CHLORHEXIDINE DIGLUCONATE

Chlorhexidine (digluconate). 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 a biocide used extensively as a topical antiseptic in hospitals and for treatment of periodontal diseases. Chlorhexidine digluconate solution is a bis(biguanide) family cationic broad spectrum antibiotic that is available in a range of concentrations and has been safely used for over 40 years for a variety of health-related applications
Chlorhexidine(digluconate)
18472-51-0
HY-B0608
Chlorhexidine digluconate, 20% w/v aqueous solution


It is common practice to use chlorhexidine gluconate and chlorhexidine digluconate interchangeably when referring to the chlorhexidine solution. 
Chlorhexidine digluconate is used in the European and International Pharmacopoeias, while chlorhexidine gluconate is used in the US Pharmacopoeia.
Chlorhexidine digluconate is used throughout this document for precision and consistency.


Chlorhexidine is characterized as being a strong base with cationic properties.
It is available in both freebase and stable salt forms, with a white or yellowish appearance.
Chlorhexidine diacetate (CHA), chlorhexidine dihydrochloride, chlorhexidine digluconate, chlorhexidine gluconate (CHG) and chlorhexidine phosphanilate are chlorhexidine solutions that are colorless, odorless and have an extremely bitter taste.

In healthcare or commercial use, CHG is one of the more commonly used forms of the chlorhexidine salts due to its ability to dissolve in water and deliver the molecule in an effective way.

Chlorhexidine digluconate, 20 % soln.
CAS name: D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
CAS number: 18472-51-0
Formula: C22H30Cl2N10 x 2 C6H12O7
Product Groups: Amino Acids for Pharma
Markets: Pharma & Healthcare
Applications: Anti-parasitic
Dermatological Products
Code: Chlorhexidine digluconate
Synonyms: 2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, di-D-gluconate
Biguanide, 1,1'-hexamethylenebis[5-(p-chlorophenyl)-, di-D-gluconate D-Gluconic acid, compd. with 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide] (2:1) Gluconic acid, compd. with 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide] (2:1), D- 1,1'-Hexamethylenebis[5-(p-chlorophenyl)biguanide] digluconate 1,6-Bis(4-chlorophenyldiguanino)hexane digluconate 1,6-Bis(p-chlorophenyldiguanido)hexane digluconate 1,6-Bis[N5-(p-chlorophenyl)biguanido]hexane digluconate 4-Chlorhexidine digluconate Bis(p-chlorophenyl)diguanidohexane digluconate Chlorhexidine bigluconate Chlorhexidine di-D-gluconate Chlorhexidine digluconate Chlorhexidine gluconate
Molecular weight: 897.77 g/mol 

Chlorhexidine Gluconate 20% is a high quality antiseptic used for a broad field of indications.

CHLORHEXIDINE DIGLUCONATE
CAS number: 18472-51-0
Origin(s): Synthetic
Other language: Digluconate de chlorhexidine
INCI name: CHLORHEXIDINE DIGLUCONATE
EINECS/ELINCS number: 242-354-0
Classification: Regulated, Preservative

GENERAL PRODUCT INFORMATION
Chlorhexidine (digluconate or gluconate) is a broad-spectrum antiseptic. 
It has been widely used in a range of applications including wound care, hand washes, preoperative body shower, oral hygiene, and general disinfection.

Chlorhexidine being poorly soluble in water is often used in its salt form (here Digluconate) in drugs or cosmetics. 
Chlorhexidine digluconate is a skin antiseptic used in Biseptine. In cosmetics, she is on the list of authorized curators (Appendix V). 
In deodorants, it can play an active role to limit the proliferation of bacteria responsible for body odor. 
In toothpastes, in the same way, it can help limit plaque formation.

Its functions (INCI)
Antimicrobial : Helps slow the growth of micro-organisms on the skin and counteracts the development of microbes
Oral care : Provides cosmetic effects to the oral cavity (cleaning, deodorization and protection)
Preservative : Inhibits the development of microorganisms in cosmetic products.

Chlorhexidine Digluconate Solution

Application Notes
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 been used to study how essential oils improve skin antisepsis when combined with chlorhexidine digluconate and is used for skin permeation studies. 
Chronic rinsing with chlorhexidine has been shown to decrease the saltiness of NaCl and the bitterness of quinine. 
Used in conjuction with cetyltrimethylammonium bromide (CTAB) can increase its effectiveness.

The antifungal effect of chlorhexidine digluconate (CHG) has been demonstrated in clinical trials and has been used successfully in a regimen for the treatment of oral candidosis in otherwise healthy individuals. 
It has been shown that chlorhexidine solutions can diminish denture biofilm

Chlorhexidine is a biocide used extensively as a topical antiseptic in hospitals and for treatment of periodontal diseases. 
Chlorhexidine has a broad spectrum of activity against a variety of organisms, including C. albicans. 
Susceptibility of C. albicans biofilms to chlorhexidine was shown to be significantly reduced compared to its action against suspended organisms 

Uses
Definition of Antiseptic (Anti-Infective Agents, Local)
Substances used on humans and animals that destroy harmful microorganisms or inhibit their activity.
Topical use
• Surgical scrub and antiseptic hand rinse for healthcare personnel
• Skin cleanser for preoperative skin preparation, skin wound and general skin cleanser for patients Oral use
• Oral rinse: Antibacterial dental rinse for gingivitis treatment
• Against periodontitis Veterinary use
• Effective protection against Mastitis by cows
• Used in the general dairy hygiene
• The typical concentration of Chlorhexidine Gluconate as an antiseptic is 0,5 – 4%.
Regulatory Status
API (Ph. Eur.)
• EU-GMP (Good Manufacturing Practice)
• CEP
• DMF (Drug Master File) issued 2006 No. 21946 Biocide (BPR)

• Product type 2: Private area and health care disinfectants
• Product type 3: Veterinary hygiene biocidal products

Cosmetic
Chlorhexidine Gluconate is registered in the CosIng (Cosmetic IngredientDatabase). 
This means that it can be used in cosmetics as a preservative witha maximum concentration of 0.3%.

Product names- CAS numbers
Chlorhexidine digluconate - cas no : 18472-51-0
Chlorhexidine dihydrochloride - cas no: 3697-42-5


This chemical compound belongs to the group of guanidines and is a strong base, practically insoluble in water. 
Combined with salts, chlorhexidine can yield different levels of water solubility. 
Chlorhexidine digluconate, which is a salt of chlorhexidine and gluconic acid, is most commonly used. 
It cannot be isolated as pure, solid substance and therefore is mainly marketed as 20 % aqueous solution.

Chlorhexidine digluconate features bacteriostatic activity; the spectrum depends on the use-solution’s pH value. 
Chlorhexidine digluconate is primarily used as preservative and basic active ingredient in disinfectants.
It shows gaps in activity against bacterial spores and only features little activity against many nonenveloped viruses. 
MRSA and several other Gram-negative bacteria may develop resistances to chlorhexidine.

Compared to Alcohols, chlorhexidine acts more slowly. 
Due to the resistances and the limited spectrum of activity, chlorhexidine is of no advantage to hand disinfection. 
However, the active ingredient has proved its worth in catheter care for the disinfection of puncture sites, e.g. for central venous catheters (CVC).


Chlorhexidine digluconate Chemical Properties, Uses, Production

Description
Chlorhexidine digluconate solution is a bis(biguanide) family cationic broad spectrum antibiotic that is available in a range of concentrations and has been safely used for over 40 years for a variety of health-related applications; but its specific use for umbilical cord care was uniquely tested in three clinical trials in Nepal, Bangladesh, and Pakistan, in the form of 7.1% chlorhexidine digluconate (CHX). 
Given the promising results of the trials, in 2013 the World Health Organization (WHO) added CHX to its Model List of Essential Medicines for Children; and in 2014 the WHO issued a new guideline on umbilical cord care, which included a formal recommendation on the use of chlorhexidine.
Chlorhexidine digluconate is a broad spectrum antiseptic. 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, the mechanism of action being membrane disruption, not ATPase inactivation as previously thought.
It is also useful against fungi and enveloped viruses, though this has not been extensively investigated. 
Chlorhexidine is harmful in high concentrations, but is used safely in low concentrations in many products, such as mouthwash and contact lens solutions.

Chemical Properties
Almost colourless or pale-yellowish liquid.


Uses
chlorhexidine digluconate is a preservative generally used in concentrations of 0.01 to 0.1 percent to protect against bacteria. 
It is unstable at high temperatures. Chlorhexidine digluconate is more widely used in europe than in the united States.

Uses
Hydrogenolysis of benzyl-nitrogen bonds

Uses
Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs.
The gluconate salt form of chlorhexidine, a biguanide compound used as an antiseptic agent with topical antibacterial activity. 
Chlorhexidine gluconate is positively charged and reacts with the negatively charged microbial cell surface, thereby destroying the integrity of the cell membrane. 
Subsequently, chlorhexidine gluconate penetrates into the cell and causes leakage of intracellular components leading to cell death. 
Since gram positive bacteria are more negatively charged, they are more sensitive to this agent.
Chlorhexidine digluconate 20% solution is a broad spectrum bacteriostatis antiseptic agent, oral care agent, disinfectant, cosmetic biocide, and preservative. 
It is very effective against plaque, oral flora including Candida and is active against gram-positive and gram-negative organisms, facultative anaerobes, aerobes, and yeast. 
It can be used in antiseptic soap, mouthwash that fights plaque, disinfecting wounds and burns, vaginal flushing, hair dyes and bleaches, makeup, and other skin and hair care products.

