Name: Chlorhexidine
CAS No: 1E-2-[6-[[amino-[[amino-[(4-chlorophenyl)amino], methylidene], amino]methylidene]amino]hexyl]-1-[amino-[(4-chlorophenyl), amino]methylidene]guanidine [55-56-1]
BP: Chlorhexidine Acetate Chlorhexidine Gluconate Solution Chlorhexidine Hydrochloride JP: Chlorhexidine Gluconate Solution Chlorhexidine Hydrochloride PhEur: Chlorhexidine Diacetate Chlorhexidine Digluconate Solution Chlorhexidine Dihydrochloride USP: Chlorhexidine Gluconate Solution Chlorhexidine is usually encountered as the acetate, gluconate, or hydrochloride salt, and a number of pharmacopeias contain monographs for such materials
1,6-bis[N0 -(p-Chlorophenyl)-N 5 -biguanido]hexane; N,N00-bis(4- chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide; chlorhexidini diacetas; chlorhexidini digluconatis solutio; chlorhexidini dihydrochloridum; 1,6-di(40 -chlorophenyldiguanido)hexane; 1,1’-hexamethylene-bis[5-(p-chlorophenyl)biguanide
1E-2-[6-[[amino-[[amino-[(4-chlorophenyl)amino], methylidene], amino]methylidene]amino]hexyl]-1-[amino-[(4-chlorophenyl), amino]methylidene]guanidine [55-56-1]
C22H30Cl2N10 505.48
Chlorhexidine salts are widely used in pharmaceutical formulations in Europe and Japan for their antimicrobial properties.(1,2) 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.(1–4) Chlorhexidine salts have additionally been used as constituents of medicated dressings, dusting powders, sprays, and creams.
Chlorhexidine occurs as an odorless, bitter tasting, white crystalline powder. See Section 17 for information on chlorhexidine salts
See Table I
Antimicrobial activity Chlorhexidine and its salts exhibit antimicrobial activity against Gram-positive and Gram-negative microorganisms.(5) At the low concentrations normally used for preservation and antisepsis, chlorhexidine salts are rapidly bactericidal. However, species of Proteus and Pseudomonas are less susceptible to chlorhexidine, which is also inactive against acid-fast bacilli, bacterial spores, and some fungi. Chlorhexidine salts are effective against some lipophilic viruses such as adenovirus, herpes virus, and influenza virus. Optimum antimicrobial activity occurs at pH 5–7. Above pH 8, the chlorhexidine base may precipitate from aqueous solutions. Bacteria (Gram-positive) Chlorhexidine salts are active against most species; the minimum inhibitory concentration (MIC) is normally in the range 1–10 mg/mL, although much higher concentrations are necessary for Streptococcus faecalis. Typical MIC values are shown in Table II. Bacteria (Gram-negative) Chlorhexidine salts are less active against Gram-negative species than against Gram-positive species. Typical MICs are 1–15 mg/mL, but pseudomonads, particularly Pseudomonas aeruginosa, may be more resistant. Serratia marcescens may also be resistant. Combinations of chlorhexidine acetate with the following substances have shown enhanced or more than additive activity towards Pseudomonas aeruginosa: benzalkonium chloride; benzyl alcohol; bronopol; edetic acid; phenylethanol, and phenylpropanol.(6,7) Typical MIC values are shown in Table III Fungi Chlorhexidine salts are slowly active against molds and yeasts, although they are generally less potent in their inhibitory activity against fungi than against bacteria. Typical MIC values are shown in Table IV Spores Chlorhexidine salts are inactive against spores at normal room temperature.(8) At 98–1008C there is some activity against mesophilic spores. Critical micelle concentration 0.6% w/v (depends on other ions in solution).(9) Melting point 132–1348C See also Section 17 for additional information. NIR spectra
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 378C and relative humidities up to 80% Heating to 1508C 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 1508C 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 1208C, 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.(10) 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 1008C, 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.(11–13) 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.
