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

pka

pKa 10.78 (Uncertain)

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)

Safety Information

Hazard Codes 

Xi,N

Risk Statements 

36/37/38-43-51/53-50/53

Safety Statements 

26-36/37-60-61

RIDADR 

UN 3077 9/PG 3

WGK Germany 

3

RTECS 

DU1925000

F 

10-34

HazardClass 

9

PackingGroup 

III

HS Code 

29215900

Hazardous Substances Data

55-56-1(Hazardous Substances Data)

Toxicity

LD50 orally in Rabbit: 5000 mg/kg

MSDS

• Language:English Provider:Hexamethylenebis(5-(4-chlorophenyl)biguanide)
• Language:English Provider:SigmaAldrich

Chlorhexidine Usage And Synthesis

Description

Chlorhexidine is a cationic broad-spectrum antimicrobial agent belonging to the bis(biguanide) family. Its mechanism of action involves destabilization of the outer bacterial membrane. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It 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. It has a LD-50 orally in mice as a diacetate at 2gm./kg. In digluconate form the LD-50 is 1800 gm./kg.

Chemical Properties

Chlorhexidine [55-56-1], 1,6-bis(4-chlorophenylbiguanido)hexane, C22H30Cl2N10, Mr 505.45, mp 134 ℃, is a widely used antiseptic (→Disinfectants). It 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).

Chemical Properties

Chlorhexidine occurs as an odorless, bitter tasting, white crystalline powder.

Originator

Hibiclens,Stuart,US,1976

History

Chlorhexidine (CHX) was the first antimicrobial agent shown to inhibit dental plaque formation and the development of chronic gingivitis (Loe and Schiott 1970).
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, CHX was initially used for disinfection of the oral cavity prior to oral surgical procedures and in endodontics. Plaque inhibition by CHX was first investigated in 1969 (Schroeder) but the first controlled clinical study was performed by Loe and Schiott (1970). [16] This study showed that rinsing for 60 sec, twice a day with 10 ml of a 0.2% (20 mg dose) CHX gluconate solution, in the absence of normal tooth cleaning, inhibited plaque regrowth and the development of gingivitis.
CHX 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. CHX 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. CHX is considered the most potent chemotherapeutic agent currently available.

Uses

Chlorhexidine is an antibacterial used for numerous applications. It 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.

1. Chlorhexidine is used as a germicidal compound in teat dips. Also used as navel treatment, udder and eye wash, surgical scrub and sterilization material.
2. Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs. it is used as an antibacterial agent in humans to control gingivitis and over all plaque control in preventative dentistry.
3. Hydrogenolysis of benzyl-nitrogen bonds.
4. Bacteriostatic;Detergent.

Uses

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.

Uses

chlorhexidine is used as a topical antiseptic in liquid cosmetics. It is strongly alkaline and may cause irritation.

Definition

ChEBI: A bisbiguanide compound with a structure consisting of two (p-chlorophenyl)guanide units linked by a hexamethylene bridge.

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.

Indications

This topical antiseptic product acts rapidly but, like hexachlorophene, persists on the skin to give a cumulative, continuing antibacterial effect. Like iodophors and alcohol, it is active against gram-positive and gram-negative bacteria, including P. aeruginosa, as well as common yeasts and fungi. It does not lose effectiveness in the presence of whole blood. Many consider it the antiseptic of choice for skin cleansing and surgical scrubs. Contact allergy is not uncommon. Chlorhexidine should not be used near the eyes or mucosal surfaces, because it may cause irritation or even anaphylaxis.

Application

Chlorhexidine is an important medical, dental and pharmaceutical antiseptic, disinfectant and preservative. It is bactericida and fungicidalsy but does not kill bacterial spores or mycobacteria, although it inhibits growth. It 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.

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.

Therapeutic Function

Antimicrobial

General Description

Effect of the chlorhexidine:hydroxypropyl-β-cyclodextrin inclusion compound on in vitro slabs of bovine dentine has been investigated.

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. It 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%.

Safety Profile

Poison by intraperitoneal andintravenous routes. Mildly toxic by ingestion.Experimental reproductive effects. A human skin irritant.Mutation data reported. When heated to decomposition itemits very toxic fumes of Cl- and NOx.

Safety

Chlorhexidine and its salts are widely used, primarily as topical disinfectants. As excipients, chlorhexidine salts are mainly used as antimicrobial preservatives in ophthalmic formulations.
Animal studies suggest that the acute oral toxicity of chlorhexidine is low, with little or no absorption from the gastrointestinal tract. However, although humans have consumed up to 2 g of chlorhexidine daily for 1 week, without untoward symptoms, chlorhexidine is not generally used as an excipient in orally ingested formulations.
Reports have suggested that there may be some systemic effects in humans following oral consumption of chlorhexidine.
Similarly, the topical application of chlorhexidine or its salts produced evidence of very slight percutaneous absorption of chlorhexidine, although the concentrations absorbed were insufficient to produce systemic adverse effects.
Severe hypersensitivity reactions, including anaphylactic shock, have been reported following the topical administration of chlorhexidine, although such instances are rare given the extensive use of chlorhexidine and it salts.
In ophthalmic preparations, irritation of the conjunctiva occurs with chlorhexidine solutions of concentration stronger than 0.1% w/v. Accidental eye contact with 4% w/v chlorhexidine gluconate solution may result in corneal damage.
The aqueous concentration of chlorhexidine normally recommended for contact with mucous surfaces is 0.05% w/v. At this concentration, there is no irritant effect on soft tissues, nor is healing delayed. The gluconate salt (1% w/v) is frequently used in creams, lotions, and disinfectant solutions.
Direct instillation of chlorhexidine into the middle ear can result in ototoxicity; when used in dental preparations, staining of teeth and oral lesions may occur.
Use of chlorhexidine on the brain or meninges is extremely dangerous.
LD₅₀ (mouse, IP): 0.04 g/kg
LD₅₀ (mouse, oral): 2.52 g/kg
LD₅₀ (rat, IP): 0.06 g/kg
LD₅₀ (rat, IV): 0.02 g/kg
LD₅₀ (rat, oral): 9.2 g/kg

