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Method of Manufacture

Aspartame is produced by coupling together L-phenylalanine (or L-phenylalanine methyl ester) and L-aspartic acid, either chemically or enzymatically. The former procedure yields both the sweet a-aspartame and nonsweet b-aspartame from which the a-aspartame has to be separated and purified. The enzymatic process yields only a-aspartame.

Safety

Aspartame is widely used in oral pharmaceutical formulations, beverages, and food products as an intense sweetener and is generally regarded as a nontoxic material. However, the use of aspartame has been of some concern owing to the formation of the potentially toxic metabolites methanol, aspartic acid, and phenylalanine. Of these materials, only phenylalanine is produced in sufficient quantities, at normal aspartame intake levels, to cause concern. In the normal healthy individual any phenylalanine produced is harmless, however it is recom- mended that aspartame be avoided or its intake restricted by those persons with phenylketonuria.(11)

The WHO has set an acceptable daily intake for aspartame at up to 40 mg/kg body-weight.(12) Additionally, the acceptable daily intake of diketopiperazine (an impurity found in aspartame) has been set by the WHO at up to 7.5 mg/kg body-weight.(13)

A number of adverse effects have been reported following the consumption of aspartame,(11,13) particularly in individuals who drink large quantities (up to 8 liters per day in one case) of aspartame-sweetened beverages. Reported adverse effects include: headaches;(14) grand mal seizure;(15) memory loss;(16) gastrointestinal symptoms; and dermatological symptoms.

Although aspartame has been reported to cause hyperactiv- ity and behavioral problems in children, a double-blind controlled trial of 48 preschool-age children fed diets contain- ing a daily intake of 38 13 mg/kg body-weight of aspartame for 3 weeks showed no adverse effects attributable to aspartame, or dietary sucrose, on children’s behavior or cognitive function.(17)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Measures should be taken to minimize the potential for dust explosion. Eye protection is recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral powder for reconstitution, buccal patch, granules, film-coated, and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

The intensity of sweeteners relative to sucrose depends upon their concentration, temperature of tasting, and pH, and on the flavor and texture of the product concerned.

Intense sweetening agents will not replace the bulk, textural, or preservative characteristics of sugar, if sugar is removed from a formulation.

Synergistic effects for combinations of sweeteners have been reported, e.g., aspartame with acesulfame potassium.

Aspartame can cause browning when used at high temperatures.

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

Specific References

Joachim J, Kalantzis G, Delonca H, et al. The compression of effervescent aspartame tablets: the influence of particle size on the strain applied on the punches during compression [in French]. J Pharm Belg 1987; 42: 17–28.

Joachim J, Kalantzis G, Delonca H, et al. The compression of effervescent aspartame tablets: the influence of particle size and temperature on the effervescence time and carbon dioxide liberation kinetics [in French]. J Pharm Belg 1987; 42: 303–314.

Manion CV, Howard J, Ogle B, et al. Aspartame effect in sickle cell anemia. Clin Pharmacol Ther 2001; 69: 346–355.

Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow and compact mechanical properties of sucrose and three high- intensity sweeteners used in chewable tablets. Int J Pharm 2003; 257(1–2): 227–236.

Brewster ME, Loftsson T, Baldvinsdo´ ttir J, Bodor N. Stabilization of aspartame by cyclodextrins. Int J Pharm 1991; 75: R5–R8.

Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation of aspartame in acidic aqueous media and its stabilization by complexation with cyclodextrins or modified cyclodextrins. Int J Pharm 1992; 88: 189–199.

Yalkowsky SH, Davis E, Clark T. Stabilization of aspartame by polyethylene glycol 400. J Pharm Sci 1993; 82: 978.

Sanyude S, Locock RA, Pagliaro LA. Stability of aspartame in water: organic solvent mixtures with different dielectric constants. J Pharm Sci 1991; 80: 674–676.

The NutraSweet Company. Technical literature: NutraSweet technical bulletin, 1991.

El-Shattawy HE, Peck GE, Kildsig DO. Aspartame-direct com- pression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 605–619.

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

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-fifth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1981; No. 669.

Butchko HH, Kotsonis FN. Aspartame: review of recent research.

