kywods

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Hexetidine may be harmful upon inhalation or on contact with the skin or eyes. Eye protection and gloves are recommended. When significant quantities are being handled, the use of a respirator with an appropriate gas filter is recommended.

Regulatory Status

Included in nonparenteral formulations licensed in Europe.

Related Substances

—

Comments

Hexetidine has been quantitatively determined in both com- mercial formulations and saliva using a reversed-phase HPLC method,(11) with determination being possible at concentra- tions below the published minimum inhibitory concentrations for a selection of microorganisms.

The EINECS number for hexetidine is 205-513-5.

Specific References

Gorman SP, McGovern JG, Woolfson AD, et al. The concomitant development of poly(vinyl chloride)-related biofilm and antimi- crobial resistance in relation to ventilator-associated pneumonia. Biomaterials 2001; 22(20): 2741–2747.

Guiliana G, Pizzo G, Milici ME, Giangreco R. In vitro activities of antimicrobial agents against Candida species. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87(1): 44–49.

Williams MJR, Adams D, Hillam DG, Ashley KC. The effect of hexetidine 0.1% in the control of dental plaque. Br Dent J 1987; 163(9): 300–302.

Wile DB, Dinsdale JRM, Joynson DHM. Hexetidine (Oraldene) – a report on its antibacterial and antifungal properties on the oral flora in healthy subjects. Curr Med Res Opin 1986; 10(2): 82–88.

Bokor M. The effect of hexetidine spray on dental plaque following periodontal surgery. J Clin Periodontol 1996; 23(12): 1080–1083.

Roberts WR, Addy M. Comparison of the in vivo and in vitro antibacterial properties of antiseptic mouthrinses containing chlorhexidine, alexidine, cetylpyridinium chloride and hexetidine – relevance to mode of action. J Clin Periodontol 1981; 8(4): 295–

310.

Pilloni AP, Buttini G, Giannerelli D, et al. Antimicrobial action of Nitens mouthwash (cetylpyridinium naproxenate) on multiple isolates of pharyngeal microbes: a controlled study against chlorhexidine, benzydamine, hexetidine, amoxicillin clavulanate, clarithromycin and cefaclor. Chemotherapy 2002; 48(4): 168–173

Sharma NC, Galustians HJ, Qaqish J, et al. Antiplaque and antigingivitis effectiveness of a hexetidine mouthwash. J Clin Periodontol 2003; 30(7): 590–594.

Jones DS, McGovern JG, Woolfson AD, Gorman SP. The effects of hexetidine (Oraldene) on the adherence of Candida albicans to human buccal epithelial cells in vitro and ex vivo and on in vitro morphogenesis. Pharm Res 1997; 14(12): 1765–1771.

Gozalbes R, Galvez J, Moreno A, Garcia-Domenech R. Discovery of new antimalarial compounds by use of molecular connectivity techniques. J Pharm Pharmacol 1999; 51(2): 111–117.

McCoy CP, Jones DS, McGovern JG, et al. Determination of the salivary retention of hexetidine in-vivo by high-performance liquid chromatography. J Pharm Pharmacol 2000; 52(11): 1355–1359.

General References

Eley BM. Antibacterial agents in the control of supragingival plaque – a review. Br Dent Rev 1999; 186(6): 286–296.

Jones DS, McGovern JG, Woolfson AD, et al. Physicochemical characterization of hexetidine-impregnated endotracheal tube poly(vinyl chloride) and resistance to adherence of respiratory bacterial pathogens. Pharm Res 2002; 19(6): 818–824.

A-17; Aeropres 17; n-butane; E943a

A-31; Aeropres 31; E943b; 2-methylpropane

A-108; Aeropres 108; dimethylmethane; E944; propyl hydride

Chemical Name and CAS Registry Number

Butane [106-97-8]

2-Methylpropane [75-28-5]

Propane [74-98-6]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Propane, butane, and isobutane are hydrocarbons (HC). They are used as aerosol propellants: alone, in combination with each other, and in combination with a hydrofluoroalkane (HFA) propellant. They are used primarily in topical pharma- ceutical aerosols (particularly aqueous foam and some spray products).