Manufacturing Process
35 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of β-etoxyethanol are stirred together at 130- 140°C for 2 hours under reflux. The mixture is then cooled and filtered. The solid is washed with water and crystallised from 50% aqueous acetic acid. 1,1'-Hexamethylene bis(5-(p-chlorophenyl)biguanide) is obtained as colorless plates, melting point 258-260°C. By addition of D-gluconic acid to aqueous solution of chlorhexidine base is prepared 1,1'-hexamethylenebis(5-(pchlorophenyl)biguanide)digluconate (1:2).
brand name
Dyna-Hex (Xttrium); Hibiclens (Regent); Peridex (Zila); Periochip (Dexcel); Periogard (Colgate); Prevacare (Johnson & Johnson).
Therapeutic Function
Antiseptic

Clinical Use
1,6-Di(4 -chlorophenyldiguanido)hexane gluconate (Hibiclens)is the most effective of a series of antibacterial biguanides originally developed in Great Britain.
The antimicrobial properties of the bi guanides were discovered as a result of earlier testing of these compounds as possible anti malarial agents. 
Although the biguanides are technically not bis quaternary ammonium compounds and, therefore, should probably be classified separately, they share many physical, chemical, and antimicrobial properties with the cationic surfactants. 
The biguanides are strongly basic, and they exist as di cations at physiological pH. 
In chlorhexidine, the positive charges are counter balanced by gluconate anions (not shown). 
Like cationic surfactants, these under go inactivation when mixed with anionic detergents and complex anions such as phosphate,carbonate, and silicate.
Chlorhexidine has broad-spectrum antibacterial activity but is not active against acid-fast bacteria, spores, orviruses. 
It has been used for such topical uses as preoperative skin disinfection, wound irrigation, mouthwashes, and general sanitization. 
Chlorhexidine is not absorbed through skin or mucous membranes and does not cause systemic toxicity.


Chlorhexidine    or    Chlorhexidine    Gluconate,    is    one    of    the    most    widely    used    antiseptics    for    oral    rinses    or    
mouthwashes    to    reduce    dental    plaque    or    oral    bacteria    as    well    as    skin    cleaners    for    surgical    scrubs    and    
preoperative    skin    preparations.                Because    of    the    positive    charge    carried    by    the    chlorhexidine    molecule    it    
reacts    with    the    cell    surface    of    bacteria    which    is    negatively    charged    and    destroys    the    cell    membrane.        


Chlorhexidine digluconate Preparation Products And Raw materials

Raw materials
4-Chlorobenzenamine hydrochloride

Chlorhexidine Digluconate is an antiseptic and disinfectant used topically in biocidal products with biguanide structure. 
It is effective on gram positive and gram negative bacteria. 
It is preferred especially because of its permanent and rapid effect.

Chlorhexidine Digluconate is a substance used in surgery, hand, skin disinfectants, preparation of surgical instruments and treatment of dental diseases. 
Chlorhexidine Digluconate is the most preferred material for disinfection of medical devices and instruments.

Chlorhexidine Digluconate containing biocidal products show a bactericidal effect. 
Chlorhexidine Digluconate is an active substance against bacteria such as Pseudomonas aeruginosa, Escherichia coli, Aerobacter aerogenes and Proteus mirabilis that can cause nosocomial infections.

Skin irritation, discoloration of the teeth or allergen effects can be seen as side effects due to the use of Chlorhexidine Digluconate.

WHO has recognized chlorhexidine as a suitable antimicrobial for neonatal care. 
According to the WHO guideline for umbilical cord care, daily chlorhexidine (7.1% chlorhexidine digluconate aqueous solution or gel, delivering 4% free chlorhexidine) application to the umbilical cord stump during the first week of life is recommended for newborns born at home in settings with high neonatal mortality (30 or more neonatal deaths per 1,000 live births).

Clean, dry cord care is recommended for newborns born in health facilities and at home in low neonatal mortality settings. 
Use of chlorhexidine in the low neonatal mortality settings does not significantly reduce the neonatal mortality rate, but may be considered only to replace application of a harmful traditional substance, such as cow dung, to the cord stump.

Chlorhexidine is identified by the UN Commission on Life-Saving Commodities for Women and Children as one of 13 lifesaving commodities for women and children. 
The gel form of 7.1% chlorhexidine digluconate is proven to be as effective as the solution form.

Chlorhexidine, both gel and solution, is included in the WHO Model List of Essential Medicines for Children (EMLc) under Specific Medicines for Neonatal Care. 
This is a higher concentration than the 5% chlorhexidine digluconate (delivering 2.8% chlorhexidine) listed on the EMLc as an antiseptic.

This document focuses on the presentation used for the umbilical cord care according to the WHO EMLc which is 7.1% chlorhexidine digluconate solution or gel, delivering 4% chlorhexidine.

CHLORHEXIDINE DIGLUCONATE EQUIVALENT TO FREE CHLORHEXIDINE NOTES

20.0%  chlorhexidine digluconate will deliver 11.3% free chlorhexidine.
20% chlorhexidine digluconate is the concentration of API used for manufacture of chlorhexidine topical solution and gel.


Chemical Name 
Chlorhexidine digluconate 
1,1'-(hexamethylene)bis[5-(4-chlorophenyl)biguanide] di-d-gluconate
1,1'-(hexane-1,6-diyl)bis[5-(4-chlorophenyl)biguanide] di-d-gluconate

ChemicalStructure
C34H54Cl2N10O14
C22H30Cl2N10, 2C6H12O7

About Chlorhexidine: Mechanism of Action
Chlorhexidine is a broad-spectrum biocide effective against Gram-positive bacteria, Gram-negative bacteria and fungi. 
Chlorhexidine inactivates microorganisms with a broader spectrum than other antimicrobials (e.g. antibiotics) and has a quicker kill rate than other antimicrobials (e.g. povidone-iodine).1 
It has both bacteriostatic (inhibits bacterial growth) and bactericidal (kills bacteria) mechanisms of action, depending on its concentration. Chlorhexidine kills by disrupting the cell membrane.22 
Upon application in vitro, chlorhexidine can kill nearly 100% of Gram-positive and Gram-negative bacteria within 30 seconds.10 

Since chlorhexidine formulations can destroy the majority of categories of microbes, there is limited risk for the development of an opportunistic infections.

Bacteria
Chlorhexidine is a positively-charged molecule that binds to the negatively-charged sites on the cell wall; it destabilizes the cell wall and interferes with osmosis.5 
The bacterial uptake of the chlorhexidine is very rapid, typically working within 20 seconds.1 In low concentrations it affects the integrity of the cell wall. 
Once the cell wall is damaged, chlorhexidine then crosses into the cell itself and attacks the cytoplasmic membrane (inner membrane). 
Damage to the cytoplasm's delicate semipermeable membrane allows for leakage of components leading to cell death.1 
In high concentrations, chlorhexidine causes the cytoplasm to congeal or solidify.1

Fungi
The mechanism of action for fungi is very similar to bacteria. 
The fungus uptakes chlorhexidine in a short amount of time1 and impairs the integrity of the cell wall and the plasma membrane entering the cytoplasm resulting in leakage of cell contents and cell death.1

Biofilm
Biofilms are a complex aggregation of microorganisms growing on a solid substrate. 
They can occur on organic (e.g. dental plaque) or inorganic surfaces. 

Biofilms are characterized by structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances. 
This matrix protects the cells within it and increases their resistance to antimicrobials. 
Many antimicrobial agents have a difficult time eliminating organisms in a biofilm. 
Chlorhexidine has shown some ability to help inhibit adherence of microorganisms to a surface thereby preventing growth and development of biofilms.6

Other Microbial Organisms
Unlike other antimicrobials, chlorhexidine has demonstrated some effectiveness against microorganisms in other forms and states as well. 
This includes bacterial spores and protozoa

It has also shown activity against enveloped viruses in vitro (e.g., herpes simplex virus, HIV, cytomegalovirus, influenza, and RSV) but has substantially less activity against nonenveloped viruses (e.g., rotavirus, adenovirus, and enteroviruses).21

MECHANISM OF ACTION IN HEALTHCARE APPLICATIONS
In topical applications, chlorhexidine is shown to have the unique ability to bind to the proteins present in human tissues such as skin and mucous membranes with limited systemic or bodily absorption.24 
Protein bound chlorhexidine releases slowly leading to prolonged activity. 
This phenomenon is known as substantivity6 and allows for a longer duration of antimicrobial action against a broad spectrum of bacteria and fungi.

In fact, chlorhexidine's antimicrobial activity has been documented to last at least 48 hours on the skin.14 
Unlike povidone-iodine, chlorhexidine is not affected by the presence of body fluids such as blood.12

In oral applications, chlorhexidine binds to the mouth tissue, oral mucosa and teeth. 
It is then released over time to kill bacteria and fungi.5 
This helps to reduce the bacterial count and prevents dental plaque. 
It has become the gold standard in dentistry due to its ability to adhere to soft and hard tissue and maintain a potent sustained release.26

Chlorhexidine has also been applied to medical devices such as dental implants, vascular catheters, needleless connectors and antimicrobial dressings. 
Chlorhexidine, when applied to or impregnated in medical devices kills organisms and protects against microbial colonization and subsequently biofilm development.