Comments Toxicol 1989; 3(4): 253–278.

Schiffman SS, Buckley E, Sampson HA, et al. Aspartame and susceptibility to headache. N Engl J Med 1987; 317: 1181–1185.

Wurtman RJ. Aspartame: possible effect on seizure susceptibility [letter]. Lancet 1985; ii: 1060.

Anonymous. Sweetener blamed for mental illnesses. New Scientist

1988; February 18: 33.

Wolraich ML, Lindgreen SD, Stumbo PJ, et al. Effects of diets high in sucrose or aspartame on the behavior and cognitive perfor- mance of children. N Engl J Med 1994; 330: 301–307.

General References

Marie S. Sweeteners. In: Smith J, ed. Food Additives User’s Handbook.

Glasgow: Blackie, 1991: 47–74.

Roy GM. Taste masking in oral pharmaceuticals. Pharm Technol Eur

1994; 6(6): 24, 26–28, 30–32, 34, 35.

Stegink LD, Filer LJ, eds. Aspartame, Physiology and Biochemistry.

New York: Marcel Dekker, 1984.

Table I: Pharmacopeial specifications for attapulgite.

Test BP 2004

Identification +

Characters +

Actapulgite; Attaclay; Attacote; Attagel; attapulgus; palygors- cite; palygorskite; Pharmsorb Regular.

Chemical Name and CAS Registry Number

Attapulgite [12174-11-7]

Acidity or alkalinity (5% w/v aqueous suspension)

7.0–9.5

Empirical Formula and Molecular Weight

Attapulgite is a purified native hydrated magnesium aluminum silicate consisting of the clay mineral palygorskite, with the empirical formula Mg(Al0.5–1Fe0–0.5)Si4O10(OH)·4H2O.

Applications in Pharmaceutical Formulation or Technology

Attapulgite is widely used as an adsorbent in solid dosage forms. Colloidal clays (such as attapulgite) absorb considerable amounts of water to form gels and in concentrations of 2–5% w/v usually form oil-in-water emulsions. Activated attapulgite, which is attapulgite that has been carefully heated to increase its absorptive capacity, is used therapeutically as an adjunct in the management of diarrhea.

Description

Attapulgite occurs as a light cream colored, very fine powder. Particle size ranges depend on the grade and manufacturer.

Pharmacopeial Specifications

See Table I. See also Section 17.

Typical Properties

Acidity/alkalinity: pH = 9.5 (5% w/v aqueous suspension)

Angle of repose: 37.2–45.28(1)

Density: 2.2 g/cm3

Density (tapped): 0.33 g/cm3(1)

Flowability: 20.9–29.6% (Carr compressibility index)(1)

Particle size distribution:

<2 mm in size for powder;

2–5 mm in size for aggregate.(1)

Stability and Storage Conditions

Attapulgite can adsorb water. It should be stored in an airtight container in a cool, dry, location.

Incompatibilities

Attapulgite may decrease the bioavailability of some drugs such as loperamide(2) and riboflavin.(3) Oxidation of hydro- cortisone is increased in the presence of attapulgite.(4)

Method of Manufacture

Attapulgite occurs naturally as the mineral palygorskite.

Safety

Attapulgite is widely used in pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material. It is not absorbed following oral administration. In oral preparations, activated attapulgite up to 9 g is used in daily divided doses as an adjunct in the management of diarrhea.(5)

LD50 (rat, IP): 0.34 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended. Attapulgite should be handled in a well-ventilated environment and dust generation should be minimized. When heated to decomposition, attapulgite emits acrid smoke and irritating fumes.

Regulatory Status

Included in nonparenteral medicines licensed in a number of countries worldwide including the UK and US.

Related Substances

Activated attapulgite; magnesium aluminum silicate.

Attapulgite 57

Activated attapulgite

Comments: activated attapulgite is a processed native mag- nesium aluminum silicate that has been carefully heated to increase its adsorptive capacity. Monographs for activated attapulgite are included in the BP 2004, USP 28, and other pharmacopeias. The USP 28 also includes a monograph for colloidal activated attapulgite.

Comments

The EINECS number for attapulgite is 302-243-0.