Veterinary Drugs and Treatments

A topical antiseptic, chlorhexidine has activity against many bacteria, but apparently not predictably active against Pseudomonas or Serratia spp. It is available with veterinary labels in many different forms (solutions, shampoos, scrubs, ointments, sprays, etc).
Because it causes less drying and is usually less irritating than benzoyl peroxide, it is sometimes used in patients that cannot tolerate benzoyl peroxide. It does not have the keratolytic, degreasing or follicular flushing effects of benzoyl peroxide however. Chlorhexidine possesses some residual effects and can remain active on skin after rinsing.
At usual concentrations, chlorhexidine acts by damaging bacterial cytoplasmic membranes. Antifungal activity can be obtained with 2% or higher concentrations. For wound irrigation, 0.05 – 0.1% dilution in water is recommended.

storage

Chlorhexidine and its salts are stable at normal storage temperatures when in the powdered form. However, chlorhexidine hydrochloride is hygroscopic, absorbing significant amounts of moisture at temperatures up to 378℃ and relative humidities up to 80%.
Heating to 1508℃ causes decomposition of chlorhexidine and its salts, yielding trace amounts of 4-chloroaniline. However, chlorhexidine hydrochloride is more thermostable than the acetate and can be heated at 1508℃ for 1 hour without appreciable formation of 4-chloroaniline.
In aqueous solution, chlorhexidine salts may undergo hydrolysis to form 4-chloroaniline, catalyzed by heating and an alkaline pH. Following autoclaving of a 0.02% w/v chlorhexidine gluconate solution at pH 9 for 30 minutes at 1208℃, it was found that 1.56% w/w of the original chlorhexidine content had been converted into 4-chloroaniline; for solutions at pH 6.3 and 4.7 the 4-chloroaniline content was 0.27% w/w and 0.13% w/w, respectively, of the original gluconate content. In buffered 0.05% w/v chlorhexidine acetate solutions, maximum stability occurs at pH 5.6.
When chlorhexidine solutions were autoclaved at various time and temperature combinations, the rate of hydrolysis increased markedly above 1008℃, and as pH increased or decreased from pH 5.6. At a given pH, chlorhexidine gluconate produced more 4- chloroaniline than the acetate.
It was predicted that in an autoclaved solution containing 0.01% w/v chlorhexidine, the amount of 4-chloroaniline formed would be about 0.00003%. At these low concentrations there would be little likelihood of any toxic hazard as a result of the increase in 4- chloroaniline content in the autoclaved solution.
Chlorhexidine solutions and aqueous-based products may be packaged in glass and high-density polyethylene or polypropylene bottles provided that they are protected from light. If not protected from light, chlorhexidine solutions containing 4-chloroaniline discolor owing to polymerization of the 4-chloroaniline.
Cork-based closures or liners should not be used in packaging in contact with chlorhexidine solutions as chlorhexidine salts are inactivated by cork.
As a precaution against contamination with Pseudomonas species resistant to chlorhexidine, stock solutions may be protected by the inclusion of 7% w/v ethanol or 4% w/v propan-2-ol.
Chlorhexidine salts, and their solutions, should be stored in wellclosed containers, protected from light, in a cool, dry place.

Incompatibilities

Chlorhexidine salts are cationic in solution and are therefore incompatible with soaps and other anionic materials. Chlorhexidine salts are compatible with most cationic and nonionic surfactants, but in high concentrations of surfactant chlorhexidine activity can be substantially reduced owing to micellar binding.
Chlorhexidine salts of low aqueous solubility are formed and may precipitate from chlorhexidine solutions of concentration greater than 0.05% w/v, when in the presence of inorganic acids, certain organic acids, and salts (e.g. benzoates, bicarbonates, borates, carbonates, chlorides, citrates, iodides, nitrates, phosphates, and sulfates). At chlorhexidine concentrations below 0.01% w/v precipitation is less likely to occur.
In hard water, insoluble salts may form owing to interaction with calcium and magnesium cations. Solubility may be enhanced by the inclusion of surfactants such as cetrimide.
Other substances incompatible with chlorhexidine salts include viscous materials such as acacia, sodium alginate, sodium carboxymethylcellulose, starch, and tragacanth. Also incompatible are brilliant green, chloramphenicol, copper sulfate, fluorescein sodium, formaldehyde, silver nitrate, and zinc sulfate.
Interaction has been reported between chlorhexidine gluconate and the hydrogel poly(2-hydroxyethyl methacrylate), which is a component of some hydrophilic contact lenses.

Regulatory Status

Chlorhexidine salts are included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

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