed to reproduce the full effects of ‘Chinese Restaurant Syndrome’ as it was originally described and symptoms may be simply due to dyspepsia. Some dose-dependent adverse reactions may be

attributed to monosodium glutamate, with doses of 5 g producing reactions in 30% of individuals tested.(5) In the USA, the FDA has stated that monosodium glutamate and related substances are safe food ingredients for most people when used at ‘customary’ levels.(6)

Monosodium glutamate monohydrate 32 g is approxi- mately equivalent to anhydrous monosodium glutamate 29 g or glutamic acid 25 g. Each gram of monosodium glutamate monohydrate represents 5.3 mmol (5.3 mEq) of sodium.

A specification for monosodium glutamate is contained in the Food Chemicals Codex (FCC). The EINECS number for monosodium glutamate is 205-538-1.

Specific References

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2573.

Kwok HM. Chinese restaurant syndrome. N Engl J Med 1968;

278: 796.

Allen DH, Baker GH. Chinese restaurant asthma. N Engl J Med

1981; 305: 1154–1155.

Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. Boca Raton, FL: CRC Press, 1992: 235–241.

Kenney RA. The Chinese restaurant syndrome: an anecdote revisited. Food Chem Toxicol 1986; 24: 351–354.

Anonymous. Monosodium glutamate safe for most people, says FDA. Pharm J 1996; 256: 83.

General References

Chevassus H, Renard E, Bertrand G, et al. Effects of oral monosodium L-glutamate on insulin secretion and glucose tolerance in healthy volunteers. Br J Clin Pharmacol 2002; 53(6): 641–643.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 335.

Walker R. The significance of excursions above the ADI. Case study: monosodium glutamate. Reg Toxicol Pharmacol 1999; 30: S119– S121.

USPNF: Monothioglycerol

Synonyms

Mercaptoglycerol; 1-mercapto-2,3-propanediol; monothio- glycerin; a-monothioglycerol; thioglycerin; 1-thioglycerol.

Chemical Name and CAS Registry Number

3-Mercapto-1,2-propanediol [96-27-5]

Empirical Formula and Molecular Weight

C3H8O2S 108.16

Structural Formula

Functional Category

Antimicrobial preservative; antioxidant.

Applications in Pharmaceutical Formulation or Technology

Monothioglycerol is used as an antioxidant in pharmaceutical formulations, mainly in parenteral preparations.(1) Monothio- glycerol is reported to have some antimicrobial activity.(2–4) It is also widely used in cosmetic formulations such as depilating agents.

Therapeutically, monothioglycerol has been used in a 0.02% w/w aqueous solution to stimulate wound healing, and as a 0.1% w/w jelly in atrophic rhinitis.

Description

Monothioglycerol occurs as a colorless or pale-yellow colored, viscous, hygroscopic liquid with a slight odor of sulfide.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for monothioglycerol.

Test USPNF 23

Specific gravity 1.241–1.250

Refractive index 1.521–1.526

pH (10% aqueous solution) 3.5–7.0

Water 45.0%

Residue on ignition 40.1%

Selenium 40.003%

Heavy metals 40.002%

Organic volatile impurities +

Assay (anhydrous basis) 97.0–101.0%

Typical Properties

Acidity/alkalinity: pH = 3.5–7.0 (10% w/v aqueous solution)

Boiling point: 1188C

Flash point: 1108C

Refractive index: n25 = 1.521–1.526

Solubility: miscible with ethanol (95%); freely soluble in water; practically insoluble in ether.

Specific gravity: 1.241–1.250

Stability and Storage Conditions

Monothioglycerol is unstable in alkaline solutions. Monothio- glycerol should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Monothioglycerol can react with oxidizing materials.

Method of Manufacture

Monothioglycerol is prepared by heating an ethanolic solution of 3-chloro-1,2-propanediol with potassium bisulfide.

Safety

Monothioglycerol is generally regarded as a relatively nontoxic and nonirritant material at the concentrations used as a pharmaceutical excipient. It is used in topical and injectable preparations.

Undiluted monothioglycerol is considered a poison by the IP and IV routes; it has also been reported to be mutagenic.(5)

LD50 (cat, IV): 0.22 g/kg(5)

LD50 (mouse, IP): 0.34 g/kg LD50 (rabbit, IV): 0.25 g/kg LD50 (rat, IP): 0.39 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Monothioglycerol is flammable when exposed to heat or flame; when heated to decomposition it emits toxic fumes of SOx.