Specific References

Viseras C, Lo´ pez-Galindo A. Characteristics of pharmaceutical grade phyllosilicate powders. Pharm Dev Technol 2000; 5(1): 47–

52.

Mboya SA, Bhargava HN. Adsorption and desorption of loperamide hydrochloride by activated attapulgites. Am J Health Syst Pharm 1995; 52: 2816–2818.

Khalil SAH, Mortada LM, Shams-Eldeen MA, El-Khawas MM. Effect of attapulgite on the bioavailability of a model low dose drug (riboflavine) in humans. Drug Dev Ind Pharm 1987; 13: 369–382.

Cornejo J, Hernosin MC, White JL, et al. Oxidative degradation of hydrocortisone in the presence of attapulgite. J Pharm Sci 1980; 69: 945–948.

Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1251.

General References

Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium trisilicate, pumice, talc. Int J Pharm Compound 1998; 2(2): 162– 163.

Viseras C, Yebra A, Lo´ pez-Galindo A. Characteristics of pharmaceu- tical grade phyllosilicate compacts. Pharm Dev Technol 2000; 5(1):

BP: Bentonite JP: Bentonite

PhEur: Bentonitum USPNF: Bentonite

Synonyms

Albagel; E558; Magnabrite; mineral soap; Polargel; soap clay; taylorite; Veegum HS; wilkinite.

Chemical Name and CAS Registry Number

Bentonite [1302-78-9]

Empirical Formula and Molecular Weight

Al2O3·4SiO2·H2O 359.16

Bentonite is a native colloidal hydrated aluminum silicate consisting mainly of montmorillonite, Al2O3·4SiO2·H2O; it may also contain calcium, magnesium, and iron. The average chemical analysis is expressed as oxides, see Table I, in comparison with magnesium aluminum silicate.

Table I: Average chemical analysis of bentonite expressed as oxides in comparison with magnesium aluminum silicate.

Applications in Pharmaceutical Formulation or Technology

Bentonite is a naturally occurring hydrated aluminum silicate used primarily in the formulation of suspensions, gels, and sols, for topical pharmaceutical applications. It is also used to suspend powders in aqueous preparations and to prepare cream bases containing oil-in-water emulsifying agents.

Bentonite may also be used in oral pharmaceutical prepara- tions, cosmetics, and food products, see Section 18. In oral preparations, bentonite, and other similar silicate clays, can be used to adsorb cationic drugs and so retard their release.(1–3) Adsorbents are also used to mask the taste of certain drugs. See Table II.

Bentonite has been investigated as a diagnostic agent for magnetic resonance imaging.(4)

Therapeutically, bentonite has been investigated as an adsorbent for lithium poisoning.(5)

Description

Bentonite is a crystalline, claylike mineral, and is available as an odorless, pale buff, or cream to grayish-colored fine powder, which is free from grit. It consists of particles about 50–150 mm in size along with numerous particles about 1–2 mm. Micro- scopic examination of samples stained with alcoholic methyl- ene blue solution reveals strongly stained blue particles. Bentonite may have a slight earthy taste.

Bentonite Magnesium aluminum silicate

Silicon dioxide 59.92% 61.1% SEM: 1

Aluminum oxide 19.78% 9.3% Excipient: Bentonite

Magnesium oxide 1.53% 13.7% Manufacturer: American Colloid Co.

Ferric oxide 2.96% 0.9% Lot No.: NMD 11780

Calcium oxide 0.64% 2.7% Magnification: 600×

Sodium oxide 2.06% 2.9% Voltage: 10 kV

Potassium oxide 0.57% 0.3%

Structural Formula

The PhEur 2005 describes bentonite as a natural clay contain- ing a high proportion of montmorillonite, a native hydrated aluminum silicate in which some aluminum and silicon atoms may be replaced by other atoms such as magnesium and iron. The USPNF 23 describes bentonite, purified benonite, and bentonite magma in three separate monographs. Bentonite is described as a native, colloidal, hydrated aluminum silicate; and purified bentonite is described as a colloidal montmor- illonite that has been processed to remove grit and nonswellable

ore compounds.

See also Section 4.

Functional Category

Adsorbent; stabilizing agent; suspending agent; viscosity- increasing agent.