Depending upon the application, the concentration of hydrocarbon propellant range is 5–95% w/w. Foam aerosols generally use about 4–5% w/w of a hydrocarbon propellant consisting of isobutane (84.1%) and propane (15.9%), or isobutane alone. Spray-type aerosols utilize propellant concen- trations of 50% w/w and higher.(1)

Hydrocarbon propellants are also used in cosmetics and food products as aerosol propellants.

Only highly purified hydrocarbon grades can be used for pharmaceutical formulations since they may contain traces of unsaturated compounds that not only contribute a slight odor to a product but may also react with other ingredients.

Description

Hydrocarbon propellants are liquefied gases and exist as liquids at room temperature when contained under their own vapor pressure, or as gases when exposed to room temperature and atmospheric pressure. They are essentially clear, colorless, odorless liquids but may have a slight etherlike odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for hydrocarbons from the USPNF 23.

Test Butane Isobutane Propane

Identification + + +

Water 40.001% 40.001% 40.001%

High-boiling residues 45 mg/mL 45 mg/mL 45 mg/mL

Acidity of residue + + +

Sulfur compounds + + +

Assay 597.0% 595.0% 598.0%

Typical Properties

See Table II for selected typical properties.

Stability and Storage Conditions

Butane and the other hydrocarbons used as aerosol propellants are stable compounds and are chemically nonreactive when used as propellants. They are, however, highly flammable and explosive when mixed with certain concentrations of air; see Section 10.(2) They should be stored in a well-ventilated area, in a tightly sealed cylinder. Exposure to excessive heat should be avoided.

326 Hydrocarbons (HC)

Table II: Selected typical properties for hydrocarbon propellants.

Butane Isobutane Propane

Autoignition temperature 4058C 4208C 4688C

Boiling point —0.58C —11.78C –42.18C

Critical pressure 3.80 MPa (37.47 atm) 3.65 MPa (36 atm) 4.26 MPa (42.01 atm)

Critical temperature 1528C 1358C 96.88C

Density: liquid at 208C 0.58 g/cm3 0.56 g/cm3 0.50 g/cm3

Explosive limits

Lower limit 1.9% v/v 1.8% v/v 2.2% v/v

Upper limit 8.5% v/v 8.4% v/v 9.5% v/v

Flash point —628C —838C —104.58C

Freezing point —138.38C —159.78C —187.78C

Kauri-butanol value 19.5 17.5 15.2

Relative 2.046 (air = 1) 2.01 (air = 1) 1.53 (air = 1)

Vapor pressure at 218C 113.8 kPa (16.5 psig) 209.6 kPa (30.4 psig) 758.4 kPa (110.0 psig)

Vapor pressure at 54.58C — 661.9 kPa (96.0 psig) 1765.1 kPa (256 psig)

Incompatibilities

Other than their lack of miscibility with water, butane and the other hydrocarbon propellants do not have any practical incompatibilities with the ingredients commonly used in pharmaceutical aerosol formulations. Hydrocarbon propel- lants are generally miscible with nonpolar materials and some semipolar compounds such as ethanol.

Method of Manufacture

Butane and isobutane are obtained by the fractional distillation, under pressure, of crude petroleum and natural gas. They may be purified by passing through a molecular sieve to remove any unsaturated compounds that are present.

Propane is prepared by the same method. It may also be prepared by a variety of synthetic methods.

Safety

The hydrocarbons are not generally regarded as toxic materials when used as aerosol propellants. However, deliberate inhala- tion of aerosol products containing hydrocarbon propellants can be fatal.

Handling Precautions

Butane and the other hydrocarbon propellants are liquefied gases and should be handled with appropriate caution. Direct contact of liquefied gas with the skin is hazardous and may result in serious cold burn injuries. Protective clothing, rubber gloves, and eye protection are recommended.