Chlorhexidine digluconate
1,6-bis(4-Chlorophenyldiguanino)hexane digluconate
(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoic acid - N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] (2:1)
(2R,3S,4R,5R)-2,3,4,5,6-Pentahydroxyhexansäure--N,N''''-hexan-1,6-diylbis[N'-(4-chlorphenyl)(imidodicarbonimidic diamid)](2:1) [German]
1,1'-Hexamethylenebis(5-[p-chlorophenyl]biguanide)
1,6-Bis(N5-[p-chlorophenyl]-N1-biguanido)hexane
18472-51-0 [RN]
242-354-0 [EINECS]
4-CHLORHEXIDINE DIGLUCONATE
acide (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoïque - diamide N,N''''-hexane-1,6-diylbis[N'-(4-chlorophényl)(imidodicarbonimidique)] (2:1) [French]
Betasept [Trade name]
Chlorhexamed [Trade name]
chlorhexidine bigluconate
chlorhexidine D-digluconate
chlorhexidine di-D-gluconate
Chlorhexidine digluconate solution
Chlorhexidine gluconate [JAN] [USAN]
Corsodyl [Trade name]
D-Gluconic Acid compd. with N,N''-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
Diamide N,N''''-1,6-hexanediylbis[N'-(4-chlorophényl)(imidodicarbonimidique)] - acide D-gluconique (1:2) [French] [ACD/IUPAC Name]
Hexidine
Hibident [Trade name]
Hibidil [Trade name]
Hibiscrub [Trade name]
Hibisol [Trade name]
hibitane [Trade name]
Imidodicarbonimidic diamide, N,N''''-1,6-hexanediylbis[N'-(4-chlorophenyl)-, compd. with D-gluconic acid (1:2) [ACD/Index Name]
Manusan [Trade name]
Maskin [Trade name]
Maskin R [Trade name]
MFCD00083599 [MDL number]
MOR84MUD8E
N,N''''-1,6-Hexandiylbis[N'-(4-chlorphenyl)(imidodikohlenstoffimiddiamid)] --D-gluconsäure (1:2) [German] [ACD/IUPAC Name]
N,N''''-1,6-Hexanediylbis[N'-(4-chlorophenyl)(imidodicarbonimidic diamide)] - D-gluconic acid (1:2) [ACD/IUPAC Name]
N,N''-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide di-D-gluconate
N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] - D-gluconic acid (1:2)
N,N''''-Hexane-1,6-diylbis[N'-(4-chlorophenyl)(imidodicarbonimidic diamide)] - D-gluconic acid (1:2)
Peridex [Trade name]
pHiso-Med [Trade name]
Plurexid [Trade name]
Rotersept [Trade name]
Septeal [Trade name]
STERILON [Trade name]
UNII-MOR84MUD8E
Unisept [Trade name]
(1E)-2-[6-[[amino-[(Z)-[amino-(4-chloroanilino)methylidene]amino]methylidene]amino]hexyl]-1-[amino-(4-chloroanilino)methylidene]guanidine;(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoic acid
[18472-51-0]
1,1?-Hexamethylenebis(5-[p-chlorophenyl]biguanide)
1,1′-Hexamethylenebis(5-[p-chlorophenyl]biguanide)
1,1'-Hexamethylene bis(5-(p-chlorophenyl)biguanide), digluconate
1,1'-Hexamethylenebis(5-(p-chlorophenyl)biguanide) di-D-gluconate
1,1'-Hexamethylenebis(5-(p-chlorophenyl)biguanide)digluconate
1,6-Bis(5-(p-chlorophenyl)biguandino)hexane digluconate
105791-72-8 [RN]
12068-31-4 [RN]
124973-71-3 [RN]
14007-07-9 [RN]
150621-85-5 [RN]
151498-43-0 [RN]
2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, di-D-gluconate
2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, digluconate
2-[amino-[6-[[amino-[[amino-(4-chloroanilino)methylidene]amino]methylidene]amino]hexylimino]methyl]-1-(4-chlorophenyl)guanidine; 2,3,4,5,6-pentahydroxyhexanoic acid
20% chlorhexidine gluconate solution
200-238-7 [EINECS]
21293-24-3 [RN]
23289-58-9 [RN]
40330-16-3 [RN]
4348068 [Beilstein]
51365-13-0 [RN]
52196-45-9 [RN]
52387-19-6 [RN]
55-56-1 [RN]
60042-57-1 [RN]
60404-86-6 [RN]
82432-16-4 [RN]
Abacil
Arlacide G
Bacticlens
Biguanide, 1,1'-hexamethylenebis(5-(p-chlorophenyl)-, digluconate
CHLORAPREP
Chlorhexidin glukonatu [Czech]
Chlorhexidine (digluconate)
Chlorhexidine Di Gluconate
Chlorhexidine digluconate, 20% in water
chlorhexidine digluconate, 20% w/v aq. soln., non-sterile
chlorhexidine gluconate solution
chlorhexidinedigluconate
D-Gluconic acid, compd with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
D-Gluconic acid, compd. with N,N'-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradeca- nediimidamide (2:1)
D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecane diimidamide (2:1)
D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
D-Gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)
Disteryl
DYNA-HEX
EXIDINE [Wiki]
Gluconic acid, compd. with 1,1'-hexamethylene bis(5-(p-chlorophenyl)biguanide) (2:1), D- (8CI)
Hibiclens [Trade name] [Wiki]
HIBISTAT
Hibitane 5
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28312
N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)]--D-gluconic acid (1/2)
Orahexal
Peridex (antiseptic)
Peridex;Periogard
PERIOGARD [Wiki]
Plac out
PwrioChip
UNII:MOR84MUD8E


Chlorhexidine is a bisbiguanide antiseptic and disinfectant that is bactericidal or bacteriostatic against a wide range of gram-positive and gram-negative bacteria. 
Chlorhexidine digluconate  inhibits mycobacteria, fungi and some viruses. 
Chlorhexidine is most active at a neutral or slightly acidic pH. 
Chlorhexidine digluconate  is used for disinfection of skin, clean instruments and hard surfaces in a concentration of 0.05 to 0.5% in water or 70% alcohol.


Solution
Chlorhexidine digluconate topical solution is a solution of “chlorhexidine digluconate solution” in a suitable vehicle. 
It contains chlorhexidine digluconate 7.1% (equivalent to 4% chlorhexidine).
Each 100 mL contains 7.1 g chlorhexidine digluconate equivalent to 4 g chlorhexidine.

Pharmaceutical Form
Topical solution—clear, colorless or pale yellow liquid
Topical gel—colorless to yellow translucent gel
Qualitative and Quantitative Composition


Solution
Chlorhexidine digluconate topical solution is a solution of “chlorhexidine digluconate solution” in a suitable vehicle. 
It contains chlorhexidine digluconate 7.1% (equivalent to 4% chlorhexidine).

Each 100 mL contains 7.1 g chlorhexidine digluconate equivalent to 4 g chlorhexidine.
List of excipients:
– Purified water
– Sodium hydroxide
– Benzalkonium chloride (optional)

Gel
Chlorhexidine digluconate topical gel is a solution of chlorhexidine digluconate in a suitable water-miscible basis. 
It contains chlorhexidine digluconate 7.1% (equivalent to 4% chlorhexidine).

Each sachet contains a 3-g dose containing 213 mg of chlorhexidine digluconate equivalent to 120 mg chlorhexidine.
List of excipients2 :
– Purified water
– Sodium acetate trihydrate
– Guar gum


Packaging and Presentation
The WHO EMLc includes two presentations for umbilical cord care:
7.1% chlorhexidine digluconate solution or gel, delivering 4% chlorhexidine.
The 7.1% chlorhexidine digluconate solution is packaged in nozzle/dropper plastic bottle.
The 7.1% chlorhexidine digluconate gel is packaged in foil laminate sachet or aluminum tube.


Related products
Other formulations of chlorhexidine that exist in the market include:
■ Topical solution (liquid, cloth, sponge applicators, swab sticks) available at concentrations 2%, 3.15%, 4%, and 5% of chlorhexidine gluconate/digluconate with and without isopropyl alcohol. 
Used for skin preparation for surgery, invasive procedures, and central lines to prevent hospital-acquired infections.

■ Scrub solution (liquid detergent) available at concentrations 2% and 4% of chlorhexidine gluconate/digluconate with isopropyl alcohol. 
Used for preoperative bathing, general skin cleansing to prevent hospital-acquired infection, and preoperative hand scrub and hand disinfection to prevent the spread of microorganisms.

■ Irrigation solution (chlorhexidine and cetrimide) available at concentrations 2% and 4% of chlorhexidine gluconate/digluconate. 
Used for irrigation of wounds to prevent infection

■ Topical cream (chlorhexidine and cetrimide) available at concentrations 0.1% of chlorhexidine gluconate/digluconate with cetostearyl alcohol. 
Used for wound cleaning (over-the-counter first-aid cream) to prevent infection.

■ Washcloth available at concentration 2% of chlorhexidine gluconate/digluconate.
Used for daily bathing in an intensive care unit (ICU) patients to prevent hospital-acquired infection.

■ Gauze dressing available at concentration 0.5% of chlorhexidine acetate. 
Used for wound or burn dressing to prevent infection.

■ Catheter dressing (gel pad, foam disk, semipermeable transparent dressing)
available at concentration 2% of chlorhexidine gluconate/digluconate. Used for
catheter dressings to prevent hospital-acquired infection.
■ Hand rub (gel) at concentrations 0.5% and 1% of chlorhexidine gluconate/digluconate with ethanol. 
Used for hand sanitizing to prevent the spread of microorganisms.

