Benzalkonium chlorides

BP Benzalkonium chloride JP Benzalkonium chloride PhEur Benzalkonii chloridum USPNF Benzalkonium chloride 

Alkylbenzyldimethylammonium chloride alkyl dimethyl benzyl ammonium chloride BKC Hyamine 3S00 Pentonium Zephiran. 

R = mixture of alkyls n-CgHiy to n-Ci8H37 mainly n-Ci2H25 (dodecyl), n-Ci4H29 (tetradecyl), and n-Ci6H33 (hexadecyl). 

Antimicrobial preservative antiseptic disinfectant solubilizing agent wetting agent. 

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

Mobile phase MeCNrbufifer 90 10 (The buffer was a 161 mM pH 5.4 propionate buffer made by mixing 75 mL 10% sodium carbonate, 1.5 L water, and 12 mL propionic acid. Make up to 2 L with water.) 

Desaulniers, M. High-performance liquid chromatographic assay of benzalkonium in plasma, J.Chromatogr., 1989, 487, 221-227. 

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Disinfectants. Several disinfecting agents can be used in hatcheries and two are of particular interest. Because they are not considered dmg or food additive uses by FDA, povidone—iodine compounds can be used to disinfect the surface of eggs (9). Benzalkonium chloride [68424-85-1] and benzethonium chloride (quaternary ammonium compounds), are allowed at 2 mg/L by FDA to disinfect water containing fish. These compounds are also known to have therapeutic properties, especially against external bacteria (9). 

Organism Peracetic acid Active chlorine Benzalkonium chloride... 

Acetic acid, boric acid, benzalkonium chloride, aluminum acetate, benzethonium chloride—provide antifungal or antibacterial action... 

Another titration method makes use of benzalkonium chloride. A solution of an anionic surfactant ( — 0.1 meq) is put into a beaker, and 20 ml of a methylene blue solution (—0.25% in water) and chloroform is added. Titration is performed against a 0.004 M solution of benzalkonium chloride under vigorous stirring. When both water and chloroform phase show the same (blue) color, the endpoint of the titration is reached. 

Fig. 10.8 Quaternary ammonium compounds (QACs) A, general structure ofQACs B, benzalkonium chloride (n - S - 18) C, cetrimide (n - 12 - 14 or 16) D, cetylpyridinium chloride.

Fig. 10.8 A where the R substituents are alkyl or heterocyclic radicals to give compounds such as cetyltrimethylammonium bromide (cetrimide), cetylpyridinium chloride and benzalkonium chloride. Inspection of the stmctures of these compounds (Fig. 10.8B) indicates the requirement for good antimicrobial activily of having a chain length in the range Cg to Cig in at least one of the R substituents. In the pyridinium compounds (Fig. 10.8C) three of the four covalent links may be satisfied by the nitrogen in a pyridine ring. Polymeric quaternary ammonium salts such as polyquatemium 1 are finding increasing use as preservatives.

Burkholderia (formeriy Pseudomonas) cepacia is intrinsically resistant to a number of biocides, notably benzalkonium chloride and chlorhexidine. Again, the outer membrane is likely to act as a permeability barrier. By contrasL Ps. stutzeri (an organism implicated in eye infections caused by some cosmetic products) is invariably intrinsically sensitive to a range of biocides, including QACs and chlorhexidine. This organism contains less wall muramic acid than other pseudomonads but it is imclear as to whether this could be a contributory factor in its enhanced biocide susceptibility. 

Examples of preservatives are phenylmercuric nitrate or acetate (0.002% w/v), chlorhexidine acetate (0.01 % w/v), thiomersal (0.01 % w/v) and benzalkorrium chloride (0.01 % w/v). Chlorocresol is too toxic to the comeal epithehum, but 8-hydroxyquinoline and thiomersal may be used in specific instances. The principal considerahon in relation to antimicrobial properties is the activity of the bactericide against Pseudomonas aeruginosa, a major source of serious nosocomial eye infections. Although benzal-konium chloride is probably the most active of the recommended preservatives, it cannot always be used because of its incompatibility with many compounds commonly used to treat eye diseases, nor should it be used to preserve eye-drops containing anaesthetics. Since benzalkonium chloride reacts with natural mbber, silicone or butyl rabber teats should be substituted. Since silicone mbber is permeable to water vapour, products should not be stored for more than 3 months after manufacture. As with all mbber components, the mbber teat should be pre-equilibrated with the preservative prior to... 

Quaternary ammonium salts are organically substituted nitrogen compounds in which the nitrogen atom is pentavalent. Four of the substituents are alkyl, aryl or heterocyclic radicals and the fifth is an anion (a cationic charge). This anion is mostly chloride. Therefore we call them benzalkonium chlorides. 