Butane, isobutane, and propane are asphyxiants and should be handled in a well-ventilated environment; it is recommended that environmental oxygen levels are monitored and not permitted to fall below a concentration of 18% v/v. These vapors do not support life; therefore when cleaning large tanks, adequate provisions for oxygen supply must be provided for personnel cleaning the tanks. Butane is highly flammable and explosive and must only be handled in an explosion-proof room that is equipped with adequate safety warning devices and explosion-proof equipment.

To fight fires, the flow of gas should be stopped and dry powder extinguishers should be used.

Regulatory Status

GRAS listed. Butane, isobutane, and propane are accepted for use as food additives in Europe. Included in the FDA Inactive Ingredients Guide (aerosol formulations for topical applica- tion). Included in nonparental medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Dimethyl ether.

Comments

Although hydrocarbon aerosol propellants are relatively inexpensive, nontoxic, and environmentally friendly (since they are not damaging to the ozone layer and are not greenhouse gases), their use is limited by their flammability. While hydrocarbon propellants are primarily used in topical aerosol formulations, it is possible that butane may also be useful in metered-dose inhalers as a replacement for chloro- fluorocarbons.

Various blends of hydrocarbon propellants that have a range of physical properties suitable for different applications are commercially available, e.g., CAP30 (Calor Gas Ltd.) is a mixture of 11% propane, 29% isobutane, and 60% butane. A- 46 (Aeropres) is a commonly used mixture for aerosol foams and consists of about 85% isobutane and 15% propane. The number following the letter denotes the approximate vapor pressure of the blend or mixture.

Specific References

Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 547–574.

Dalby RN. Prediction and assessment of flammability hazards associated with metered-dose inhalers containing flammable propellants. Pharm Res 1992; 9: 636–642.

Hydrocarbons (HC) 327

General References

Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE Dorland, 1982: 199–255, 335–361.

Randall DS. Solving the problems of hydrocarbon propellants. Manuf Chem Aerosol News 1979; 50(4): 43, 44, 47.

Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: Van Nostrand Reinhold, 1979: 36–44.

Sciarra JJ. Pharmaceutical aerosols. In: Lackman L, Lieberman HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 3rd edn. Philadelphia: Lea and Febiger, 1986: 589–618.

Sciarra CJ, Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore, MD: Lippincott Williams and Wilkins, 2000: 963–979.

Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger M, Banker G, eds. Pharmaceutical Dosage Forms: Disperse

Systems, vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319– 356.

Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging.

New York: Wiley, 1974: 131–137.

Authors

CJ Sciarra, JJ Sciarra.

BP: Hydrochloric acid JP: Hydrochloric acid

PhEur: Acidum hydrochloridum concentratum USPNF: Hydrochloric acid

Synonyms

Chlorohydric acid; concentrated hydrochloric acid; E507.

Chemical Name and CAS Registry Number

Hydrochloric acid [7647-01-0]

Empirical Formula and Molecular Weight

HCl 36.46

Table I: Pharmacopeial specifications for hydrochloric acid.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters + + —

Appearance of solution — + —

Residue on ignition 41.0 mg — 40.008%

Residue on evaporation — 40.01% —

Bromide or iodide + — +

Free bromine + — +

Free chlorine + 44 ppm +

Sulfate + 420 ppm +

Sulfite + — +

Arsenic 41 ppm — —

Heavy metals 45 ppm 42 ppm 45 ppm

Mercury 40.04 ppm — —

Assay (of HCl) 35.0–38.0% 35.0–39.0% 36.5–38.0%

10 Typical Properties

Acidity/alkalinity: pH = 0.1 (10% v/v aqueous solution)

Boiling point: 1108C (constant boiling mixture of 20.24% w/w

Applications in Pharmaceutical Formulation or Technology

Hydrochloric acid is widely used as an acidifying agent, in a variety of pharmaceutical and food preparations (see Section 16). It may also be used to prepare dilute hydrochloric acid, which in addition to its use as an excipient has some therapeutic use, intravenously in the management of metabolic alkalosis, and orally for the treatment of achlorhydria. See Section 17.