■ Dental solution (oral rinse or spray) at concentrations 0.12% and 0.2% of chlorhexidine gluconate/digluconate with ethanol. 
Used to decontaminate oral cavity to prevent ventilator-associated pneumonia and for periodontal disease and mucositis treatment.

■ Concentrated stock solution available at concentration 20% of chlorhexidine gluconate/digluconate. 
Used for preparation of dilutions for skin cleansing and general disinfection.
It is important to note that the WHO EMLc recommends only chlorhexidine 7.1% (digluconate) delivering 4% chlorhexidine solution or gel for topical application umbilical cord care to prevent cord infection and/or sepsis and reduce neonatal mortality. 
Therefore, it is recommended that the procurement agency must focus on procurement of the presentations as per the WHO EMLc.

Manufacturing process
Both chlorhexidine digluconate solution and gel are straightforward products to manufacture, involving a standard manufacturing process.
Solution and gel form have very similar manufacturing processes, with the only difference being in the step where guar gum is added to thicken the product into a gel.
For solution form, the typical manufacturing process involves preparing chlorhexidine digluconate solution in water, followed by pH adjustment and filling into bottles.

For gel form, the typical manufacturing process involves dissolving sodium acetate trihydrate in water, followed by dispersion and hydration of guar gum. 
The solution is heated at this stage to aid hydration of the guar gum. 
The resultant gel is then cooled, before addition and mixing of chlorhexidine digluconate solution. 
The gel is subsequently de-aerated using vacuum and then discharged into a holding vessel prior to being filled into aluminum tube or foil laminate sachets using suitable form-fill seal packaging equipment.

Large-scale production of the gel formulation containing guar gum requires specialized equipment (high-pressure homogenizer). 
High-pressure homogenization is essential to the quality and stability of gel formulation since this is a very effective way to create homogeneity in the gel texture while at the same time producing a very stable product as compared to the traditional devices such as agitators, stirrers, rotor-stator devices, or colloid mills. 
The result is a homogeneous, effective product with superior stability and shelf life.

Satisfactory operating parameters and in-process controls should be defined at each stage of manufacture. 
When adding/dispersing the guar gum, the gel temperature and high-shear mixing time should be well defined. The gel should be cooled before the addition of chlorhexidine digluconate solution.


Packaging
The primary package material must comply with USP, Ph.Eur., and/or European Community requirements. 
Since sunlight adversely affects the stability of chlorhexidine digluconate,transparent primary containers should be avoided.

Solution
The 7.1% chlorhexidine digluconate solution is packaged in an HDPE bottle with polypropylene screw closure.

The nozzle/dropper bottles provide the best product coverage on the umbilical stump. 
The nozzle minimizes occasions in which users directly contact the umbilical cord. 
However, depending upon the country, users may associate the small (single-day) application size nozzle/dropper bottles with newborn eye or ear drops. 
Therefore, clear instructions should be put on the product label.

Spray bottles work only in the upright position and might make it difficult for users to achieve complete coverage of the cord stump.

Wide-mouth bottles may increase the risk of product contamination and spillage.

Gel
The 7.1% chlorhexidine digluconate gel is packaged in a foil laminate sachet or aluminum tube.
Aluminum tubes are commonly used for semi-solid pharmaceuticals. However, depending upon the country, users may associate the small (single-day) application size tubes with newborn eye ointment. 
Therefore, clear instructions should be put on the product label.

Sachets could be a lower-cost option. However, depending on the country, sachets might not be commonly used for pharmaceuticals; therefore, manufacturers might not have the appropriate equipment, and users might associate sachets with cosmetics rather than medicines, leading to confusion. 

Application
Chlorhexidine has been used to study how essential oils improve skin antisepsis when combined with chlorhexidine digluconate and is used for skin permeation studies. 
Chronic rinsing with chlorhexidine has been shown to decrease the saltiness of NaCl and the bitterness of quinine.

Used to study mechanism of membrane dysruption by bis(biguanide) molecules.


Biochem/physiol Actions
Cationic broad-spectrum antimicrobial agent belonging to the bis(biguanide) family. Its mechanism of action involves destabilization of the outer bacterial membrane. 
It is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs.

Other Notes
Keep container tightly closed in a dry and well-ventilated place. 
Containers which are opened must be carefully resealed and kept upright to prevent leakage. 
Light sensitive.


Chlorhexidine (commonly known by the salt forms chlorhexidine gluconate and chlorhexidine digluconate (CHG) or chlorhexidine acetate), is a disinfectant and antiseptic that is used for skin disinfection before surgery and to sterilize surgical instruments.
It may be used both to disinfect the skin of the patient and the hands of the healthcare providers.
It is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking.
It is used as a liquid or powder.

Side effects may include skin irritation, teeth discoloration, and allergic reactions.
It may cause eye problems if direct contact occurs.
Use in pregnancy appears to be safe.[4] Chlorhexidine may come mixed in alcohol, water, or surfactant solution.
It is effective against a range of microorganisms, but does not inactivate spores.

Chlorhexidine came into medical use in the 1950s.
Chlorhexidine is available over the counter (OTC) in the United States.
It is on the World Health Organization's List of Essential Medicines.
In 2017, it was the 286th most commonly prescribed medication in the United States, with more than one million prescriptions.


Uses
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).
A 2019 Cochrane review concluded that based on very low certainty evidence in those who are critically ill "it is not clear whether bathing with chlorhexidine reduces hospital‐acquired infections, mortality, or length of stay in the ICU, or whether the use of chlorhexidine results in more skin reactions."

In endodontics, chlorhexidine is used for root canal irrigation and as an intracanal dressing, but has been replaced by the use of sodium hypochlorite bleach in much of the developed world.

Antiseptic
There is strong evidence that it is more effective than povidone-iodine and is it proved to kill 99.9% of germs in 30 sec.

CHG is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts.
It 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. 
The effectiveness against Covid-19 viruses has been established. 
The effectiveness against herpes viruses has not yet been established unequivocally.

Chlorhexidine, like other cation-active compounds, remains on the skin. 
It is frequently combined with alcohols (ethanol and isopropyl alcohol).

Dental use

Perichlor brand 0.12% chlorhexidine gluconate solution
Use of a CHG-based mouthwash in combination with normal tooth care can help reduce the build-up of plaque and improve mild gingivitis.
There is not enough evidence to determine the effect in moderate to severe gingivitis.

About 20 mL twice a day of concentrations of 0.1% to 0.2% is recommended for mouth-rinse solutions with a duration of at least 30 seconds. 
Such mouthwash also has a number of adverse effects including damage to the mouth lining, tooth discoloration, tartar build-up, and impaired taste.
Extrinsic tooth staining occurs when chlorhexidine rinse has been used for 4 weeks or longer.

Mouthwashes containing chlorhexidine which stain teeth less than the classic solution have been developed, many of which contain chelated zinc.

Using chlorhexidine as a supplement to everyday mechanical oral hygiene procedures for 4 to 6 weeks and 6 months leads to a moderate reduction in gingivitis compared to placebo, control or mechanical oral hygiene alone.

Chlorhexidine is a cation which interacts with anionic components of toothpaste, such as sodium lauryl sulfate and sodium monofluorophosphate, and forms salts of low solubility and antibacterial activity. 
Hence, to enhance the antiplaque effect of chlorhexidine, "it seems best that the interval between toothbrushing and rinsing with CHX [chlorhexidine] be more than 30 minutes, cautiously close to 2 hours after brushing."

Topical
Nepal was the first country in the world to use chlorhexidine to treat the umbilical cord of newborn babies, and received a USAID Pioneers Prize for reducing the neonatal death rate.
Chlorhexidine is very effective for poor countries like Nepal and its use is growing in the world for treating the umbilical cord. 
A 2015 Cochrane review has yielded high-quality evidence that within the community setting, chlorhexidine skin or cord care can reduce the incidence of omphalitis (inflammation of the umbilical cord) by 50% and also neonatal mortality by 12%.
Chlorhexidine gluconate is used as a skin cleanser for surgical scrubs, as a cleanser for skin wounds, for preoperative skin preparation, and for germicidal hand rinses.
Chlorhexidine eye drops have been used as a treatment for eyes affected by Acanthamoeba keratitis.

Side effects
CHG is ototoxic; if put into an ear canal which has a ruptured eardrum, it can lead to deafness.

CHG does not meet current 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 U.S., 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, CHG 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, it can be fatal due to the high risk of acute respiratory distress syndrome.

Mechanism of action
At physiologic pH, chlorhexidine salts dissociate and release the positively charged chlorhexidine cation. 
The bactericidal effect is a result of the binding of this cationic molecule to negatively charged bacterial cell walls. 
At low concentrations of chlorhexidine, this results in a bacteriostatic effect; at high concentrations, membrane disruption results in cell death.

Chemistry
It is a cationic polybiguanide (bisbiguanide).
It is used primarily as its salts (e.g., the dihydrochloride, diacetate, and digluconate).

Deactivation
Chlorhexidine is deactivated by forming insoluble salts with anionic compounds, including the anionic surfactants commonly used as detergents in toothpastes and mouthwashes, anionic thickeners such as carbomer, and anionic emulsifiers such as acrylates/C10-30 alkyl acrylate crosspolymer, among many others. 
For this reason, chlorhexidine mouth rinses should be used at least 30 minutes after other dental products.
For best effectiveness, food, drink, smoking, and mouth rinses should be avoided for at least one hour after use. 
Many topical skin products, cleansers, and hand sanitizers should also be avoided to prevent deactivation when chlorhexidine (as a topical by itself or as a residue from a cleanser) is meant to remain on the skin.

