55-56-1 Usage
Uses
Used in Medical, Dental, and Pharmaceutical Applications:
Chlorhexidine is used as an antiseptic, disinfectant, and preservative for its bactericidal and fungicidal properties. It is effective in controlling gingivitis and overall plaque control in preventative dentistry.
Used in Veterinary Applications:
Chlorhexidine is used as a germicidal compound in teat dips, navel treatment, udder and eye wash, and as a surgical scrub and sterilization material.
Used in Cosmetics:
Chlorhexidine is used as a topical antiseptic in liquid cosmetics, although it is strongly alkaline and may cause irritation.
Used in Surgical Applications:
Chlorhexidine is used as the "gold standard" in oral antiseptics and has been used to optimize novel slow-release chlorhexidine coatings based on fatty acids in surgical sutures.
Used in Dental Treatment:
Chlorhexidine has been used in preparing chlorhexidine-functionalized calcium phosphate nanoparticles, which are useful for oral hygiene and dental treatment.
Used in Chemical Synthesis:
Chlorhexidine is also used in the hydrogenolysis of benzyl-nitrogen bonds and as a bacteriostatic and detergent agent.
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.
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.
Manufacturing Process
25 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline
hydrochloride and 250 parts of beta-ethoxyethanol are stirred together at130°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
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.
Check Digit Verification of cas no
The CAS Registry Mumber 55-56-1 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 5 respectively; the second part has 2 digits, 5 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 55-56:
(4*5)+(3*5)+(2*5)+(1*6)=51
51 % 10 = 1
So 55-56-1 is a valid CAS Registry Number.
InChI:InChI=1S/C22H30Cl2N10/c23-15-5-9-17(10-6-15)31-21(27)33-19(25)29-13-3-1-2-4-14-30-20(26)34-22(28)32-18-11-7-16(24)8-12-18/h5-12H,1-4,13-14H2,(H5,25,27,29,31,33)(H5,26,28,30,32,34)
55-56-1Relevant articles and documents
Preparation method of chlorhexidine
-
Paragraph 0021, (2020/07/13)
The invention discloses a preparation method of chlorhexidine. The preparation method comprises the following steps: mixing n-butyl alcohol, hexanediamine and hydrochloric acid, adding triethylamine and sodium dicyandiamide, carrying out a primary condensation reaction, adding parachloroaniline, water and hydrochloric acid after the primary condensation reaction is finished, carrying out a secondary condensation reaction, adding liquid caustic soda after the secondary condensation reaction is finished, alkalizing, crystallizing, and carrying out centrifugal filtration to obtain a chlorhexidinecrude product; and washing, carrying out centrifugal filtration, and drying to obtain chlorhexidine. According to the method, chlorhexidine is prepared by adopting a one-pot boiling principle, so that the reaction steps and the wastewater amount are reduced, the operation is simplified, and the quality and the yield are remarkably improved.
Oral disinfectants inhibit protein-protein interactions mediated by the anti-apoptotic protein Bcl-xL and induce apoptosis in human oral tumor cells
Graeber, Martin,Hell, Michael,Groest, Corinna,Friberg, Anders,Sperl, Bianca,Sattler, Michael,Berg, Thorsten
supporting information, p. 4487 - 4491 (2013/05/22)
Chlorhexidine and alexidine have long been used as oral disinfectants by humans. Both compounds inhibit protein-protein interactions mediated by the anti-apoptotic protein Bcl-xL at physiologically relevant concentrations and induce apoptosis in a series of tumor cell lines derived from the tongue and pharynx (see picture). Inhibition of protein-protein interactions is a potential mode of action of drugs in current human use. Copyright
Nanomaterial wound dressing assembly
-
, (2011/05/16)
Wound dressing assemblies and methods of producing the wound dressing assemblies. The wound dressing assemblies various comprise individual layers of nanomaterials that have been formed according to an electrospinning process. Each of the layers can have different characteristics and qualities. The invention also provides guidance in selecting materials to form a wound dressing assembly, as well as possible adaptations to the electrospinning process to provide different characteristics for particular materials.
Antimicrobial Composite Material and Method for Fluid Treatment
-
Page/Page column 10, (2009/08/14)
Composite materials with broad spectrum antimicrobial properties and methods and devices for fluid treatment utilizing said materials are provided. The antimicrobial composite materials may include combinations of activated carbon and a biguanide hydrate. A particular composition includes a mixture of carbon particles and particles of chlorhexidine hydrate, which is useful in fixed particle bed water treatment devices and methods.
Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof
-
, (2008/06/13)
The present invention provides novel hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon contacting an aqueous environment. Methods of using the novel polyester copolymers of the invention in humans are also disclosed for providing a protective barrier to prevent post-surgical adhesion, treatment of defects in conduits such as blood vessels, and controlled release of a biologically active agent for modulating cellular events such as wound healing and tissue regeneration or therapeutic treatment of diseases such as infection of the periodontium, dry socket, bone, skin, vaginal, and nail infections.
Hydrogel-forming , self-solvating absorbable polyester copolymers, and methods for use therefor
-
, (2008/06/13)
The present invention provides novel hydrogel-forming, self-solvatirig, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon contacting aqueous environment. Pharmaceutical formulations comprising the novel polyester copolymers of the invention are also disclosed which provide a protective barrier to prevent post-surgical adhesion, can be used to treat of defects in conduits such as blood vessels, and for controlled release of a biologically active agent for modulating cellular events such as wound healing and tissue regeneration or therapeutic treatment of diseases such as infection of the periodontium, dry socket, bone, skin, vaginal, and nail infections.
Intraoral medicament delivery and procedure
-
, (2008/06/13)
A method for cushioning dental appliance in the mouth using a visible light cured polymeric material which can also be used in a method for intraoral medicament delivery in the mouth is provided. When used with an orthodontic bracket, for example, the light cured polymeric material is dispensed on the orthodontic bracket after the bracket is in place and the material is light cured on the bracket. When used in a method of intraoral delivery of a medicament, a medicament is added to the polymeric material and the polymeric material is applied in the same manner as described for cushioning an orthodontic bracket.
Dentifrice containing a poly(hydroxypropyl ether) non-ionic surfactant and a specified cationic polymer
-
, (2008/06/13)
Dentifrice containing, in combination, (A) a poly(hydroxypropyl ether) nonionic surfactant, and (B) a cationic polymer selected from the group consisting of (i) a vinylpyrrolidone/dialkylaminoalkyl or -hydroxyalkyl acrylate or methacrylate, quaternized or nonquaternized and (ii) a cationic polysaccharide. This dentifrice is characterized by good foamability, pleasant taste and it does not attack the buccal mucosae and the gums.