The benzalkonium chlorides are very foaming and can cause severe foam problems in spas and pools. 

Substances that have been used as preservatives for disperse systems include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others [76,77]. The use of cationic antimicrobial agents such as quaternary ammonium compounds (e.g., benzalkonium chloride) is contraindicated in many cases because they may be inactivated by other formulation components and/or they may alter the charge of the dispersed phase. Clay suspensions and gels should be adequately preserved with nonionic antimicrobial preservatives. The use of preservatives is generally limited to products that are not intended for parenteral use. Intravenous injectable... 

Although this chapter is directed toward ophthalmic products, it is largely applicable to parenteral and even nonsterile products (solutions, emulsions, and suspensions). The choice of preservative is limited to only a few chemicals that have been found, over the years, to be safe and effective for this purpose. These are benzalkonium chloride, thimerosal, methyl- and propylparaben, phenylethanol, chlorhexidine,... 

The most widely used preservative remains benzalkonium chloride, which often is supplemented with disodium edetate. The benzalkonium chloride defined in the USP monograph is the quaternary ammonium compound alkylbenzyldimethylammonium chloride, in which the alkyl portion is composed of a mixture of chain lengths ranging from C8 to C16. This compound s popularity is based, despite its compatibility limitations, on its being the most effective and rapid-acting preservative with excellent chemical stability. It is stable over a wide pH range and does not... 

The conventional concentration of benzalkonium chloride in eyedrops is 0.01%, with a range of 0.004-0.02% [111]. While uptake of benzalkonium chloride itself into ocular tissues is limited [113], even lower concentrations of benzalkonium chloride have been reported to enhance corneal penetration of other compounds including therapeutic agents [93,112,114]. The differential effect of this preservative on the cornea compared to the conjunctiva can be exploited to target a drug for corneal absorption and delivery to the posterior segment of the eye [115]. Its use has been proposed as a means of delivering systemic doses by an ocular route of administration [116]. 

Richards [117], Mullen et al. [118], and the American College of Toxicology [119] have summarized the literature of benzalkonium chloride. The conclusion drawn was that benzalkonium chloride, up to 0.02%, has been well substantiated as being suitable for use in topical ophthalmic solutions when the conditions of its use are properly controlled. McDonald [121] found up to 0.02% to be permissible in ophthalmic solutions following extensive testing in rabbits. 

Numerous studies comparing benzalkonium chloride with other preservatives have been described in the literature. Many of the articles give conflicting results, not surprising considering the many different test methods, formulas, and criteria used to arrive at these diverse conclusions. However, adequate information is available in the literature to permit the manufacturer to select... 

Some strains of P. aeruginosa are resistant to benzalkonium chloride and, in fact, can be grown in solutions concentrated in this agent. This has caused great concern because of the virulent nature of this organism in ocular infections, as discussed previously. Thus, it was an important finding in 1958 that the acquired resistance could be eliminated by the presence of ethylenediaminetetracetic acid (sodium edetate) in the formulation. This action of EDTA has been correlated with its ability to chelate divalent cations, and it is commonly used as a preservative aid [125]. The use of disodium EDTA, where compatible, is recommended in concentrations up to 0.1%. 

Other quaternary ammonium germicides, ben-zethonium chloride and benzalkonium bromide, have been used in several ophthalmic solutions. While these have the advantage of not being a chemical mixture, they do not possess the bactericidal effectiveness of benzalkonium chloride and are subject to the same incompatibility limitations. In addition, the maximum concentration for benzethonium chloride is 0.01%. Several new products that form gels in the eye, like Timolol Gel Forming Solution and Timoptic-XE, employ another quaternary preservative, BDAB, in the formulation. 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Chlorhexidine, a bisbiguanide, has been demonstrated to be somewhat less toxic than benzalkonium chloride and thimerosal at clinically relevant concentrations [87,89,95,144,145]. This work was confirmed in a series of in vitro and in vivo experiments [137,146-148],... 

Using regression analysis on a data set of about 50 different molecules, it was found that a. = —4.4,8 = —0.5, Df = 12 cm2/s, and =2.5x 10 5 cm2/s [192], A graphic representation of the effect of relative molecular mass (Mr) and distribution coefficient on corneal permeability is shown in Fig. 13. One observes a rapid reduction in permeability coefficient with decreasing P and increasing Mr. The addition of pores to the model, a mathematical construct, is necessary to account for permeability of polar molecules, such as mannitol and cromolyn. These would also be required for correlating effects of compounds, such as benzalkonium chloride, which may compromise the... 

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