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Chlorhexidine is a cationic broad-spectrum antimicrobial agent belonging to the bis(biguanide) family.
Chlorhexidine's mechanism of action involves destabilization of the outer bacterial membrane.
Chlorhexidine is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria.
CAS: 55-56-1
MF: C22H30Cl2N10
MW: 505.45
EINECS: 200-238-7
Synonyms
1,1’-hexamethylenebis(5-(p-chlorophenyl)-biguanid;1,6-bis(5-(p-chlorophenyl)biguandino)hexane;1,6-bis(p-chlorophenyldiguanido)hexane;1,6-di(4’-chlorophenyldiguanido)hexane;2,4,11,13-tetraazatetradecanediimidamide,n,n’’-bis(4-chlorophenyl)-3,12-diim;chlorhexidin;fimeil;hexadol
Chlorhexidine has both bactericidal and bacteriostatic mechanisms of action.
Chlorhexidine's antimicrobial effects are associated with the attractions between chlorhexidine (cation) and negatively charged bacterial cells.
After chlorhexidine is absorpted onto the organism's cell wall, it disrupts the integrity of the cell membrane and causes the leakage of intracellular components of the organisms.
Aqueous solutions of chlorhexidine are most stable within the pH range of 5-8.
Above pH 8.0 chlorhexidine base is precipitated and in more acid conditions there is gradual deterioration of activity because the compound is less stable.
Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs.
Chlorhexidine was the first antimicrobial agent shown to inhibit dental plaque formation and the development of chronic gingivitis.
Chlorhexidine is a cationic chlorophenyl bisbiguanide antiseptic.
Bisbiguanides are the primary second generation antiplaque agents exhibiting considerable substantivity and broad spectrum antibacterial properties.
In dental medicine, Chlorhexidine was initially used for disinfection of the oral cavity prior to oral surgical procedures and in endodontics.
Plaque inhibition by Chlorhexidine was first investigated in 1969 (Schroeder) but the first controlled clinical study was performed by Loe and Schiott.
This study showed that rinsing for 60 sec, twice a day with 10 ml of a 0.2% (20 mg dose) Chlorhexidine gluconate solution, in the absence of normal tooth cleaning, inhibited plaque regrowth and the development of gingivitis.
Chlorhexidine is one of the most widely investigated and used antiplaque agents.
The advantage of CHX over other cationic agents is that it can bind strongly to many sites in the oral cavity and is released slowly over 7 to 12 hours after rinsing, thus providing considerable substantivity and a sustained antimicrobial effect restricting bacterial proliferation.
Chlorhexidine binds strongly with anionic glycoproteins and phosphoproteins on the oral mucosa and tooth pellicle in addition to its property of binding to the surfaces of bacterial cell membranes affecting the cells ability to adhere.
Chlorhexidine is considered the most potent chemotherapeutic agent currently available.
A bisbiguanide compound with a structure consisting of two (p-chlorophenyl)guanide units linked by a hexamethylene bridge.
Effect of the Chlorhexidine:hydroxypropyl-β-cyclodextrin inclusion compound on in vitro slabs of bovine dentine has been investigated.
Chlorhexidine is a disinfectant and antiseptic which is used for skin disinfection before surgery and to disinfect surgical instruments.
Chlorhexidine is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking.
Chlorhexidine is used as a liquid or a powder.
Chlorhexidine is commonly used in salt form, either the gluconate or the acetate.
Side effects may include skin irritation, tooth discoloration, and allergic reactions, although, apart from discoloration, the risk appears to be the same as that for povidone-iodine.
Chlorhexidine rinse is also known to have a bitter metallic aftertaste. Rinsing with water is not recommended as it is known to increase the bitterness.
Chlorhexidinet may cause eye problems if direct contact occurs.
Use in pregnancy appears to be safe.
Chlorhexidine may come mixed in alcohol, water, or surfactant solution.
Chlorhexidine is effective against a range of microorganisms, but does not inactivate spores.
Chlorhexidine came into medical use in the 1950s and is available over the counter in the United States.
Chlorhexidine is on the World Health Organization's List of Essential Medicines.
In 2023, it was the 270th most commonly prescribed medication in the United States, with more than 900,000 prescriptions.
Chlorhexidine Chemical Properties
Melting point: 134-136 °C (lit.)
