4-Hydroxybenzoic acid esters preservatives

Acidic preservatives are the most widely used for oral preparations, such as the p-Hydroxybenzoic acid esters and salts of benzoic acid. These are adequately soluble in aqueous systems and possess both antifungal and antibacterial properties. Methyl and propyl p-hydroxybenzoic acid are often used together in a 10 1 ratio. Concomitant use of multiple esters makes possible a higher total preservative concentration owing to the independent solubilities of each and, according to some researchers, maximizes the antimicrobial effect. 

Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters as preservatives I uses, antibacterial and antifungal studies, properties and determination. ] Am Pharm Assoc (Sci) 1953 42 449-457. 

Matthews C, Davidson J, Bauer E, et al. p-Hydroxybenzoic acid esters as preservatives II acute and chronic toxicity in dogs, rats and mice. / Am Pharm Assoc Sci) 1956 45 260—267. 

The hydroxybenzoic acid esters are among the most widely used preservatives in pharmacy preparation. They are used in oral liquids, enemas and cutaneous preparations. They are not very active against gram-negative bacteria. The combination with disodium edetate is not commonly used although it may overcome this drawback. 

As p-hydroxybenzoic acid esters present a relatively high pKa value (approx. 8.5), their antimicrobial action is less dependent on the pH value of the type of food to be preserved. In this respect they are superior to the organic preservative acids. Unfavourably, as in the case of phenol, p-hydroxybenzoic acid esters may be linked to some extent to proteins, emulsifiers or other food components on account of their phenolic hydroxylic-group and thus be inactivated. The antimicrobial action of the p-hydroxybenzoic acid esters is proportional to the alkyl chain length. Thus the antimicrobial action of the methyl ester is some 3 to 4 times, that of the ethyl ester some 5 to 8 times, that of the propyl ester about 25 times as powerful as phenol (Thompson, 1994). However, superimposed on this effect may be the water solubility of the esters, which is inversely proportional to the alkyl chain length. Since the activity spectra of the individual p-hydroxybenzoic acid esters are different, the application of mixtures can be profitable. 

The parabens are a class of 4-hydroxybenzoic acid esters (primarily methyl, ethyl, propyl, and butyl esters) that are used as biological preservatives in liquid and semisolid dosage forms.Another preservative often used is benzyl alcohol. Parabens and benzyl alcohol are compendial items. These materials are very stable... 

Perfumes, Flavors, Cosmetics, and Soap. Many naturally occurring esters in essential oils and some synthetic esters are important fragrance and flavor compounds (61,62). They are used in perfumes, flavors, cosmetics, soaps, detergents, and air fresheners. Benzyl, butyl, ethyl, methyl, and phenyl esters of benzoic acid are used as flavors, perfumes, and food preservatives. Glyceryl 4-aminobenzoate [136-44-7] and 2-ethyUiexyl 4-dimethylaminobenzoate [21245-02-3] are used in cosmetic sunscreen preparations. Alkyl esters of 4-hydroxybenzoic acid, called parabens, have been used under various names for fungus infections of the skin, and as preservatives in lotions and creams (101). Soap and cosmetic fragrances use large amounts of amyl and benzyl saHcylate. Benzyl saHcylate [118-58-1] is also used in deodorant sprays. 2-Ethylhexyl saHcylate [118-60-5] and 2-ethylhexyl 4-methoxycinnamate [5466-77-3] are used in sunscreen formulations (102). 

The use of preservative eombinations may be used to extend the range and speetrum of preservation. Thus, in the series of alkyl esters of 4-hydroxybenzoic (/ -hydroxybenzoic) acid (parabens), water solubility deereases in the order methyl, ethyl, propyl and butyl ester. By eombining these produets it is possible to aehieve a situation where both the aqueous and oil phase of an emulsion are proteeted. 

In emulsions, partitioning of the incorporated preservative can occur between the aqueous and the oil phase. A lipophilic preservative may pass into the oil phase so that a significant portion is removed from the aqueous phase. Since it is the latter in which microorganisms tend to grow, the use of water-soluble preservatives can be more effective, especially for O/W emulsions. For most emulsion systems, the esters of p-hydroxybenzoic acid (parabens) appear to be the most satisfactory. Since microorganisms can also reside within the oil phase, it is further recommended that a pair of preservatives having different oil and water solubilities be used in order to ensure appropriate concentrations in both phases. 

TE Haag, DF Loncrini. Esters of para-hydroxybenzoic acid. In JJ Kabara, ed. Cosmetic and Drug Preservation. New York Marcel Dekker, 1984, pp 63-77. 

Related to salicylic acid as isomers are / -hydroxybenzoic acid [99-06-9] andy>-hydroxybenzoic acid [99-96-7]. The three are commonly known as the monohydroxybenzoic acids because of the shared chemical reactions, the three isomers are discussed together herein. These monohydroxybenzoic acids have a broad range of applications from paper coatings and liquid crystal preparations to drugs. Salicylic acid and its derivatives are interesting because of their demonstrated activity as analgesics, antipyretics, and antiinflammatory agents, whereas the para-substituted acids and esters known as parabens have activity as preservatives for food. 

Hydroxybenzoic acid is of significant commercial importance. The most familiar application is the use of several of its esters as preservatives, known as parabens. Also of interest is the use in liquid crystal polymer applications. 

Liquid dosage forms which are disperse systems (colloidal, i.e., microspheres, nanoparticles, and micelles suspensions and emulsions) often contain preservatives which are methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid in various combinations. A typical example is the antacid suspensions which have high pH values which make the esters of the preservatives susceptible to hydrolysis. One way to circumvent this problem is to use several preservatives in combination with the hope that some quantities of the preservatives will remain to prevent the suspension from microbial attack. A report showing the assay of the four esters and the parent acid (one of the decomposition products) in drug products in which all the preservatives were used has been given [13]. 