Monothioglycerol 483

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM, IV and other injections). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

The EINECS number for monothioglycerol is 202-495-0.

Specific References

Kasraian K, Kuzniar AA, Wilson GG, Wood JA. Developing an injectable formula containing an oxygen sensitive drug: case study of danofloxacin injectable. Pharm Dev Technol 1999; 4(4): 475–

480.

Jensen KK, Javor GT. Inhibition of Escherichia coli by thioglycerol.

Antimicrob Agents Chemother 1981; 19: 556–561.

Javor GT. Depression of adenoslymethionine content of Escher- ichia coli by thioglycerol. Antimicrob Agents Chemother 1983; 24:

860–867.

Javor GT. Inhibition of respiration of Escherichia coli by thioglycerol. Antimicrob Agents Chemother 1983; 24: 868–870.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2574.

General References

Nealon DA, Pettit SM, Henderson AR. Diluent pH and the stability of the thiol group in monothioglycerol, N-acetyl-L-cysteine, and 2- mercaptoethanol. Clin Chem 1981; 27(3): 505–506.

Authors

PJ Sheskey, PJ Weller.

Edenor C14 98-100; n-tetradecanoic acid; 1-tridecanecar- boxylic acid.

Chemical Name and CAS Registry Number

Tetradecanoic acid [544-63-8]

Empirical Formula and Molecular Weight

C14H28O2 228.37

Structural Formula

Functional Category

Emulsifying agent; skin penetrant; tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Myristic acid is used in oral and topical pharmaceutical formulations. Myristic acid has been evaluated as a penetration enhancer in melatonin transdermal patches in rats(1) and bupropion formulations on human cadaver skin.(2) Further studies have assessed the suitability of myristic acid in oxymorphone formulations(3) and clobetasol 17-propionate topical applications.(4)

Description

Myristic acid occurs as an oily white crystalline solid with a faint odor.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Boiling point: 326.28C Flash point: >1108C Melting point: 54.58C

Solubility: soluble in acetone, benzene, chloroform, ethanol (95%), ether, and aromatic and chlorinated solvents; practically insoluble in water.

Specific gravity: 0.860–0.870

Stability and Storage Conditions

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

Incompatibilities

Myristic acid is incompatible with strong oxidizing agents and bases.

Method of Manufacture

Myristic acid occurs naturally in nutmeg butter and in most animal and vegetables fats. Synthetically, it may be prepared by electrolysis of methyl hydrogen adipate and decanoic acid or by Maurer oxidation of myristyl alcohol.

Safety

Myristic acid is used in oral and topical pharmaceutical formulations and is generally regarded as nontoxic and nonirritant at the levels employed as an excipient. However, myristic acid is reported to be an eye and skin irritant at high levels and is poisonous by intravenous administration. Muta- tion data have also been reported.(5)

LD50 (mouse, IV): 43 mg/kg(5) LD50 (rat, oral): >10 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled. Acrid smoke and irritating fumes are emitted when myristic acid is heated to decomposition.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral capsules). Included in nonparenteral medicines licensed in the UK.

Related Substances

Lauric acid; myristyl alcohol; palmitic acid; potassium myr- istate; sodium myristate; stearic acid.

Myristyl alcohol

Empirical formula: C14H30O

Molecular weight: 214.39

CAS number: [112-72-1] Melting point: 37–398C Boiling point: 277–2888C Specific gravity: 0.8

Solubility: practically insoluble in water.

Potassium myristate

Empirical formula: C14H28O2K

Molecular weight: 267.52

CAS number: [13429-27-1]

Myristic Acid 485

Comments: potassium myristate is used as surfactant and emulsifying agent in pharmaceutical formulations. The EINECS number for potassium myristate is 236-550-5.

Sodium myristate

Empirical formula: C14H28O2Na

Molecular weight: 251.41

CAS number: [822-12-8]

Comments: sodium myristate is used as an emulsifying agent in pharmaceutical formulations. The EINECS number for sodium myristate is 212-487-9.

Comments

Although not included in any pharmacopeias, a specification for myristic acid is contained in the Food Chemicals Codex (FCC) and in the Japanese Pharmaceutical Excipients (JPE), see Table I.

The EINECS number for myristic acid is 208-875-2.