Description

Hydrochloric acid occurs as a clear, colorless, fuming aqueous solution of hydrogen chloride, with a pungent odor.

The JP 2001 specifies that hydrochloric acid contains 35.0–38.0% w/w of HCl; the PhEur 2005 specifies that hydrochloric acid contains 35.0–39.0% w/w of HCl; and the USPNF 23 specifies that hydrochloric acid contains

36.5–38.0% w/w of HCl. See also Section 9.

Pharmacopeial Specifications

See Table I.

Freezing point: ≈—248C

Refractive index: n20 = 1.342 (10% v/v aqueous solution)

Solubility: miscible with water; soluble in diethyl ether, ethanol (95%), and methanol.

Stability and Storage Conditions

Hydrochloric acid should be stored in a well-closed, glass or other inert container at a temperature below 308C. Storage in close proximity to concentrated alkalis, metals, and cyanides should be avoided.

Incompatibilities

Hydrochloric acid reacts violently with alkalis, with the evolution of a large amount of heat. Hydrochloric acid also reacts with many metals, liberating hydrogen.

Method of Manufacture

Hydrochloric acid is an aqueous solution of hydrogen chloride gas produced by a number of methods including: the reaction of sodium chloride and sulfuric acid; the constituent elements; as a by-product from the electrolysis of sodium hydroxide; and as a by-product during the chlorination of hydrocarbons.

Safety

When used diluted, at low concentration, hydrochloric acid is not usually associated with any adverse effects. However, the concentrated solution is corrosive and can cause severe damage on contact with the eyes and skin, or if ingested.

LD50 (mouse, IP): 1.4 g/kg(1) LD50 (rabbit, oral): 0.9 g/kg

Hydrochloric Acid 329

Handling Precautions

Caution should be exercised when handling hydrochloric acid and suitable protection against inhalation and spillage should be taken. Eye protection, gloves, face mask, apron, and respirator are recommended, depending on the circumstances and quantity of hydrochloric acid handled. Spillages should be diluted with copious amounts of water and run to waste. Splashes on the skin and eyes should be treated by immediate and prolonged washing with large amounts of water and medical attention should be sought. Fumes can cause irritation to the eyes, nose, and respiratory system; prolonged exposure to fumes may damage the lungs. In the UK, the recommended short-term exposure limit for hydrogen chloride gas and aerosol mists is 8 mg/m3 (5 ppm). The long-term exposure limit (8-hour TWA) is 2 mg/m3 (1 ppm).(2)

Regulatory Status

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

Related Substances

Dilute hydrochloric acid.

Dilute hydrochloric acid

Synonyms: acidum hydrochloridum dilutum; diluted hydro- chloric acid.

Density: ≈1.05 g/cm3 at 208C

Comments: the JP 2001 and PhEur 2005 specify that dilute hydrochloric acid contains 9.5–10.5% w/w of HCl and is

prepared by mixing 274 g of hydrochloric acid with 726 g of water. The USPNF 23 specifies 9.5–10.5% w/v of HCl, prepared by mixing 226 mL of hydrochloric acid with sufficient water to make 1000 mL.

Comments

In pharmaceutical formulations, dilute hydrochloric acid is usually used as an acidifying agent in preference to hydro- chloric acid. Hydrochloric acid is also used therapeutically as an escharotic.(3) The PhEur 2005 also contains a specification for hydrochloric acid, dilute; see Section 17.

A specification for hydrochloric acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for hydrochloric acid is 231-595-7.

Specific References

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1980.

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

Sweetman S, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1699.

General References

Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 228.