Bentonite 59

Table II: Uses of bentonite.

Use Concentration (%)

Adsorbent (clarifying agent) 1.0–2.0

Emulsion stabilizer 1.0

Suspending agent 0.5–5.0

SEM: 2

Excipient: Bentonite

Manufacturer: American Colloid Co.

Lot No: NMD 11780

Magnification: 2400×

Voltage: 20 kV

Pharmacopeial Specifications

See Table III.

Table III: Pharmacopeial specifications for bentonite.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters + + —

Alkalinity — + —

Microbial limit — 4103/g +

Coarse particles — 40.5% —

pH (2% w/v suspension) 9.0–10.5 — 9.5–10.5

Loss on drying 5.0–10.0% 415% 5.0–8.0%

Arsenic 42 ppm — 45 ppm

Lead — — 40.004%

Heavy metals 450 ppm 450 ppm —

Organic volatile impurities — — +

Gel formation + — +

Sedimentation volume — 42 mL —

Swelling power 520 mL 522 mL 524 mL

Fineness of powder + — +

The USPNF 23 also contains specifications for bentonite magma and purified bentonite. See Section 17.

Typical Properties

Acidity/alkalinity: pH = 9.5–10.5 for a 2% w/v aqueous suspension.

Flowability: no flow.

Hygroscopicity: bentonite is hygroscopic.(6) See also Figure 1.

Moisture content: 5–12%.

Solubility: practically insoluble in ethanol, fixed oils, glycerin, propan-2-ol, and water. Bentonite swells to about 12 times its original volume in water, to form viscous homogeneous suspensions, sols, or gels depending upon the concentration. Bentonite does not swell in organic solvents. Sols and gels may be conveniently prepared by sprinkling the bentonite on the surface of hot water and allowing to stand for 24 hours, stirring occasionally when the bentonite has become thoroughly wetted. Water should not be added to bentonite alone, but bentonite may be satisfactorily dispersed in water if it is first triturated with glycerin or mixed with a powder such as zinc oxide. A 7% w/v aqueous suspension of bentonite is just pourable. See also Section 12.

Viscosity (dynamic): 75–225 mPa s (75–225 cP) for a 5.5% w/v aqueous suspension at 258C. Viscosity increases with increasing concentration.

Stability and Storage Conditions

Bentonite is hygroscopic, and sorption of atmospheric water should be avoided.

Aqueous bentonite suspensions may be sterilized by auto- claving. The solid material may be sterilized by maintaining it at 1708C for 1 hour after drying at 1008C.

Bentonite should be stored in an airtight container in a cool, dry place.

Figure 1: Equilibrium, moisture content of bentonite USPNF.

Incompatibilities

Aqueous bentonite suspensions retain their viscosity above pH 6, but are precipitated by acids. Acid-washed bentonite

60 Bentonite

does not have suspending properties. The addition of alkaline materials, such as magnesium oxide, increases gel formation.

Addition of significant amounts of alcohol to aqueous preparations will precipitate bentonite, primarily by dehydra- tion of the lattice structure; see also Section 18.

Bentonite particles are negatively charged and flocculation occurs when electrolytes or positively charged suspensions are added. Bentonite is thus said to be incompatible with strong electrolytes, although this effect is sometimes used beneficially to clarify turbid liquids.

The antimicrobial efficacy of cationic preservatives may be reduced in aqueous bentonite suspensions, but nonionic and anionic preservatives are unaffected.(7)

Bentonite is incompatible with acriflavine hydrochloride.

Method of Manufacture

Bentonite is a native, colloidal, hydrated aluminum silicate, found in regions of Canada and the USA. The mined ore is processed to remove grit and nonswelling materials so that it is suitable for pharmaceutical applications.

Safety

Bentonite is mainly used in topical pharmaceutical formula- tions but has also been used in oral pharmaceutical prepara- tions, food products, and cosmetics.

Following oral administration, bentonite is not absorbed from the gastrointestinal tract. Bentonite is generally regarded as a nontoxic and nonirritant material.

LD50 (rat, IV): 0.035 g/kg(8)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended. Bentonite should be handled in a well-ventilated environment and dust generation minimized.