Table I: Food Chemicals Codex(6) and Japanese Pharmaceutical Excipients(7) specifications for myristic acid.

Specific References

Kanikkannan N, Andega S, Burton S, et al. Formulation and in vitro evaluation of transdermal patches of melatonin. Drug Dev Ind Pharm 2004; 30: 205–212.

Gondaliya D, Pundarikakshudu K. Studies in formulation and pharmacotechnical evaluation of controlled release transdermal delivery system of bupropion. AAPS PharmSci Tech 2003; 4: E3.

Aungst BJ, Blake JA, Rogers NJ, Hussain MA. Transdermal oxymorphone formulation development and methods for evaluat- ing flux and lag times for two skin permeation-enhancing vehicles. J Pharm Sci 1990; 79: 1072–1076.

Fang JY, Shen KL, Huang YB, et al. Evaluation of topical application of clobetasol 17-propionate from various cream bases. Drug Dev Ind Pharm 1999; 25: 7–14.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2586.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 262.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 572.

20 General References

Neohesperidin Dihydrochalcone

Nonproprietary Names

BP: Neohesperidin dihydrochalcone PhEur: Neohesperidin dihydrochalconum

Synonyms

Citrosa; 3,5-dihydroxy-4-(3-hydroxy-4-methoxyhydrocinna- moyl)phenyl-2-O-(6-deoxy-a-L-mannopyranosyl)-b-D-gluco- pyranoside; 3,5-dihydroxy-4-[3-(3-hydroxy-4-methoxyphenyl) propionyl]phenyl-2-O-(6-deoxy-a-L-mannopyranosyl)-b-D- glucopyranoside; E959; neohesperidin DC; neohesperidin DHC; neohesperidine dihydrochalcone; NHDC; 1-propanone, 1-[4-[[2-O-6-deoxy-a-L-mannopyranosyl)-b-D-glycopyranosyl

]oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl);

Sukor.

Chemical Name and CAS Registry Number

1-[4-[[2-O-(6-Deoxy-a-L-mannopyranosyl)-b-D-glucopyrano- syl]oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphe- nyl)propan-1-one [20702-77-6]

Empirical Formula and Molecular Weight

C28H36O15 612.58

Structural Formula

Functional Category

Flavor enhancer; sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Neohesperidin dihydrochalcone is a synthetic intense sweet- ening agent approximately 1500–1800 times sweeter than sucrose and 20 times sweeter than saccharin. Structurally it is an analogue of neohesperidin, a flavanone that occurs naturally in Seville oranges (Citrus aurantium). Neohesperidin dihydro- chalcone is used in pharmaceutical and food applications as a sweetening agent and flavor enhancer. The sweetness profile is characterized by a lingering sweet/menthol-like aftertaste.(1)

The typical level used in foods is 1–5 ppm although much higher levels may be used in certain applications such as chewing gum. Synergistic effects occur with other intense and bulk sweeteners such as acesulfame K, aspartame, polyols, and saccharin.(2)

In pharmaceutical applications, neohesperidin dihydrochal- cone is useful in masking the unpleasant bitter taste of a number of drugs such as antacids, antibiotics, and vitamins. In antacid preparations levels of 10–30 ppm result in improved palat- ability.

Description

Neohesperidin dihydrochalcone occurs as a white or yellowish- white powder with an intensely sweet taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for neohesperidin dihydrochalcone.

Test PhEur 2005

Identification +

Characters +

Appearance of solution +

Assay (anhydrous substance) 96.0–101.0%

Typical Properties

Hygroscopicity: slightly hygroscopic; absorbs up to 15% of water.

Melting point: 156–1588C

Solubility: see Table II.

Table II: Solubility of neohesperidin dihydrochalcone.

Solvent Solubility at 258C unless otherwise stated

Dichloromethane Practically insoluble

Dimethyl sulfoxide Freely soluble

Methanol Soluble

Water 1 in 2000 at 228C

1 in 1.54 at 808C

Stability and Storage Conditions

Neohesperidin dihydrochalcone is stable for over three years when stored at room temperature.(1)

Accelerated stability studies on aqueous solutions stored at 30–608C and pH 1–7 for 140 days indicate that neohes-

Neohesperidin Dihydrochalcone 487

peridin dihydrochalcone solutions are likely to be stable for 12 months at room temperature and pH 2–6.(3) Solutions formulated with some or all of the water replaced by solvents with a lower dielectric constant are reported to have longer shelf-lives.(4)

The bulk material should be stored in a cool, dry, place protected from light.