Hydroxyethyl Cellulose

Nonproprietary Names

BP: Hydroxyethylcellulose PhEur: Hydroxyethylcellulosum USPNF: Hydroxyethyl cellulose

Synonyms

Cellosize HEC; cellulose hydroxyethyl ether; cellulose hydr- oxyethylate; ethylhydroxy cellulose; ethylose; HEC; HE cellulose; 2-hydroxyethyl cellulose ether; hydroxyethyl ether cellulose; hydroxyethyl starch; hyetellose; Natrosol; oxycellu- lose; Tylose PHA.

Chemical Name and CAS Registry Number

Cellulose, 2-hydroxyethyl ether [9004-62-0]

Empirical Formula and Molecular Weight

The USPNF 23 describes hydroxyethyl cellulose as a partially substituted poly(hydroxyethyl) ether of cellulose. It is available in several grades that vary in viscosity and degree of substitution; some grades are modified to improve their dispersion in water. The grades are distinguished by appending a number indicative of the apparent viscosity in mPa s, of a 2% w/v solution measured at 208C. Hydroxyethyl cellulose may also contain a suitable anticaking agent.

See Section 10.

Structural Formula

where R is H or [—CH2CH2O—]mH

Functional Category

Coating agent; suspending agent; tablet binder; thickening agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Hydroxyethyl cellulose is a nonionic, water-soluble polymer widely used in pharmaceutical formulations. It is primarily used as a thickening agent in ophthalmic(1) and topical formula- tions,(2) although it is also used as a binder(3) and film-coating agent for tablets.(4) It is present in lubricant preparations for dry eye, contact lens care, and dry mouth.(5)

The concentration of hydroxyethyl cellulose used in a formulation is dependent upon the solvent and the molecular weight of the grade.

Hydroxyethyl cellulose is also widely used in cosmetics.

Description

Hydroxyethyl cellulose occurs as a light tan or cream to white- colored, odorless and tasteless, hygroscopic powder.

SEM: 1

Excipient: Hydroxyethyl cellulose (Natrosol)

Manufacturer: Aqualon

Magnification: 120×

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 5.5–8.5 for a 1% w/v aqueous solution.

Ash:

2.5% w/w for Cellosize; 3.5% w/w for Natrosol.

Autoignition temperature: 4208C

Density (bulk):

0.35–0.61 g/cm3 for Cellosize;

0.60 g/cm3 for Natrosol.

Melting point: softens at 135–1408C, decomposes at about 2058C.

Hydroxyethyl Cellulose 331

SEM: 2

Excipient: Hydroxyethyl cellulose (Natrosol)

Manufacturer: Aqualon

Magnification: 600×

Solubility: hydroxyethyl cellulose is soluble in either hot or cold water, forming clear, smooth, uniform solutions. Practically insoluble in acetone, ethanol (95%), ether, toluene, and most other organic solvents. In some polar organic solvents, such as the glycols, hydroxyethyl cellulose either swells or is partially soluble.

Specific gravity: 1.38–1.40 for Cellosize; 1.0033 for a 2% w/v aqueous hydroxyethyl cellulose solution.

Surface tension: see Table II.

Table II: Surface tension (mN/m) of different Cellosize (Amerchol Corp.) grades at 258C

Concentration of aqueous solution

(% w/v)