Regulatory Status

Accepted in Europe as a food additive in certain applications. Included in the FDA Inactive Ingredients Guide (oral capsules, tablets and suspensions, topical suspensions, controlled release transdermal films and vaginal suppositories). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Bentonite magma; kaolin; magnesium aluminum silicate; magnesium trisilicate; purified bentonite; talc.

Bentonite magma

Comments: a 5% w/w suspension of bentonite in purified water appears in some pharmacopeias, such as the USPNF 23.

Purified bentonite

Acidity/alkalinity: pH = 9.0–10.0 for a 5% w/w aqueous suspension.

Viscosity (dynamic): 40–200 mPa s (40–200 cP) for a 5% w/w aqueous suspension.

Comments: specifications for purified bentonite occur in some pharmacopeias such as the USPNF 23. Purified bentonite is bentonite that has been processed to remove grit and nonswellable ore components.

Comments

Bentonite may be used with concentrations of up to 30% ethanol or propan-2-ol; 50% glycerin; 30% propylene glycol; or high molecular weight polyethylene glycols. The EINECS number for bentonite is 215-108-5.

Bentonite is used in the food industry as a processing aid as a clarifying or filter agent. A specification for bentonite is contained in the Food Chemicals Codex (FCC).

Specific References

Stul MS, Vliers DP, Uytterhoven JB. In vitro adsorption-desorption of phenethylamines and phenylimidazoles by a bentonite and a resin. J Pharm Sci 1984; 73: 1372–1375.

Shrivastava R, Jain SR, Frank SG. Dissolution dialysis studies of metronidazole–montmorillonite adsorbates. J Pharm Sci 1985; 74:

214–216.

Forni F, Iannuccelli V, Coppi G, Bernabei MT. Effect of montmorillonite on drug release from polymeric matrices. Arch Pharm 1989; 322: 789–793.

Listinsky JJ, Bryant RG. Gastrointestinal contrast agents: a diamagnetic approach. Magn Reson Med 1988; 8(3): 285–292.

Ponampalam R, Otten EJ. In vitro adsorption of lithium by bentonite. Singapore Med J 2002; 43(2): 86–89.

Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8: 355–369.

Harris WA. The inactivation of cationic antiseptics by bentonite suspensions. Aust J Pharm 1961; 42: 583–588.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 351.

General References

Altagracia M, Ford I, Garzon ML, Kravzov J. A comparative mineralogical and physico-chemical study of some crude Mexican and pharmaceutical grade montmorillonites. Drug Dev Ind Pharm 1987; 13: 2249–2262.

Sadik F, Fincher JH, Hartman CW. X-Ray diffraction analysis for identification of kaolin NF and bentonite USP. J Pharm Sci 1971; 60: 916–918.

Benzalkonium Chloride

Nonproprietary Names

BP: Benzalkonium chloride JP: Benzalkonium chloride PhEur: Benzalkonii chloridum

USPNF: Benzalkonium chloride

Synonyms

Alkylbenzyldimethylammonium chloride; alkyl dimethyl ben- zyl ammonium chloride; BKC; Hyamine 3500; Pentonium; Zephiran.

Chemical Name and CAS Registry Number

Alkyldimethyl(phenylmethyl)ammonium chloride [8001-54-5]

Empirical Formula and Molecular Weight

The USPNF 23 describes benzalkonium chloride as a mixture of alkylbenzyldimethylammonium chlorides of the general for- mula [C H CH N(CH ) R]Cl, where R represents a mixture

In ophthalmic preparations, benzalkonium chloride is one of the most widely used preservatives,(1) at a concentration of 0.01–0.02% w/v. Often it is used in combination with other preservatives or excipients, particularly 0.1% w/v disodium edetate, to enhance its antimicrobial activity against strains of Pseudomonas.

In nasal,(2) and otic formulations a concentration of 0.002–0.02% w/v is used, sometimes in combination with 0.002–0.005% w/v thimerosal. Benzalkonium chloride 0.01% w/v is also employed as a preservative in small-volume parenteral products. Benzalkonium chloride was also shown to enhance the topical penetration of lorazepam.(3)

Benzalkonium chloride is additionally used as a preservative in cosmetics.