Synthesis
The structure is based on two molecules of proguanil, linked with a hexamethylenediamine spacer.


Brands
Chlorhexidine topical is sold as Betasept, Biopatch, Calgon Vesta, ChloraPrep One-Step, Dyna-Hex, Hibiclens, Hibistat Towelette, Scrub Care Exidine, Spectrum-4 among others.

Chlorhexidine gluconate mouthwash is sold as Dentohexinm, Paroex, Peridex, PerioChip, Corsodyl and Periogard, among others.

Hexoralettene N contains benzocaine, menthol and chlorhexidine hydrochloride. 
It is used as oral antiseptic candies.

Terminology
The name "Chlorhexidine" breaks down as chlor(o) + hex(ane) + id(e) + (am)ine), is a cationic polybiguanide. 
It is used primarily as its gluconate salt.

Veterinary medicine
In animals, chlorhexidine is used for topical disinfection of wounds, and to manage skin infections.
Chlorhexidine-based disinfectant products are used within the dairy farming industry.

Post-surgical respiratory problems have been associated with the use of chlorhexidine products in cats.

CHLORHEXIDINE DIGLUCONATE
18472-51-0
Chlorhexidine gluconate
Unisept
Chlorhexidine D-digluconate
Peridex
UNII-MOR84MUD8E
Chlorhexidine di-D-gluconate
Periogard
MOR84MUD8E
Exidine
1,1'-Hexamethylene bis(5-(p-chlorophenyl)biguanide), digluconate
Kleersight
Fight bac
Chlorhexidin glukonatu
MFCD00083599
Prevacare
pHiso-Med
Chlorhexidine digluconate solution
Hibitane gluconate
Hibiclens (TN)
Periogard (TN)
Peridex (TN)
Chlohexidine gluconate
Chlorhexidine gluconate [USAN:USP:JAN]
EC 242-354-0
SCHEMBL34468
CHEMBL4297088
DTXSID5034519
CHEBI:28312
Chx plus concentrate premium chlorhexidine teat dip concentrate
Chlorhexidine gluconate (JP17/USP)
AKOS015896303
AKOS025310696
D-Gluconic acid, compd. with N1,N14-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
M166
C08038
D00858
Chlorhexidine digluconate solution, 20% in H2O
J-011837
Chlorhexidine digluconate, Pharmaceutical Secondary Standard; Certified Reference Material
1,6-Bis(N5-[p-chlorophenyl]-N1-biguanido)hexane; 1,1'-Hexamethylenebis(5-[p-chlorophenyl]biguanide)
1-(4-chlorophenyl)-3-[N-[6-[[N-[N-(4-chlorophenyl)carbamimidoyl]carbamimidoyl]amino]hexyl]carbamimidoyl]guanidine; (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoic acid
2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, digluconate
D-Gluconic acid, compd with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
Gluconic acid, compd. with 1,1'-hexamethylene bis(5-(p-chlorophenyl)biguanide) (2:1), D- (8CI)
N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)]--D-gluconic acid (1/2)


It is common practice to use chlorhexidine gluconate and chlorhexidine digluconate interchangeably when referring to the chlorhexidine solution. 
Chlorhexidine digluconate is used in the European and International Pharmacopoeias, while chlorhexidine gluconate is used in the US Pharmacopoeia.
Chlorhexidine digluconate is used throughout this document for precision and consistency.


An investigation of the bactericidal activity of chlorhexidine digluconate against multidrug-resistant hospital isolates
Melike EKİZOĞLU1
, Meral SAĞIROĞLU1,*, Ekrem KILIÇ1
, Ayşe Gülşen HASÇELİK21
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, Sıhhiye, Ankara, Turkey 2
Department of Medical Microbiology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey


Background/aim: Hospital infections are among the most prominent medical problems around the world. 
Using proper biocides in an appropriate way is critically important in overcoming this problem. 
Several reports have suggested that microorganisms may develop resistance or reduce their susceptibility to biocides, similar to the case with antibiotics. 

In this study we aimed to determine the antimicrobial activity of chlorhexidine digluconate against clinical isolates.
Materials and methods: The susceptibility of 120 hospital isolated strains of 7 bacterial genera against chlorhexidine digluconate was determined by agar dilution test, using minimum inhibitory concentration (MIC) values and the EN 1040 Basic Bactericidal Activity

Test to determine the bactericidal activity. 
According to MIC values, Pseudomonas aeruginosa and Stenotrophomonas maltophilia were found to be less susceptible to chlorhexidine digluconate.

Results: Quantitative suspension test results showed that 4% chlorhexidine digluconate was effective against antibiotic resistant and susceptible bacteria after 5 min of contact time and can be safely used in our hospital. 
However, concentrations below 4% chlorhexidine digluconate caused a decrease in bactericidal activity, especially for Staphylococcus aureus and P. aeruginosa.
Conclusion: It is crucial to use biocides at appropriate concentrations and to perform surveillance studies to trace resistance or low susceptibility patterns of S. aureus, P. aeruginosa, and other hospital isolates.
Key words: Biocides, resistance, chlorhexidine digluconate, quantitative suspension test, EN 1040


Disinfectants are chemical agents used to kill microorganisms on surfaces or in order to eliminate them from the environment. 
Some of these chemical agents, which have been used to prevent or limit microbial infection on the skin, are called antiseptic or topical antimicrobial. 
On the other hand, there are chemical agents that have been used as preservatives against microbial contamination by adding them into pharmaceuticals, cosmetics, and other products. 
Those chemical substances with antiseptic, disinfectant, and/or preservative activity have been defined as biocides. 
As an example, chlorhexidine salts and quaternary ammonium compounds can be used for these 3 purposes while others, like glutaraldehyde, and ortho-phthalaldehyde, are mainly used for the disinfection of endoscopes (1–3). 
The disinfectant used in this study, chlorhexidine digluconate, has a biguanide structure, low toxicity, low tolerability, and a wide antimicrobial spectrum (2,4).

Biocide resistance, similar to antibiotic resistance, is described as microbial growth when bacteria are tested with in-use concentrations. 
Furthermore, resistance or insusceptibility to biocides can be either intrinsic, as a result of natural characteristics of microorganisms, or it can be acquired. 
Acquired resistance to biocides may arise from mutation and horizontal transfer of genetic material such as plasmids or transposons (2,3,5–8).

Efflux pumps are common mechanisms of acquired resistance to chlorhexidine digluconate. 
By means of this mechanism, not only chlorhexidine but also other chemical substances are excluded from the cell, which can therefore also lead to resistance to antibiotics (3,4,7).

Antimicrobial effectiveness of chlorhexidine may differ within pathogenic bacteria. 
Horner et al. (4) classified chlorhexidine and bacterial interactions into 4 different groups. 

Chlorhexidine tolerance is described as when bacterial growth is inhibited but bacteria are not killed at bacteriostatic concentrations (4 mg/L). 
On the other hand, chlorhexidine resistance is described as survival of bacteria at bactericidal concentrations (40 000 mg/L) (4).

Hospital infections are one of the main problems in Turkey, as well as around the world. 

In order to prevent these infections,  it is of great importance  to determine  which  microorganisms are responsible.

Moreover, relevant biocides must be chosen and proper disinfection and sterilization applications need to be ensured. 
The diversity of clinical isolates and the different options in using biocides, varying the bacterial susceptibility profile, may cause problems in disinfection and antisepsis implementations in hospitals. 

To this end, it is important to conduct susceptibility tests for biocides that have been widely used against problematic, multidrugresistant microorganisms (e.g., MRSA) in order to prevent the development of hospital infections (7,9,10).

In this study, the bactericidal activity of chlorhexidine digluconate against hospital-isolated multidrugresistant bacteria was determined. 

We aimed to identify susceptibility profiles of bacteria isolated frequently from several services of our hospital against chlorhexidine digluconate and to collect data in order to monitor the changes in susceptibility over time. 
The data obtained from this study are of great importance because according to the European Committee for Standardization (CEN) there are not many studies investigating the susceptibility of isolates from our hospital against chlorhexidine digluconate, a commonly used disinfectant/antiseptic agent in our hospital


Determination of minimum inhibitory concentration

The determination of minimum inhibition concentration (MIC) was performed for all of the clinical strains except for Enterococcus sp. 

The MICs of chlorhexidine digluconate were determined by the agar dilution method as described by the Clinical and Laboratory Standards Institute (CLSI) (11). 
Chlorhexidine digluconate was prepared prior to the test at concentrations of 0.125–512 µg/mL

. Determination of bactericidal effect of chlorhexidine digluconate

The bactericidal effect of chlorhexidine digluconate was determined as previously described by the EN 1040 quantitative suspension test method (12). 
Tested concentrations of chlorhexidine digluconate were 4%, 2%, 0.5%, 0.1%, 0.05%, and 0.02%. 
Disinfectants solutions were prepared prior to the test using sterile distilled water. 
The methods for preparing bacterial inoculum and performing the suspension test were described in detail earlier (13).
Briefly, a single isolated colony of bacteria was inoculated in tryptic soy broth (TSB, Merck) for 24 h at 37 °C. 
After incubation, the bacterial suspension was centrifuged, and the cell pellets were washed with TSB and adjusted between 1.5 × 108 and 5 × 108 cfu/mL. 
In the test, bacterial suspension was added to the disinfection solutions (1:10) for 5 min of contact time at room temperature, and then 1 mL was removed to 9 mL of the neutralizing solution (0.75% w/v lecithin, 5% v/v Tween 80 in TSB) and serially diluted in sterile distilled water. 
One hundred microliters of each dilution was then inoculated onto tryptic soy agar (TSA, Merck) by the spread plate technique and incubated at 37 °C for 24 h. The samples were studied in triplicate.