Cellosize grade

WP-02 WP-09 WP-300 QP-4400 QP-52000 QP-100M

0.01 65.8 65.7 66.4 66.3 65.9 66.1

0.1 65.3 65.4 65.8 65.3 65.4 65.4

1.0 64.4 65.1 65.5 65.8 66.1 66.3

2.0 64.2 65.0 66.3 67.3 — —

5.0 64.1 64.7 — — — —

10.0 64.4 65.9 — — — —

Table I: Pharmacopeial specifications for hydroxyethyl cellulose

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Viscosity 75.0–140.0% +

pH 5.5–8.5 6.0–8.5

Loss on drying 410.0% 410.0%

Lead — 40.001%

Residue on ignition 44.0% 45.0%

Chlorides 41.0% —

Heavy metals 420 ppm 420 mg/g

Organic volatile impurities — +

Nitrates + —

Glyoxal 420 ppm —

Ethylene oxide 41 ppm —

2-Chloroethanol 45 ppm —

Nitrates + —

Moisture content: commercially available grades of hydro- xyethylcellulose contain less than 5% w/w of water. However, as hydroxyethyl cellulose is hygroscopic, the amount of water absorbed depends upon the initial moisture content and the relative humidity of the surrounding air. Typical equilibrium moisture values for Natrosol 250 at 258C are: 6% w/w at 50% relative humidity and 29% w/w at 84% relative humidity.

Particle size distribution:

Cellosize: 100% through a US #80 mesh (177 mm); Natrosol (regular grind): 10% retained on a US #40 mesh (420 mm);

Natrosol (X-grind): 0.5% retained on a US #60 mesh (250 mm).

Refractive index: n20 = 1.336 for a 2% w/v aqueous solution.

Viscosity (dynamic): hydroxyethyl cellulose is available in a wide range of viscosity types; e.g. Cellosize is manufactured in 11 regular viscosity grades. Hydroxyethyl cellulose grades differ principally in their aqueous solution viscosities which range from 2–20 000 mPa s for a 2% w/v aqueous solution. Two types of Cellosize are produced, a WP-type, which is a normal-dissolving material, and a QP-type, which is a rapid-dispersing material.

The lowest viscosity grade (02) is available only in the WP-type. Five viscosity grades (09, 3, 40, 300, and 4400) are produced in both WP- and QP-types. Five high-viscosity grades (10000, 15000, 30000, 52000, and 100 M) are

produced only in the QP-type.

For the standard Cellosize grades and types available and their respective viscosity ranges in aqueous solution, see Table III.

Natrosol 250 has a degree of substitution of 2.5 and is produced in 10 viscosity types. The suffix ‘R’ denotes that Natrosol has been surface-treated with glyoxal to aid in solution preparation; see Table IV.

Aqueous solutions made using a rapidly dispersing material may be prepared by dispersing the hydroxyethyl cellulose in mildly agitated water at 20–258C. When the hydroxyethyl cellulose has been thoroughly wetted, the temperature of the solution may be increased to 60–708C to increase the rate of dispersion. Making the solution slightly alkaline also increases the dispersion process. Typically, complete dispersion may be achieved in approximately an hour by controlling the temperature, pH, and rate of stirring.

Normally dispersing grades of hydroxyethyl cellulose require more careful handling to avoid agglomeration during dispersion; the water should be stirred vigorously. Alternatively, a slurry of hydroxyethyl cellulose may be prepared in a nonaqueous solvent, such as ethanol, prior to dispersion in water.

See also Section 11 for information on solution stability.

332 Hydroxyethyl Cellulose

Table III: Approximate viscosities of various grades of aqueous

Cellosize (Amerchol Corp.) solutions at 258C.

Incompatibilities

Hydroxyethyl cellulose is insoluble in most organic solvents. It

Type Grade Concentration

Viscosity (mPa s)(a)

is incompatible with zein and partially compatible with the

(% w/v)

following water-soluble compounds: casein; gelatin; methyl-

Low High

WP 02 5 7–14 14–20

cellulose; polyvinyl alcohol, and starch.

Hydroxyethyl cellulose can be used with a wide variety of water-soluble antimicrobial preservatives. However, sodium

300 2 250–325 325–400

4400 2 4 200–4 700 700–5 200

pentachlorophenate produces an immediate increase in viscos- ity when added to hydroxyethyl cellulose solutions.

Hydroxyethyl cellulose has good tolerance for dissolved electrolytes, although it may be salted out of solution when mixed with certain salt solutions. For example, the following salt solutions will precipitate a 10% w/v solution of Cellosize

QP 10000 2 5 700 6 500

15000 2 15 000–18 000 18 000–21 000

30000 1 950–1 230 1 230–1 500

52000 1 1 500–1 800 1 800–2 100

100M 1 2 500 3 000

(a) Cellosize viscosity grades are available in narrower ranges, as noted by the Low and High designation.