Description

Benzalkonium chloride occurs as a white or yellowish-white amorphous powder, a thick gel, or gelatinous flakes. It is hygroscopic, soapy to the touch, and has a mild aromatic odor and very bitter taste.

6 5 2 3 2

of alkyls, including all or some of the group beginning with n-C8H17 and extending through higher homologs, with n-C12H25, n-C14H29, and n-C16H33 comprising the major portion.

The average molecular weight of benzalkonium chloride is 360.

Structural Formula

R = mixture of alkyls: n-C8H17 to n-C18H37; mainly n-C12H25 (dodecyl), n-C14H29 (tetradecyl), and n-C16H33 (hexadecyl).

Functional Category

Antimicrobial preservative; antiseptic; disinfectant; solubilizing agent; wetting agent.

Applications in Pharmaceutical Formulation or Technology

Benzalkonium chloride is a quaternary ammonium compound used in pharmaceutical formulations as an antimicrobial preservative in applications similar to other cationic surfac- tants, such as cetrimide.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for benzalkonium chloride.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters + + —

Acidity or alkalinity — + —

Appearance of + + —

solution

Water 415.0% 410.0% 415.0%

Residue on ignition 40.2% — 42.0%

Sulfated ash — 40.1% —

Water-insoluble — — +

of n-C12H25 — — 540.0%

of n-C14H29 — — 520.0%

of n-C12H25 and — — 570.0%

Acidity/alkalinity: pH = 5–8 for a 10% w/v aqueous solution.

62 Benzalkonium Chloride

Antimicrobial activity: benzalkonium chloride solutions are active against a wide range of bacteria, yeasts, and fungi. Activity is more marked against Gram-positive than Gram- negative bacteria and minimal against bacterial endospores and acid-fast bacteria, see Table II. The antimicrobial activity of benzalkonium chloride is significantly dependent upon the alkyl composition of the homolog mixture.(4) Benzalkonium chloride is ineffective against some Pseudo- monas aeruginosa strains, Mycobacterium tuberculosis, Trichophyton interdigitale, and T. rubrum. However, combined with disodium edetate (0.01–0.1% w/v), benzyl alcohol, phenylethanol, or phenylpropanol, the activity against Pseudomonas aeruginosa is increased.(5) Antimicro- bial activity may also be enhanced by the addition of phenylmercuric acetate, phenylmercuric borate, chlorhex- idine, cetrimide, or m-cresol.(6,7) In the presence of citrate and phosphate buffers (but not borate), activity against Pseudomonas can be reduced. See also Sections 11 and 12. Benzalkonium chloride is relatively inactive against spores and molds, but is active against some viruses, including HIV.(8) Inhibitory activity increases with pH, although antimicrobial activity occurs at pH 4–10.

Table II: Minimum inhibitory concentrations (MICs) of benzalkonium chloride.

Microorganism MIC (mg/mL)

Aerobacter aerogenes 64

Clostridium histolyticum 5

Clostridium oedematiens 5

Clostridium tetani 5

Clostridium welchii 5

Escherichia coli 16

Pneumococcus II 5

Proteus vulgaris 64

Pseudomonas aeruginosa 30

Salmonella enteritidis 30

Salmonella paratyphi 16

Salmonella typhosa 4

Shigella dysenteriae 2

Staphylococcus aureus 1.25

Streptococcus pyrogenes 1.25

Vibrio cholerae 2

The bulk material should be stored in an airtight container, protected from light and contact with metals, in a cool, dry place.

Incompatibilities

Incompatible with aluminum, anionic surfactants, citrates, cotton, fluorescein, hydrogen peroxide, hypromellose,(9) iodides, kaolin, lanolin, nitrates, nonionic surfactants in high concentration, permanganates, protein, salicylates, silver salts, soaps, sulfonamides, tartrates, zinc oxide, zinc sulfate, some rubber mixes, and some plastic mixes.

Benzalkonium chloride has been shown to be adsorbed to various filtering membranes, especially those that are hydro- phobic or anionic.(10)

Method of Manufacture

Benzalkonium chloride is formed by the reaction of a solution of N-alkyl-N-methylbenzamine with methyl chloride in an organic solvent suitable for precipitating the quaternary compound as it is formed.

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