Colony forming units counted from plates that had a colony count between 30 and 300 were taken into account. 
The test was repeated using sterile distilled water instead of the disinfectant solutions as the control. 
The reduction factor (RF) was calculated as the expression of the disinfectant efficacy according to the following formula (12,13):
RF = log10 predisinfection control − log10 disinfectioncontrol Log10 reductions of 5 or more were taken as an indication of satisfactory bactericidal activity.


The determination of bactericidal susceptibility to antibiotics was carried out using a Sceptor system. 
All of the isolates had multiple antibiotic resistance. 
However, the Acinetobacter isolates possessed a higher level of resistance than other gram-negative bacteria.
The MIC values of chlorhexidine digluconate against hospital isolates were investigated using an agar dilution test. 
The obtained MIC values for all of the isolates are shown in Table 1. 
According to these results, S. aureus including MRSA and E. coli isolates had low MIC values, while P. aeruginosa and S. maltophilia isolates had the highest MIC values.

The bactericidal activity of chlorhexidine digluconate was identified by using the quantitative suspension test. 

According to the results shown in Tables 2 and 3, all hospital isolates that were studied were found to be susceptible to 4% chlorhexidine digluconate after 5 min of contact time. 
There was no decrease in the bactericidal activity against the isolates, except for MRSA, in 2% chlorhexidine digluconate (no data available for P. aeruginosa). 
Acinetobacter sp., Enterobacter sp., S.maltophilia, Klebsiella sp., and Enterococcus sp. isolates were found to be susceptible in 0.5% chlorhexidine digluconate, whereas 11 P. aeruginosa, 14 MRSA, and 5 MSSA isolates were found to be resistant. 

All of the Enterococcus isolates and 9 isolates of S. maltophilia were susceptible in 0.02% chlorhexidine digluconate.
Chlorhexidine digluconate at a concentration of 0.02% was active against only 2 S. aureus isolates (4.7%), whereas at the same concentration it was active against all Enterococcus isolates.

This result showed that S.aureus isolates (MRSA and MSSA) had a lower level of susceptibility than Enterococcus in low concentrations of chlorhexidine digluconate.


3.2. Evaluation of neutralizing efficacy
After conducting the neutralizing efficacy test, it was observed that the neutralizing agent could inactivate chlorhexidine digluconate and had no antibacterial effect on studied bacteria. 

4. Discussion
Hospital infections constitute a serious problem in Turkey,as well as around the world. 
Hospital infections rank sixth in the list of causes of death in the United States, where the most reliable data are available (15). 
The rate of hospital infection in a university hospital in Turkey was found to be 13.4% and 10.9% in 2 surveys conducted monthly in 2 months (16). 
Achieving control over these hospital infections is extremely important to maintain the safety of patients and hospital staff.  
For this reason, intensive activity has been implemented in hospitals in order to prevent the development of infections. 
Among these activities, establishing appropriate disinfection policies and providing their activation play an important role.

The core of these policies is to determine the appropriateconcentrations, implementation methods, and application areas of disinfectants (7,17). 
Despite all these activities,infection epidemics caused by the wrong use of biocides have still been reported (18,19).


In our study, the MIC values and bactericidal activities were determined for a total of 120 strains (82gram-negative and 38 gram-positive) belonging to 7 bacterial types isolated from patients admitted to the Hacettepe University Adult Hospital. 
The MIC values of chlorhexidine digluconate were specified with the agar dilution method and the bactericidal activity with an EN1040 basic bactericidal activity test, as recommended by the European Committee for Standardization.

Bacterial resistance can be shown clearly and reliably by determining the MIC values of the antibiotics.

Although the MIC values give an indication in the first stage of the antimicrobial activity of the biocides, they fail to give specific results about the decreasing susceptibility or the resistance of biocides to in-use concentrations. 
The reason for the latter is that MIC values for biocides, unlike antibiotics, are lower than in in-use concentrations. 
The fact that the bacteria are growing at this low concentration does not mean that they are resistant to biocides. 
This should be defined as ‘increasing MIC value’ or decreasing susceptibility. 
However, a resistance can be relevant if the logarithmic decrease value is also below 5. 
This means that it is important to evaluate the bactericidal impacts rather than the inhibitory effects of biocides (4,6,20). 

Thus, in comparing the results of different studies, the methods employed should also be taken into consideration. 
The results of a study where the bacteriostatic activity wasdetermined should not be compared with the results of bactericidal activity. 

In our study, chlorhexidine digluconate was found to be bactericidally effective against all strains at a concentration of 0.05%, while the MIC50 and MIC90 values of the S. maltophilia isolates were found to be very high (512 and >512 µg/mL, respectively).

On the other hand, although S. aureus isolates have low MIC50 and MIC90 values (2 µg/mL), only 2 isolates were found to be susceptible at the 0.05% concentration of chlorhexidine digluconate. 

In this case, no link was detected between MIC values and bactericidally effective concentration values. 
However, more research with an extended range of isolates is needed in order to reach a more certain conclusion.

In this study, the bactericidal activity of the chlorhexidine digluconate was tested at in-use concentrations  (4%, 2%, 0.5%, 0.1%, 0.05%, and 0.02%) according to the recommendations of the manufacturer, for close to, or lower than 5 min of contact time. 
Since chlorhexidine was used in concentrations of 0.05%–0.12% as an antiseptic, the determination of the effectiveness at lower concentrations is also important (4).

In this study, 4% chlorhexidine digluconate was observed to have a bactericidal effect in 5 min of contact time against all studied bacteria. 

However, as the concentration of chlorhexidine digluconate decreases, the susceptibility of the isolates of S. aureus and P. aeruginosain particular increase rapidly. 
The fact that those bacteria are the ones causing most of the hospital infections makes the especially frequent use of biocides, using chlorhexidine digluconate at appropriate concentrations, even more important. 
Similarly, in studies done in Turkey, it has been suggested that 4% chlorhexidine digluconate was bactericidally effective on gram-negative and grampositive bacteria causing hospital infections (21,22).

However, Eryılmaz et al. reported that the bactericidal activity of chlorhexidine decreased at low concentrations against P. aeruginosa (22). 
We conducted a similar study in the pediatric hospital of our facilities that indicated that 4% chlorhexidine digluconate was effective against gram-negative bacteria. 
Thus, it is clear that there is no development of resistance over time (13).
There is no clear evidence that there is a link between antibiotic resistance and biocide resistance and studies still continue in this area (3,5,7,20,23). 
The fact that antibiotic and biocide resistance mechanisms are similar suggests that there is a possible link between them (3). 

In moststudies, it has been shown that antibiotic resistance does not alter the susceptibility of bacteria to chlorhexidine (3,24). 

However, there are also studies suggesting that chlorhexidine digluconate susceptibility of multidrugresistant gram-negative bacteria has decreased (25,26). 
In our study, the phenotypic antibiotic resistance profiles of all the isolates used are known. 

In this respect, there is no evidence that the biocide susceptibility of the antibioticresistant bacteria has decreased. 
The only exception found was for MRSA isolates, where the bactericidal concentration was 40 g/L (4%), while it was 20 g/L (2%) for MSSA isolates. 
However, subsequently both bacteria groups were susceptible to chlorhexidine digluconate at in-use concentrations. 
The existence of studies suggesting that the biocide resistances of MRSA and MSSA are different while there are also studies providing the opposite result proves that there is no consensus yet on this issue (4,7). 
On the other hand, although there is a study showing that Enterococcus spp. are more resistant to chlorhexidine digluconate than S. aureus isolates, it was shown in this study that the susceptibility of S. aureus isolates was lower (26).

Some published studies demonstrate that, in hospitals, the contact of bacteria with biocides at low concentrations can create selective pressure for some isolates, similar to the subinhibitory concentration effects of antibiotics (2,3,20,27). 
In a recent study, it was also reported that quaternary ammonium compounds used in lower concentrations caused an increase in expression of virulence genes in bacteria (28). 

Thus, it appears that biocide concentration is a major factor in the development of bacterial resistance. 

If the surface to be disinfected was not clean and yet to be dried after disinfection, if the disinfectant was prepared at lower concentrations than in-use concentrations, and if the diluted disinfectant was kept longer than suggested by the manufacturer, then a low concentration of biocide is in contact with the bacteria (20). 

Irrizary et al. showed that chlorhexidine digluconate residues can have a selective effect on MRSA isolates(29). 

In another study, it was found that subinhibitory concentrations of chlorhexidine digluconate can cause a permanent increase in MIC values of P. aeruginosa isolates (30). 

These findings emphasize how important it is to clean surfaces first before disinfection occurs.

It is thereby important to pay attention to possible biofilm formation in wet surfaces. 

Moreover, using the appropriate concentrations of disinfectant with less residue is particularly recommended against bacteria such as Acinetobacter sp. MRSA and P. aeruginosa which can survive longer periods in hospital environments and can be exposed to subinhibitory concentrations of biocides.

It has been observed that chlorhexidine digluconate can have bactericidal activity on antibiotic-susceptible and antiobiotic-resistant bacteria when treated for 5 min at inuse chlorhexidine digluconate concentrations. 