Table IV: Approximate viscosities of various grades of aqueous

Natrosol 250 (Aqualon Inc.) solutions at 258C.

Type Viscosity (mPa s) for varying concentrations (% w/v)

WP-09 and a 2% w/v solution of Cellosize WP-4400: sodium carbonate 50% and saturated solutions of aluminum sulfate; ammonium sulfate; chromic sulfate; disodium phosphate; magnesium sulfate; potassium ferrocyanide; sodium sulfate; sodium sulfite; sodium thiosulfate; and zinc sulfate.

Natrosol is soluble in most 10% salt solutions, excluding sodium carbonate and sodium sulfate, and many 50% salt solutions with the exception of the following: aluminum sulfate; ammonium sulfate; diammonium phosphate; disodium phosphate; ferric chloride; magnesium sulfate; potassium ferrocyanide; sodium metaborate; sodium nitrate; sodium sulfite; trisodium phosphate; and zinc sulfate. Natrosol 150 is generally more tolerant of dissolved salts than is Natrosol 250. Hydroxyethyl cellulose is also incompatible with certain

fluorescent dyes or optical brighteners, and certain quaternary

disinfectants which will increase the viscosity of aqueous

solutions.

Method of Manufacture

A purified form of cellulose is reacted with sodium hydroxide to produce a swollen alkali cellulose, which is chemically more reactive than untreated cellulose. The alkali cellulose is then reacted with ethylene oxide to produce a series of hydroxyethyl cellulose ethers.

The manner in which ethylene oxide is added to cellulose can be described by two terms, the degree of substitution (DS) and the molar substitution (MS). The DS designates the average number of hydroxyl positions on the anhydroglucose unit that have been reacted with ethylene oxide. Since each anhydroglu- cose unit of the cellulose molecule has three hydroxyl groups,

Stability and Storage Conditions

Hydroxyethyl cellulose powder is a stable though hygroscopic material.

Aqueous solutions of hydroxyethyl cellulose are relatively stable at pH 2–12 with the viscosity of solutions being largely unaffected. However, solutions are less stable below pH 5 owing to hydrolysis. At high pH, oxidation may occur.

Increasing the temperature reduces the viscosity of aqueous hydroxyethyl cellulose solutions. However on cooling, the original viscosity is restored. Solutions may be subjected to freeze–thawing, high-temperature storage, or boiling without precipitation or gelation occurring.

Hydroxyethyl cellulose is subject to enzymatic degradation, with consequent loss in viscosity of its solutions.(6) Enzymes that catalyze this degradation are produced by many bacteria and fungi present in the environment. For prolonged storage, an antimicrobial preservative should therefore be added to aqueous solutions. Aqueous solutions of hydroxyethyl cellulose may also be sterilized by autoclaving.

Hydroxyethyl cellulose powder should be stored in a well- closed container, in a cool, dry place.

the maximum value for DS is 3. MS is defined as the average number of ethylene oxide molecules that have reacted with each anhydroglucose unit. Once a hydroxyethyl group is attached to each unit, it can further react with additional groups in an end- to-end formation. This reaction can continue and there is no theoretical limit for MS.

Safety

Hydroxyethyl cellulose is primarily used in ophthalmic and topical pharmaceutical formulations. It is generally regarded as an essentially nontoxic and nonirritant material.(7,8)

Acute and subacute oral toxicity studies in rats have shown no toxic effects attributable to hydroxyethyl cellulose con- sumption; the hydroxyethyl cellulose being neither absorbed nor hydrolyzed in the rat gastrointestinal tract. However, although used in oral pharmaceutical formulations, hydro- xyethyl cellulose has not been approved for direct use in food products; see Section 16.