Boiling point: 641.45°C (rough estimate)
density: 1.1555 (rough estimate)
refractive index: 1.6300 (estimate)
storage temp.: 2-8°C
solubility: water: soluble0.08% at 20°C
form: Solid
pka: pKa 10.78 (Uncertain)
color: White to off-white
Water Solubility: 0.08 g/100 mL (20 ºC)
Merck: 13,2108
BRN: 2826432
Stability: Stable. Incompatible with strong oxidizing agents.
InChIKey: GHXZTYHSJHQHIJ-UHFFFAOYSA-N
LogP: 0.080
CAS DataBase Reference: 55-56-1(CAS DataBase Reference)
EPA Substance Registry System: Chlorhexidine (55-56-1)
Chlorhexidine, 1,6-bis(4-chlorophenylbiguanido)hexane, C22H30Cl2N10, Mr 505.45, mp 134 ℃, is a widely used antiseptic (→Disinfectants).
Chlorhexidine can be prepared, for example, from 1,6-hexamethylenebis(dicyandiamide) and 4-chloroaniline hydrochloride.
Chlorhexidine is used primarily as its salts (e.g., the dihydrochloride, diacetate, and digluconate) in disinfectants (disinfection of the skin and hands), cosmetics (additive to creams, toothpaste, deodorants, and antiperspirants), and pharmaceutical products (preservative in eyedrops, active substance in wound dressings and antiseptic mouthwashes).
Uses
Chlorhexidine is an antibacterial used for numerous applications.
Chlorhexidine is a cationic polybiguanide (bisbiguanide) used primarily as its salts, dihydrochloride, diacetate, and digluconate.
Chlorhexidine is one of those drugs which are enlisted/included in the World Health Organization's List of Essential Medicines, a list of the most important drugs needed in a basic health system.
Chlorhexidine is used as a germicidal compound in teat dips.
Also used as navel treatment, udder and eye wash, surgical scrub and sterilization material.
Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs.
Chlorhexidine is used as an antibacterial agent in humans to control gingivitis and over all plaque control in preventative dentistry.
Hydrogenolysis of benzyl-nitrogen bonds.
Bacteriostatic;Detergent.
Chlorhexidine is used in disinfectants (disinfection of the skin and hands), cosmetics (additive to creams, toothpaste, deodorants, and antiperspirants), and pharmaceutical products (preservative in eye drops, active substance in wound dressings and antiseptic mouthwashes).
In endodontics, chlorhexidine has been used for root canal irrigation and as an intracanal dressing.
Antiseptic
Chlorhexidine is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts.
Chlorhexidine is particularly effective against Gram-positive bacteria (in concentrations ≥ 1 μg/L).
Significantly higher concentrations (10 to more than 73 μg/mL) are required for Gram-negative bacteria and fungi.
Chlorhexidine is ineffective against polioviruses and adenoviruses.
The effectiveness against herpes viruses has not yet been established unequivocally.
There is strong evidence that chlorhexidine is more effective than povidone-iodine for clean surgery.
Evidence shows that Chlorhexidine is an effective antiseptic for upper limb surgery.
Meta-data spanning several decades shows that the efficacy of chlorhexidine (against organisms that cause surgical site infection) has not changed, dispelling concerns over emerging resistance.
Chlorhexidine is used to treat gingivitis.
Chlorhexidine helps to reduce the inflammation (redness) and swelling of your gums and to reduce gum bleeding.
Gingivitis is caused by the bacteria that grow in the coating (plaque) that forms on your teeth between tooth brushings.
Chlorhexidine is an important medical, dental and pharmaceutical antiseptic, disinfectant and preservative.
Chlorhexidine is bactericida and fungicidalsy but does not kill bacterial spores or mycobacteria, although it inhibits growth.
Chlorhexidine has a low order of activity against viruses, but high concentrations are effective in killing cysts of Acanthamoeba spp., organisms of potential clinical significance to the wearers of contact lenses.
Properties Chlorhexidine is a bisbiguanide which is available as the acetate (diacetate), hydrochloride and gluconate salts.
These are stable in solution and can be autoclaved although small amounts of chloroaniline are released.”
As a cationic agent, chlorhexidine is incompatible with anionic surfactants and its antimicrobial activity is reduced in the presence of non-ionic surface-active agents.
Activity is also reduced or abolished by phospholipids (a factor of significance in neutralizing chlorhexidine activity during the performance of biocidal tests) and by organic matter including serum.
Some of these aspects have been well documented in the recent comprehensive paper of Nicoletti et al.”
They also point out that the efficacy of chlorhexidine is influenced by formulation components and by the composition of the culture medium in which minimum inhibitory concentrations (MICs) are determined.