However,there is a need for surveillance studies in order to monitor the possibility of a decrease in susceptibility and/or the development of resistance of bacteria, especially for S. aureus and P. aeruginosa


Chlorhexidine digluconate–an agent for chemical plaque control and prevention of gingival inflammation
NiklausP. Lang  Michel C. Brecx
First published: November 1986 https://doi.org/10.1111/j.1600-0765.1986.tb01517.xCitations: 136

In selecting antimicrobial agents for the prevention and treatment of periodontal diseases, the following factors should be considered: 
1. Specificity
2. Efficacy 
3. Substantivity
4. Safety 
5. Stability

Using these criteria, several antibiotics and antiseptics have been evaluated in recent years for chemical plaque control. 
While antibiotics are mostly used under a specific plaque hypothesis, antiseptics are more suitable for a non‐specific plaque concept. 
Several antiseptics hinder plaque formation or even break up old plaque. 
For example, quaternary ammonium compounds, combinations of metal ions with pyrimidines or with fluorides, phenolic compounds, and plant alkaloids have yielded a plaque reducing effect of 20–20% and have also delayed slightly the development of gingivitis. 
Years of documented research have established that chlorhexidine digluconate is safe, stable, and, owing to its great substantivity, effective in preventing and controlling plaque formation, breaking up existing plaque, and inhibiting and reducing the development of gingivitis. 
In studies of 6 months and longer, chlorhexidine has been shown to reduce gingivitis by 50–50% compared to a placebo control. 
Chlorhexidine is the most effective and most thoroughly tested antiplaque and antigingivitis agent known today.

Chlorhexidine digluconate as corrosion inhibitor for carbon steel dissolution in emulsified diesel fuel
Author links open overlay panelM.A.DeyabS.T.KeeraS.M.El Sabagh
Egyptian Petroleum Research Institute (EPRI), Nasr City, Cairo, Egypt


Abstract
Nitrogen oxide (NOx) and particulate matter (PM) emissions from diesel engines are reduced by mixing water in the diesel fuel in the form of water-in-diesel emulsion. 
The results of experiment showed that blend of span 80 and tween 80 at HLB 6 was found to be the most suitable emulsifier for water/diesel emulsion. 
The effect of chlorhexidine digluconate on the corrosion of carbon steel electrode in aerated stagnant water/diesel emulsion solution has been studied using potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques. 
The inhibition efficiency was found to increase with increasing inhibitor concentration. 
The inhibition is attributed to adsorption of the inhibitor on the carbon steel surface. 
The adsorption behavior of chlorhexidine digluconate on the carbon steel surface follows Temkin-type isotherm. 
The standard free energies of adsorption are lower than 40 kJ mol−1 confirming the physical adsorption of chlorhexidine digluconate on the electrode surface. 

Chlorhexidine digluconate has a significant inhibiting effect on the growth of micro-organisms in the liquid fuel and protection efficiencies up to 99.9% were measured


Highlights
► Water/diesel emulsion stability reaching a maximum value at HLB 6. 
► Chlorhexidine digluconate show good performance as micro-organisms growth inhibitor in the liquid fuel. 
► Chlorhexidine digluconate is considered as an efficient corrosion inhibitor for carbon steel in water/diesel emulsion. 
► The inhibitive action of chlorhexidine digluconate takes place through the physically adsorption on the metal surface. 
► The adsorption of Chlorhexidine digluconate on a carbon steel surface obeyed the Temkin adsorption isotherm.


An Investigation of the Bactericidal Activity of Chlorhexidine Digluconate Against Multidrug-Resistant Hospital Isolates

Author Ekizoglu, Melike Sağıroğlu, Meral Kılıç, Ekrem Hasçelik, Ayşe Gülşen
Background/aim: Hospital infections are among the most prominent medical problems around the world. 
Using proper biocides in an appropriate way is critically important in overcoming this problem. 
Several reports have suggested that microorganisms may develop resistance or reduce their susceptibility to biocides, similar to the case with antibiotics. 
In this study we aimed to determine the antimicrobial activity of chlorhexidine digluconate against clinical isolates. 
Materials and methods: The susceptibility of 120 hospital isolated strains of 7 bacterial genera against chlorhexidine digluconate was determined by agar dilution test, using minimum inhibitory concentration (MIC) values and the EN 1040 Basic Bactericidal Activity Test to determine the bactericidal activity. 
According to MIC values, Pseudomonas aeruginosa and Stenotrophomonas maltophilia were found to be less susceptible to chlorhexidine digluconate. 
Results: Quantitative suspension test results showed that 4% chlorhexidine digluconate was effective against antibiotic resistant and susceptible bacteria after 5 min of contact time and can be safely used in our hospital. 
However, concentrations below 4% chlorhexidine digluconate caused a decrease in bactericidal activity, especially for Staphylococcus aureus and P. aeruginosa. 
Conclusion: It is crucial to use biocides at appropriate concentrations and to perform surveillance studies to trace resistance or low susceptibility patterns of S. aureus, P. aeruginosa, and other hospital isolates

FACTS ABOUT CHLORHEXIDINE IN ORAL CARE

Chlorhexidine is an antiseptic and antimicrobial often used as an active ingredient in oral rinse.
It provides protection against a wide range of bacteria. It kills bacteria by binding to bacteria cell walls.
The FDA approved chlorhexidine 0.12% in August 1986 as ANDA 19-028
Chlorhexidine, to date is the most potent anti-plaque agent. 
It is considered gold standard anti plaque agent, against which efficacy of other anti-plaque and anti -gingivitis agents is measured. 
Its efficacy can be attributed to: Immediate bactericidal action
Prolonged bacteriostatic action.
The antimicrobial properties of Chlorhexidine are attributed to its bi-cationic molecule.


FOR WHICH INDICATION CAN WE USE CHLORHEXIDINE?

Gingivitis which causes redness, swelling, and bleeding of the gums.  
Chlorhexidine gluconate has a positive chemical charge; it is attracted to the negative charge on certain bacteria in the mouth. 
This attraction affects the bacterial cell membrane and causes increased permeability for immediate antimicrobial activity. 
Chlorhexidine gluconate is also attracted to negatively charged surfaces on oral tissue. 
This additional attraction gives chlorhexidine gluconate a sustained action that can help prevent the formation of plaque
Periodontitis disease occurs when inflammation or infection of the gums (gingivitis) is allowed to progress without treatment. 
Chip impregnated with chlorhexidine are used to reduce or eliminate the sub-gingival microorganisms associated with periodontal diseases.
Prevention of Early Childhood Caries. Dental plaque is the main source for dental caries and there is no proper vaccine that can affect dental plaques. 
Studies have demonstrated that chlorhexidine was superior to other indicated products in its ability to maintain low plaque scores
Dental traumas, such as subluxation, intrusion associated with pulp exposure are treated with  mechanical decontamination and intracanal medication composed by 2% of chlorhexidine gel.
Wisdom tooth extraction. Use of Chlorhexidine (CHX)-based mouthwash immediately before third molar extraction reduces bacteria levels in patients’ blood after the procedure.
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection among ventilated patients and is associated with increased mortality and morbidity. 
Oral chlorhexidine has been used to decontaminate the airway in critically ill patients, as studies suggest a risk reduction in VAP

Composition: 2, 4, 11, 13 – Tetraazatetradecanediimidamide N,N’’-bis(4-chlorophenyl) – 3,12- diimino –di D-gluconate
1,1’- Hexamethylenebis[5- (p-chlorophenyl) biguanide] di-D-gluconate.

Appearance: Almost colorless or pale yellowish, clear liquid.

Solubility: Miscible with glacial acetic acid and with water; miscible with three times its volume of acetone and with five times its volume of dehydrated alcohol; further addition of acetone or dehydrated alcohol yields a white turbidity.


Saving Newborn Lives With Scale Up of Quality-Assured Chlorhexidine
Summary
8,000 newborns die each day: 98% of these deaths occurring in developing countries 13 percent are due to infections.1
Hundreds of thousands of newborn lives can be saved with scale up and widespread use of quality-assured 7.1% chlorhexidine digluconate in target, high-risk populations.2
The Promoting the Quality of Medicines (PQM) program contributes to these efforts by providing technical assistance to local manufacturers and national regulatory authorities in Africa and Asia, so they can increase the availability of quality-assured 7.1% chlorhexidine digluconate  in communities where it is needed most to treat neonatal infections and reduce preventable deaths. 
The PQM program is helping to save newborn lives by supporting the introduction and scale up of 7.1% chlorhexidine digluconate.

Scaling up proven solutions in newborn health—so they reach more people and save more lives—is a major component of USAID’s response to the call to end preventable child and maternal deaths. 
Chlorhexidine digluconate, 7.1%—an effective and inexpensive WHO-recommended treatment for sepsis during the first week of life—is one of those proven solutions.3 
According to the United Nations, its widespread use in settings with extremely high neonatal mortality rates and high rates of home births has the potential to save hundreds of thousands of newborn lives.2


About Chlorhexidine
Few other interventions have as much promise as Chlorhexidine to rapidly reduce newborn deaths at an affordable price—less than $1 per dose.

1% chlorhexidine digluconate, a low-cost antiseptic, prevents deadly infections that enter an infant’s body through a newly cut umbilical cord.  
Few other interventions have as much promise to rapidly reduce newborn deaths at an affordable price—less than $1 per dose[1]. 
Chlorhexidine has no toxicity risks and virtually no potential for misuse. 
It has a long shelf life, requires no cold chain, and is extremely easy to apply with minimal training and no equipment. 
These factors make it suitable for hospital, health center, and home care alike. 
Few other interventions have demonstrated such potential for rapidly reducing newborn mortality across so many settings for such a low cost.