Glyoxal-treated hydroxyethyl cellulose is not recommended for use in oral pharmaceutical formulations or topical

Hydroxyethyl Cellulose 333

preparations that may be used on mucous membranes. Hydroxyethyl cellulose is also not recommended for use in parenteral products.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Hydroxyethyl cellulose dust may be irritant to the eyes and eye protection is recommended. Excessive dust generation should be avoided to minimize the risks of explosion. Hydroxyethyl cellulose is combustible.

When heated to decomposition, hydroxyethyl cellulose emits acrid smoke and irritating vapors, in which case a ventilator is recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (ophthalmic preparations; oral syrups and tablets; otic and topical prepara- tions). Included in nonparenteral medicines licensed in the UK. Hydroxyethyl cellulose is not currently approved for use in food products in Europe or the USA, although it is permitted for use in indirect applications such as packaging. This restriction is due to the high levels of ethylene glycol residues

that are formed during the manufacturing process.

Related Substances

Hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hypromellose; methylcellulose.

Comments

The limited scope for the use of hydroxyethyl cellulose in foodstuffs is in stark contrast to its widespread application as an excipient in oral pharmaceutical formulations.

Hydroxyethyl cellulose hydrogels may also be used in various delivery systems.(9)

Specific References

Grove J, Durr M, Quint M-P, Plazonnet B. The effect of vehicle viscosity on the ocular bioavailability of L-653328. Int J Pharm 1990; 66: 23–28.

Gauger LJ. Hydroxyethylcellulose gel as a dinoprostone vehicle.

Am J Hosp Pharm 1984; 41: 1761–1762.

Delonca H, Joachim J, Mattha A. Influence of temperature on disintegration and dissolution time of tablets with a cellulose component as binder [in French]. J Pharm Belg 1978; 33: 171– 178.

Kova´cs B, Mere´nyi G. Evaluation of tack behavior of coating solutions. Drug Dev Ind Pharm 1990; 16(15): 2302–2323.

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1579.

Wirick MG. Study of the substitution pattern of hydroxyethyl cellulose and its relationship to enzymic degradation. J Polym Sci 1968; 6(Part A-1): 1705–1718.

Anonymous. Final report on the safety assessment of hydro- xyethylcellulose, hydroxypropylcellulose, methylcellulose, hydro- xypropyl methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 5(3): 1–60.

Durand-Cavagna G, Delort P, Duprat P, et al. Corneal toxicity studies in rabbits and dogs with hydroxyethyl cellulose and benzalkonium chloride. Fundam Appl Toxicol 1989; 13: 500–508.

Li J, Xu Z. Physical characterization of a chitosan-based hydrogel delivery system. J Pharm Sci 2002; 91(7): 1669–1677.

General References

Amerchol Corp. Technical literature: Cellosize, hydroxyethyl cellulose, 1993.

Amerchol Corp. Technical literature: Cellosize, hydroxyethyl cellulose, 2002.

Aqualon. Technical literature: Natrosol, hydroxyethyl cellulose, 1999. Chauveau C, Maillols H, Delonca H. Natrosol 250 part 1: characterization and modeling of rheological behavior [in French].

Pharm Acta Helv 1986; 61: 292–297.

Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. Haugen P, Tung MA, Runikis JO. Steady shear flow properties, rheological reproducibility and stability of aqueous hydroxyethyl-

cellulose dispersions. Can J Pharm Sci 1978; 13: 4–7.

Klug ED. Some properties of water-soluble hydroxyalkyl celluloses and their derivatives. J Polym Sci 1971; 36(Part C): 491–508.

Rufe RG. Cellulose polymers in cosmetics and toiletries. Cosmet Perfum 1975; 90(3): 93–94, 99–100.

Hydroxyethylmethyl Cellulose

Nonproprietary Names

BP: Hydroxyethylmethylcellulose PhEur: Methylhydroxyethylcellulosum

kywods

728x90

468x60.

mob

mercredi 6 novembre 2024

Aucun commentaire:

Enregistrer un commentaire

pop

slder

redect

push