Chlorhexidine, the "gold standard" in oral antiseptics, has been used to optimize novel slow release chlorhexidine coatings based on fatty acids in surgical sutures.
Chlorhexidine, antibacterial agent, has been used in preparaing chlorhexidine-functionalized calcium phosphate nanoparticles, useful for oral hygiene and dental treatment.
chlorhexidine is used as a topical antiseptic in liquid cosmetics.
Chlorhexidine is strongly alkaline and may cause irritation.
Pharmaceutical Applications
Chlorhexidine salts are widely used in pharmaceutical formulations in Europe and Japan for their antimicrobial properties.
Although mainly used as disinfectants, chlorhexidine salts are also used as antimicrobial preservatives.
As excipients, chlorhexidine salts are mainly used for the preservation of eye-drops at a concentration of 0.01% w/v; generally the acetate or gluconate salt is used for this purpose.
Solutions containing 0.002–0.006% w/v chlorhexidine gluconate have also been used for the disinfection of hydrophilic contact lenses.
For skin disinfection, chlorhexidine has been formulated as a 0.5% w/v solution in 70% v/v ethanol and, in conjunction with detergents, as a 4% w/v surgical scrub.
Chlorhexidine salts may also be used in topical antiseptic creams, mouthwashes, dental gels, and in urology for catheter sterilization and bladder irrigation.
Chlorhexidine salts have additionally been used as constituents of medicated dressings, dusting powders, sprays, and creams.
Clinical Use
Chlorhexidine is a biguanide topical antiseptic and disinfectant with broad antimicrobial efficacy.
Chlorhexidine is increasingly being used as an aseptic but it is also gaining use as a biocidal ingredient in shampoos, conditioners, hair dyes, sunscreens, toothpastes, mouthwashes (Corsodyl), wet wipes (also for babies), eye creams, antiwrinkle creams, moisturizers, contact lens solutions, and instillation gels for urinary catheters.
Urticaria following application to intact skin or mucosae, in some cases accompanied by dyspnea, angioedema, syncope, or anaphylaxis has been described via the mucosal route at much lower concentration than elsewhere, generally as low as 0.05%.
Production Methods
Chlorhexidine may be prepared either by condensation of polymethylene bisdicyandiamide with 4-chloroaniline hydrochloride or by condensation of 4-chlorophenyl dicyandiamine with hexamethylenediamine dihydrochloride.
Chlorhexidine may also be synthesized from a series of biguanides.
Manufacturing Process
25 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of beta-ethoxyethanol are stirred together at
130°C to 140°C for 2 hours under reflux.
The mixture is then cooled and filtered and the solid is washed with water and crystallized from 50% aqueous acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanido-N5,N5')hexane dihydrochloride is obtained as colorless plates of MP 258°C to 260°C.
The following is an alternative route: 19.4 parts of pchlorophenyldicyandiamide, 9.4 parts of hexamethylene diaminedihydrochloride and 100 parts of nitrobenzene are stirred together and heated at 150 C to 160°C for 6 hours.
The mixture is cooled, diluted with 200 parts of benzene and filtered.
The solid residue is washed with benzene and crystallized from 50% acetic acid.
1,6-di(N1,N1'-p-chlorophenyldiguanidoN5,N5')hexane dihydrochloride is obtained.
Side effects
Side effects may include skin irritation, tooth discoloration, and allergic reactions, although apart from discoloration the risk appears to be the same as povidone-iodine.
Chlorhexidine is ototoxic (toxic to the inner ear).
If put into the ear canal (middle ear) with a ruptured ear drum, it may lead to deafness.
Chlorhexidine does not meet European specifications for a hand disinfectant.
Under the test conditions of the European Standard EN 1499, no significant difference in the efficacy was found between a 4% solution of chlorhexidine digluconate and soap.
In the US, between 2007 and 2009, Hunter Holmes McGuire Veterans Administration Medical Center conducted a cluster-randomized trial and concluded that daily bathing of patients in intensive care units with washcloths saturated with chlorhexidine gluconate reduced the risk of hospital-acquired infections.
Whether prolonged exposure over many years may have carcinogenic potential is still not clear.
The US Food and Drug Administration recommendation is to limit the use of a chlorhexidine gluconate mouthwash to a maximum of six months.
When ingested, chlorhexidine is poorly absorbed in the gastrointestinal tract and can cause stomach irritation or nausea.
If aspirated into the lungs at high enough concentration, as reported in one case, Chlorhexidine can be fatal due to the high risk of acute respiratory distress syndrome.