Incompatibilities

—

Method of Manufacture

Neohesperidin dihydrochalcone is synthesized commercially from either of the bitter-flavanones neohesperidin or naringin by catalytic hydrogenation under alkaline conditions in a process first described in the 1960s, in which neohesperidin is purified by recrystallization from water solutions.(5) Neohes- peridin dihydrochalcone is obtained by the alkaline hydro- genation of neohesperidin.(6)

Safety

Neohesperidin dihydrochalcone is accepted for use in food products either as a sweetener or flavor modifier in a number of areas including Europe, US, Australia, New Zealand, and several countries in Africa and Asia. It is also used in a number of oral pharmaceutical formulations.

Animal toxicity studies suggest that neohesperidin dihy- drochalcone is a nontoxic, nonteratogenic, and noncarcino- genic material at the levels used in foods and pharmaceuticals.(7,8) In Europe, an acceptable daily intake of 0–5 mg/kg bodyweight has been established.(9,10)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe.

Related Substances

Hesperidin.

Hesperidin

Empirical formula: C28H34O15

Molecular weight: 610.56

CAS number: [520-26-3]

Synonyms: (2S)-7-[[6-O-(6-Deoxy-a-L-mannopyranosyl)-b-D- glucopyranosyl]oxy]-2,3-dihydro-5-hydroxy-2-(3-hydroxy- 4-methoxyphenyl)-4H-1-benzopyran-4-one; hesperitin 7- rhamnoglucoside; hesperetin-7-rutinoside.

Melting point: 258–2628C

Solubility: freely soluble in diluted alkalis and pyridines; soluble in formamide; slightly soluble in methanol and hot glacial acetic acid.

Comments: hesperedin is the predominant flavonoid in lemons and sweet oranges (Citrus sinensis).

Comments

Neohesperidin dihydrochalcone is sufficiently soluble in aqueous solutions for most pharmaceutical and food applica- tions; however, solubility may be improved by dissolving in

ethanol, glycerin, propylene glycol, or aqueous mixtures of these solvents.(10) Solubility may also be improved by mixing with other intense or bulk sweeteners.(2)

Neohesperidin dihydrochalcone in weak concentrations has been shown not to enhance the taste of aqueous sucrose solutions.(6)

The EINECS number for neohesperidin dihydrochalcone is 243-978-6.

Specific References

Cano J, Montijano H, Lopez Cremades F. Masking the bitter taste of pharmaceuticals. Manuf Chem 2000; 71(7): 16–17.

Benavente-Garcia O, Castillo J, Del Bano MJ, Lorente J. Improved water solubility of neohesperidin dihydrochalcone sweetener blends. J Agric Food Chem 2001; 49(1): 189–191.

Canales I, Borrego F, Lindley MG. Neohesperidin dihydrochalcone stability in aqueous buffer solutions. J Food Sci 1993; 58: 589– 591, 643.

Montijano H, Borrego F. Hydrolysis of the intense sweetener neohesperidine dihydrochalcone in water–organic solvent mix- tures. Int J Food Sci Technol 1999; 34: 291–294.

Horowitz RM, Gentili B. Dihydrochalcone derivatives and their use as sweetening agents. US Patent No. 3,087,821; 1963.

Kroeze JH. Neohesperidine dihydrochalcone is not a taste enhancer in aqueous solutions. Chem Senses 2000; 25(5): 555–

559.

Lina BAR, Dreef-van der Meulen HC, Leegwater DC. Subchronic (13-week) oral toxicity of neohesperidin dihydrochalcone in rats. Food Chem Toxicol 1990; 28(7): 507–513.

Waalkens-Berendsen DH, Kuilman-Wahls ME, Bar A. Embryo- toxicity and teratogenicity study with neohesperidin dihydrochal- cone in rats. Regul Toxicol Pharmacol 2004; 40(1): 74–79.

Horowitz RM, Gentili B. Dihydrochalcone sweeteners from citrus flavanones. In: O’Brien Nabors L, Gelardi RC, eds. Alternative Sweeteners, 2nd edn. New York: Marcel Dekker, 1991: 97–115.

Borrego F, Montijano H. Neohesperidin dihydrochalcone. In: O’Brien Nabors L, ed. Alternative Sweeteners, 3rd edn. New York: Marcel Dekker, 2001: 87–104.