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).(14) 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.(15,16) 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.(17,18)
Chlorhexidine may be prepared either by condensation of polymethylene bisdicyandiamide with 4-chloroaniline hydrochloride or by condensation of 4-chlorophenyl dicyandiamine hexamethylenediamine dihydrochloride. Chlorhexidine may also be synthesized from a series of biguanides.(19
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.(20–22) 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.(23) Severe hypersensitivity reactions, including anaphylactic shock, have been reported following the topical administration of chlorhexidine,(24–28) 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.(29) 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;(30) when used in dental preparations, staining of teeth and oral lesions may occur.(31,32) Use of chlorhexidine on the brain or meninges is extremely dangerous. LD50 (mouse, IP): 0.04 g/kg(33) 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
Observe normal precautions appropriate to the circumstances and quantity of material handled. The dust of chlorhexidine and its salts may be irritant to the skin, eyes, and respiratory tract. Gloves, eye protection, and a respirator are recommended.
Chlorhexidine salts are included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
Chlorhexidine acetate; chlorhexidine gluconate; chlorhexidine hydrochloride. Chlorhexidine acetate Empirical formula C22H30Cl2N102C2H4O2 Molecular weight 625.64 CAS number [56-95-1] Synonyms Chlorhexidini acetas; chlorhexidine diacetate; 1,10 - hexamethylenebis[5-(4-chlorophenyl)biguanide] diacetate; Hibitane diacetate. Appearance A white or almost white, microcrystalline powder. Melting point 1548C Moisture content Chlorhexidine acetate is hygroscopic, absorbing significant amounts of moisture at relative humidities up to about 80% and temperatures up to 378C. Partition coefficients Mineral oil : water = 0.075; Peanut oil : water = 0.04. Solubility Soluble 1 in 15 of ethanol (95%), 1 in 55 of water; slightly soluble in glycerin, propylene glycol and polyethylene glycols. Safety LD50 (mouse, IP): 0.04 g/kg(33) LD50 (mouse, IV): 0.03 g/kg LD50 (mouse, oral): 2 g/kg LD50 (mouse, SC): 0.33 g/kg Comments Aqueous solutions may be sterilized by autoclaving; the solutions should not be alkaline or contain other ingredients that affect the stability of chlorhexidine. See Sections 11 and 12. The EINECS number for chlorhexidine acetate is 200-302-4. Chlorhexidine gluconate Empirical formula C22H30Cl2N102C6H12O7 Molecular weight 897.88 CAS number [18472-51-0] Synonyms Chlorhexidine digluconate; chlorhexidini digluconatis; Corsodyl; 1,10 -hexamethylenebis[5-(4-chlorophenyl)biguanide] digluconate; Hibiclens; Hibiscrub; Hibitane; Unisept. Appearance Chlorhexidine gluconate is usually used as an almost colorless or pale yellow-colored aqueous solution. Acidity/alkalinity pH = 5.5–7.0 for a 5% w/v aqueous dilution. Solubility Miscible with water; soluble in acetone and ethanol (95%). Safety LD50 (mouse, IV): 0.02 g/kg(33) LD50 (mouse, oral): 1.8 g/kg LD50 (mouse, SC): 1.14 g/kg LD50 (rat, IV): 0.02 g/kg LD50 (rat, oral): 2 g/kg LD50 (rat, SC): 3.32 g/kg Comments The commercially available 5% w/v chlorhexidine gluconate solution contains a nonionic surfactant to prevent precipitation and is not suitable for use in body cavities or for the disinfection of surgical instruments containing cemented glass components. Aqueous dilutions of commercially available chlorhexidine gluconate solutions may be sterilized by autoclaving. See Sections 11 and 12. TheEINECSnumber forchlorhexidine gluconateis242-354-0 Chlorhexidine hydrochloride Empirical formula C22H30Cl2N102HCl Molecular weight 578.44 CAS number [3697-42-5] Synonyms Chlorhexidine dihydrochloride; chlorhexidini hydrochloridum; 1,10 -hexamethylenebis[5-(4-chlorophenyl)biguanide]dihydrochloride. Appearance A white or almost white, crystalline powder. Melting point 2618C, with decomposition. Solubility Sparingly soluble in water; very slightly soluble in ethanol (95%); soluble 1 in 50 of propylene glycol. Safety LD50 (mouse, SC): >5 g/kg(33) Comments Chlorhexidine hydrochloride may be sterilized by dry heat. See Sections 11 and 12. The EINECS number for chlorhexidine hydrochloride is 223- 026-6
The EINECS number for chlorhexidine is 200-238-7. The PubChem Compound ID (CID) for chlorhexidine is 9552079.