This part of the chapter describes HPLC techniques for the separation and determination of preservatives, as follows S02, postharvest preservatives (PPs), benzoic acid (BA), sorbic acid (SA), and the ethyl, methyl, propyl esters of 4-hydroxybenzoic acid (EsHBA) and 5-nitrofury-lacrylic acid (5-NFA). The propionic, lactic, acetic acids are discussed in the chapter on organic acids. 

After benzoylation, it was possible to analyze together the food substances of varying chemical structures, such as alcohols, esters of 4-hydroxybenzoic acid, phenolic antioxidants, saccharides, and sugar alcohols. The method allowed the determination of these substances in different matrices by the same analytical procedure, using the same cleanup. The preservatives were separated on an RP-18 column. Acetonitrile-water (50 35) or acetonitrile-water-butylmethyl ether (110 35 40) were used as mobile phases. Detection was UV at 230 nm (71). 

Commonly used preservative agents include organic acids such as benzoic acid and salts, the parabens, (alkyl esters ofp-hydroxybenzoic acid), sorbic acid and salts, phenolic compounds, quaternary ammonium compounds, alcohols, and mercurials such as thimerosal in 0.001-0.004% concentration. 

Some compounds are employed in only one of these areas, for example, the parabens (esters of 4-hydroxybenzoic acid) are used as preservatives in some types of cosmetic and pharmaceutical products, whereas chlorhexi-dine salts are utilized in all three areas. The collective term biocide (bios, life cido, to kill) is used widely nowadays to denote a compound used in one or more of these fields [2],... 

Microbial degradation of biocides has been described by Hugo [72] who points out that soil organisms are able to break down substances such as phenols added as fumigants. He also reviewed the utilization by bacteria of aromatic compounds (including the preservatives cresol, phenol, benzoic acid and esters of 4-hydroxybenzoic acid). Several types of preservatives and disinfectants, such as the QACs (e.g. cetrimide, cetylpyridinium chloride, benzalkonium chloride), chlorhexidine and phenylethanol can also be inactivated. Significantly, this only occurs at concentrations well below inhibitory or in-use concentrations [33] and thus cannot be responsible for insusceptibility. A further comment about chlorhexidine is given below. 

SYNS ASEPTOFORM P BETACIDE P BONOMOLD OP 4-HYDROXYBENZOIC ACID PROPYL ESTER p-HYDROXYBENZOIC ACID PROPYL ESTER NIPASOL p-OXYBENZOESAEUREPRO-PYLESTER (GERMAN) PARABEN PARj SEPT PASEPTOL PRESERVAL P PROPYL p-HYDROXY-BENZOATE n-PROP X p-HYDROXYBENZOATE PROPYLPARABEN (FCC) PROPYLPARASEPT PROTABEN P TEGOSEPT P... 

Parabens (methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid) are used as preservatives in concentrations of 0.1-0.3% in pharmaceutical formulations and in concentrations of 0.01-0.1% in cosmetics and foods. In such concentrations they are devoid of systemic toxic effects, but allergic reactions have been reported. 

The alkyl esters (methyl, ethyl, and propyl) of p-hydroxybenzoic acid (the parabens) are widely used for their antifungal properties. The preservative effect of parabens tends to increase with increasing molecular mass. The methyl ester appears to be more effective against molds, whereas the propyl ester is more effective against yeasts (favored for oils and fats, for solubility reasons) (Gonzalez, Gallego, and Valcarcel, 1998). 

The very commonly used sorbic acid has been detected with low recoveries in raw beef (52-84%) by photometry, after distillation and extraction. Better recoveries ( 100%) and less manipulation have been achieved by the fluorescence technique in determination of 4-hydroxybenzoic methyl ester in nonalcoholic beverages. Additives can be present in combinations, and chromatographic methods are often used for selective individual or joint determination. Sorbic and benzoic acids have also been determined by thin-layer chromatography in beverages. This method involves minimal sample manipulation. HPLC is often the preferred method for determining additives present in mixtures, which are usually only just volatile. Simultaneous determination of additives, such as sweeteners, preservatives, and colorings in soft drinks is usually done by HPLC with UV... 

Phenol acids are phenols in which there is also a carboxylic acid group attached to the benzene ring. They include salicylic acid (ortho-hydroxybenzoic acid) and para-hydroxy-benzoic acid (Figure 25.8). Acetylsalicylic acid (aspirin) and sodium salicylate are derivatives of salicylic acid. Like phenol, they have antipyretic and analgesic properties. The methyl, ethyl and propyl esters of para-hydroxybenzoic acid (parabens) are used as preservatives in pharmaceuticals, cosmetics and foodstuffs. 

Preservatives are often needed to prevent microbial and fungal growth in LDLDs. Preservatives commonly used are formaldehyde, gluteraldehyde, benzoic acid, Kathon , Dowicil , Bronopol , various esters of hydroxybenzoic acid, and others. 

Beilstein Handbook Reference) Benzoic acid, 4-hydroxy-, heptyl ester Benzoic acid, P-hydroxy-, heptyl ester BRN 2726540 EINECS 214-115-0 Heptyl 4-hydroxybenzoate Heptyl p-hydroxybenzoate n-Heptyl p-hydroxybenzoate Heptyl paraben p-Hydroxybenzoic acid heptyl ester Nipaheptyl NSC 309818 p-Oxybenzoesaureheptylester Staypro WS 7, Preservative, bactericide, fungicide for pharmaceuticals, cosmetics, foods, medicinal preparations and industrial applications. Nipa. 

---