General References

Borrego F, Montijano H. Potential applications of the sweetener neohesperidin dihydrochalcone in drugs [in German]. Pharm Ind 1995; 57: 880–882.

Borrego F. Neohesperidine DC. In: Birch G, ed. Ingredients Handbook: Sweeteners, 2nd edn. Leatherhead: Leatherhead Publishing, 2000: 205–220.

Colaizzi JL. Synthetic sweeteners—toxicity problems and current status. J Am Pharm Assoc 1971; NS11(Mar): 135–138.

DuBois GE, Crosby GA, Saffron P. Non-nutritive sweeteners: taste– structure relationships for some new simple dihydrochalcones. Science 1977; 195: 397–399.

Lautenbacher L. Neohesperidin DC (PhEur): an exceptional sweetener from Spanish bitter oranges—application and approval in finished drugs [in German]. Pharm Ind 2003; 65: 82–83.

Lindley MG. Neohesperidine dihydrochalcone: recent findings and technical advances. In: Grenby TH, ed. Advances in Sweeteners. Glasgow: Blackie Academic and Professional, 1996: 240–252.

Nakazato M, Kobayashi C, Yamajima Y, et al. Determination of neohesperidin dihydrochalcone in foods [in Japanese]. Shokuhin Eiseigaku Zasshi 2001; 42(1): 40–44.

BP: Nitrogen JP: Nitrogen

PhEur: Nitrogenium USPNF: Nitrogen

Synonyms

Azote; E941.

Chemical Name and CAS Registry Number

Nitrogen [7727-37-9]

Empirical Formula and Molecular Weight

N2 28.01

Structural Formula

Functional Category

Aerosol propellant; air displacement.

Applications in Pharmaceutical Formulation or Technology

Nitrogen and other compressed gases such as carbon dioxide and nitrous oxide are used as propellants for topical pharmaceutical aerosols. They are also used in other aerosol products that work satisfactorily with the coarse aerosol spray produced with compressed gases, e.g. furniture polish and window cleaner. Nitrogen is insoluble in water and other solvents, and therefore remains separated from the actual pharmaceutical formulation.

Advantages of compressed gases as aerosol propellants are that they are inexpensive; of low toxicity; and practically odorless and tasteless. In contrast to liquefied gases, their pressures change relatively little with temperature. However, there is no reservoir of propellant in the aerosol and as a result the pressure decreases as the product is used, changing the spray characteristics.

Misuse of a product by the consumer, such as using a product inverted, results in the discharge of the vapor phase instead of the liquid phase. Most of the propellant is contained in the vapor phase and therefore some of the propellant will be lost and the spray characteristics will be altered. Additionally, the sprays produced using compressed gases are very wet. However, recent developments in valve technology have reduced the risk of misuse by making available valves which will spray only the product (not propellant) regardless of the position of the container. Additionally, barrier systems will also prevent loss of propellant.

Nitrogen is also used to displace air from solutions subject to oxidation, by sparging, and to replace air in the headspace above products in their final packaging, e.g. in parenteral

products packaged in glass ampoules. Nitrogen is also used for the same purpose in many food products.

Description

Nitrogen occurs naturally as approximately 78% v/v of the atmosphere. It is a nonreactive, noncombustible, colorless, tasteless, and odorless gas. It is usually handled as a compressed gas, stored in metal cylinders.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for nitrogen.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Odor — — +

Carbon monoxide — 45 ppm 40.001%

Carbon dioxide + 4300 ppm —

Water — 467 ppm —

Oxygen — 450 ppm 41.0%

Assay 599.5% 599.5% 599.0%

Typical Properties

Boiling point: —195.88C

Critical pressure: 3.39 mPa (33.49 atm) Critical temperature: —147.28C Density: 0.967 g/cm3 for vapor at 218C. Flammability: nonflammable

Melting point: —2108C

Solubility: practically insoluble in water and most solvents; soluble in water under pressure.

Vapor density (absolute): 1.25 g/cm3 at standard temperature and pressure.

Vapor density (relative): 0.97 (air = 1)

Stability and Storage Conditions

Nitrogen is stable and chemically unreactive. It should be stored in tightly sealed metal cylinders in a cool, dry place.

kywods

728x90

468x60.

mob

mercredi 6 novembre 2024

Aucun commentaire:

Enregistrer un commentaire

pop

slder

redect

push