Antimicrobial and antifungal preservatives
●compounds necessary for protection of medicinal preparations
against unwanted microorganisms being able to decompose active
ingredients and/or other excipients or evoke dangerous microbial
contamination (vaccines)
Outline of the most often used structural groups of
preservatives
1. Organic compounds of mercury
2. Alcohols and phenols
3. Aldehydes and their precursors
4. Carboxylic acids
5. Quarternary ammonium salts
1.Organic compounds of mercury
● preservation of sterile ocular and parenteral preparations, namely
vaccines in multi-dose bottles
● one of the last rests of heavy metals compounds, formerly widely
spread in medicine
●much less toxic than soluble inorganic mercuric salts (HgCl2
)
●bactericidal and fungicidal effect, slightly to spores
● mode of action: interaction with -SH groups of microbial proteins
1.1 Phenylmercuric salts
●covalent salts of inorganic or caboxylic acids with phenylmercuric moiety
●mixtures of such salts with phenylmercuric hydroxide are often acceptable by many
●pharmacopoeias
Hg
O CH3
O
Hg
O
Hg
O
B
OHH
OH
Hg
OH
Hg
O
Hg
OB
OH
Hg
OH
Hg
O N
O
O
Hg
OH
.
or
. .
Phenylmecuric acetate Phenylmercuric borate Phenylmercuric nitrate
Phenylhydrargyri acetas Phenylhydrargyri boras Phenylhydrargyri nitras
Famosept ®
●
1.2 Thiomersal
S
Hg
O O
CH3
Na
+
syn. thimerosal, merthiolate
sodium 2-(ethylhydrargyriumsulfanyl)benzoate
sodium 2-(ethylmercurithio)benzoate
sodium ethylmerkurithiosalicylate
●typically preservation of multi-dose vaccines
●possible relationship between autism of some of vaccinated
childern and thiomersal discussed, but no evidence
●stepwise abandoned
2. Alcohols and phenols
2.1 Alcohols
●preservation ability of short-chain alconols like ethanol and propane-2-ol is usable
only if their concentration in a preparation is satisfactory (cca 20 % for ethanol);
typical preservatives are aromatic-aliphatic alcohols with orderly lower active
concentrations
OH
OH
O
OH
benzyl alcohol phenethyl alcohol phenoxyethanol
phenylmethanol 2-phenylethan-1-ol 2-phenoxyethan-1-ol
Alcohol benzylicus ČL 2005 Phenoxyethanolum ČL2005
●parenteralia, inj. radiopharmaceutics
● preservation of vaccines and topical preparations
l
2.2 Phenols
OH OH
CH3
OH
CH3
Cl
CH3
CH3
CH3
OH
phenol
Phenolum ČL 2009
Phenolum liquefactum
ČL 2009 contains 10
% water
●inactivation and
preservation of live
vaccines
●preparation Solutio
Galli-Valerio ČL 2009
for preservation of
medical instruments
cresols
2-, 3-, 4-methylphenol
Cresolum crudum ČL
2009 = mixture of all 3
isomers
Metacresolum ČL
2009
chlorocresol
4-chloro-3-methylphenol
Chlorocresolum ČL 2009
thymol
2-isopropyl-5-methylphenol
Thymolum ČL 2009
2.2 Phenols (continued)
Parabens
OH
O
R
O
alkyl 4-hydroxybenzoates
R = Cn
H2n+1
most often 1 ≥ n ≥ 5
●mainly linear, from branched R = iso-C4
H7
in cosmetics
Methyl- butylparabenum ČL 2009; also sodium salts: Methyl- propylparabenum natricum
●preservation of external and also p.o. preparations: Aqua conservans ČL 2009 0,67 % MP +
0,33 % PP
●active in acid, neutral and alkaline media
●antifungl activity: R = -CH3
more active against moulds, R = -C3
H7
against yeasts
●antibacterial activity increaces with chain length and lipophilicity
●less suitable for foods, slight local anesthetic activity lowering taste (but used)
3. Aldehydes and their precursors
H H
O
OH
OH
BrO2N
formaldehyde
methanal
Formaldehydum ČL 2009
●preparation: Sol. Galli-Valerio ČL 2009
bronopol
2-brom-2-nitro-1,3-propandiol
●first prepared by Henry in 1898
●antimikrobial aditive in external
preparations and in cosmetics
●self mode of action: reaction with
-SH groups of Cys
H H
O
OH
BrO2
N
H H
O
OH
OH
BrO2
N
BrO2N
OH
BrO2
N
+
+
●common mode of action of aldehydes: denaturation of superficial proteins
by forming of Schiff bases from free amino groups
4. Carboxylic acids
benzoic acid
benzenecarboxylic acid
Acidum benzoicum ČL 2009
●
active for pH ≤ 7.3
sorbic acid
(E,E)-hexa-2,4-dienic acid
Acidum sorbicum ČL 2009
OHO
CH3 OH
O
5. Quarternary ammonium salts
R = C8H17-C18H37 (mixture)
alkylbenzyldimethylammonium chloride
benzalkonium chloride
Benzalkonii chloridum ČL 2009
●eye drops
●mode of action: removing of superficial proteins from
cellular membrane of microorganisms
N
+
R CH3
CH3
Cl