In July 2013, WHO included 7.1% chlorhexidine digluconate (delivering 4% chlorhexidine) for umbilical cord care on the WHO Model List of Essential Medicines for Children[2]. 
In October 2013, WHO issued new guidelines for umbilical cord care that recommend daily application of 7.1% chlorhexidine digluconate to the umbilical cord stump for the first week of life in areas with high neonatal mortality[3].

The product is available in a gel and an aqueous solution (liquid). 
The global Chlorhexidine Working Group’s recommended dose for a single day application is 3g of gel (as currently practiced in Nepal) or 10ml of liquid. 
For a 7-day application, the recommended dose is 20g of gel and 30ml of liquid. 
These product sizes allow for wastage and will provide sufficient product for the indicated term of application.

The WHO recommends daily chlorhexidine application to the umbilical cord stump during the first week of life for newborns who are born at home in settings with high neonatal mortality (30 or more neonatal deaths per 1000 live births). 
In low neonatal mortality settings, clean, dry cord care is recommended for newborns born in health facilities and at home. 
Use of chlorhexidine in these situations may be considered only to replace application of a harmful traditional substance, such as cow dung, to the cord stump.

Where consumer research has been conducted, mothers have shown a strong latent demand for a purpose-made antiseptic like chlorhexidine. 
They have demonstrated the ability to use chlorhexidine correctly and have accepted that chlorhexidine makes cord detachment take 1-2 days longer.

Products Available
Chlorhexidine digluconate, in various forms, has been used for nearly 50 years and has applications across a broad range of veterinary, dental, and medical indications. 
However, 7.1% chlorhexidine digluconate is a novel formulation specifically intended for umbilical cord care and at this time there are a limited number of manufacturers.

The global Chlorhexidine Working Group is committed to establishing a supply of high-quality chlorhexidine for umbilical cord care and is actively engaged in evaluating and providing technical assistance to qualified manufacturers. 
Currently, Lomus Pharmaceuticals Pvt. Ltd (Nepal) and Drugfield Pharmaceuticals Ltd. (Nigeria) are producing 7.1% chlorhexidine digluconate gel commercially and manufacturing in East Africa and Bangladesh are expected to be underway in 2015. 
A 7.1% chlorhexidine digluconate aqueous solution (liquid) is also available at through the UNICEF supply catalogue

Product Efficacy
Recent community-level randomized controlled trials in Nepal, Pakistan, and Bangladesh have shown that applying a 7.1% chlorhexidine digluconate (delivering 4% chlorhexidine) product to the umbilical cord saves lives[5; 6; 7]. 
Across the three countries, data from over 54,000 newborns showed an aggregate 23% reduction in neonatal mortality (not including deaths in the first few hours of life) and a 68% reduction in severe infections for the chlorhexidine intervention groups. 
These are some of the largest effect sizes seen in any neonatal intervention[8]. 
It is estimated that chlorhexidine has the potential to reduce overall newborn mortality risk by up to 18%, resulting in over half a million newborn lives saved[8; 9].


CHLORHEXIDINE DIGLUCONATE
CHLORHEXIDINE DIGLUCONATE is classified as :
Antimicrobial
Oral care
Preservative
CAS Number    18472-51-0
EINECS/ELINCS No:    242-354-0
Restriction (applies to EU only):    VI/42
COSING REF No:    32659
INN Name:    chlorhexidine gluconate
PHARMACEUTICAL EUROPEAN NAME:    chlorhexidini gluconati solutio
Chem/IUPAC Name:    D-Gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Chlorhexidine Digluconate Effects on Planktonic Growth and Biofilm Formation in Some Field Isolates of Animal Bacterial Pathogens
Background: To study chlorhexidine digluconate disinfectant effects on planktonic growth and biofilm formation in some bacterial field isolates from animals.

Objectives: The current study investigated chlorhexidine digluconate effects on planktonic growth and biofilm formation in some field isolates of veterinary bacterial pathogens.

The present study was designed to determine the inhibiting effect of chlorhexidine on biofilm and planktonic growth of some animal bacterial pathogens. 
No significant planktonic growth and biofilm formation were observed in the presence of chlorhexidine in concentrations of one and two fold MIC, P < 0.05.


Interaction between Chlorhexidine Digluconate and EDTA
Brian J. Rasimick, BS 
Michelle Nekich, BS
Megan M. Hladek, BS
Barry L. Musikant, DMD
Allan S. Deutsch, DMD

Abstract
The combination of chlorhexidine and EDTA produces a white precipitate. 
The aim of this study was to determine if the precipitate involves the chemical degradation of chlorhexidine. 
The precipitate was produced and redissolved in a known amount of dilute trifluoroacetic acid. 
The amount of chlorhexidine and EDTA present in the dissolved precipitate was determined by reverse-phase high performance liquid chromatography (HPLC) with ultraviolet detection at 288 nm. 
More than 90% of the precipitate's mass was found to be EDTA or chlorhexidine. 
The remainder is suspected to be water, gluconate, and sodium. Parachloroaniline, a potentially carcinogenic decomposition product of chlorhexidine, was not detected in the precipitate (the limit of detection was 1%). 
The molar ratio of chlorhexidine to EDTA in the precipitate was about 1.6 to 1. 
Based on the results, chlorhexidine forms a salt with EDTA rather than undergoing a chemical reaction.


Residual Antimicrobial Effect of Chlorhexidine Digluconate and Octenidine Dihydrochloride on Reconstructed Human Epidermis
Müller G.a · Langer J.b · Siebert J.c · Kramer A.a
Author affiliations

Keywords: 
Antiseptics  
Chlorhexidine digluconate  
Octenidine dihydrochloride  
Pseudomonas aeruginosa
Staphylococcus aureus
Reconstructed human epidermis
Residual antimicrobial effect


Octenidine Dihydrochloride, a Modern Antiseptic for Skin, Mucous Membranes and Wounds
Octenidine dihydrochloride (octenidine) was introduced for skin, mucous membrane and wound antisepsis more than 20 years ago. 
Until now, a wealth of knowledge has been gained, including in vitro and animal studies on efficacy, tolerance, safety and clinical experience both from case reports and prospective controlled trials. 
Nowadays, octenidine is an established antiseptic in a large field of applications and represents an alternative to older substances such as chlorhexidine, polyvidone-iodine or triclosan. 
ATAMAN CHEMICALS has Octenidine Dihydrochloride in stocks.

Abstract
The objective of the present investigation was to examine the residual antimicrobial activity after a topical exposure of reconstructed human epidermis (RHE) to equimolar solutions of either chlorhexidine digluconate (CHG, 0.144% w/v) or octenidine dihydrochloride (OCT, 0.1% w/v) for 15 min. 
RHE-associated antiseptic agents were more effective on Staphylococcus aureus than on Pseudomonas aeruginosa. S. aureus was not detected after 24 h of contact, which demonstrated a microbicidal efficacy of greater than 5-log10 reduction. 
In contrast, P. aeruginosa was reduced by approximately 2 log10 at the same incubation time, which parallels the growth of the initial inoculum. 
This result could be interpreted either as a microbiostatic effect or as an adherence of P. aeruginosa to a low positively charged surface. 
Small amounts of CHG and OCT can penetrate the stratum corneum. 
Using these antiseptic agents, the viability of keratinocytes was reduced to 65-75% of that of the untreated RHE control following 24 h incubation in the presence of test microorganisms. 
With consideration of antimicrobial activity and cytotoxic effect, OCT corresponds better to a biocompatible antiseptic agent than CHG.

20% Aqueous Solution
1, 6-Bis (N-P-Chlorophenyl-Biguanido) Hexane Digluconate
Powerful activity against bacteria & fungi at low concentrations
Effective against gram negative & gram positive bacteria
Effectiveness enhanced in alcohols
Activity unaffected by presence of blood & other biological fluids
Sporicidal effects at approximately 0.1% solutions at 60-80°C
Most effective at pH 5.0 to 8.0

Anti-bacterial agent for a variety of formulations for hospitals and veterinary applications.

Preservative in cosmetic & pharmaceutical preparations. Used at concentrations up to 0.3% in creams, 0.05% in toothpastes, 0.1% in deodorants.


PubMed ID (PMID): 21842009PAGES 687-700, LANGUAGE: ENGLISH
Eick, Sigrun / Goltz, Susann / Nietzsche, Sandor / Jentsch, Holger / Pfister, Wolfgang
Efficacy of chlorhexidine digluconate-containing formulations and other mouthrinses against periodontopathogenic microorganisms


Objective: To determine in vitro the action of chlorhexidine digluconate and different commercially available mouthrinses on oral microorganisms. 
Method and Materials: Minimal inhibitory concentrations and possible induction of resistance by chlorhexidine digluconate, an essential oil-containing mouthwash and an amine fluoride/stannous fluoride solution, were determined against microorganisms normally found in the oral cavity (10 streptococci, 2 enterobacteria, 1 Candida albicans, 8 Porphyromonas gingivalis, 6 Aggregatibacter actinomycetemcomitans, and 1 Fusobacterium nucleatum). 
Further, the effect of a 1-minute exposure on cell and bacterial viability was studied. 
Results: The susceptibility of the oral microorganisms to chlorhexidine digluconate ranged from 0.01% to 0.50%. 
Passages on agar plates containing subinhibitory concentrations of chlorhexidine digluconate resulted in a transitory moderate increase in the tolerance to chlorhexidine digluconate in five of the 24 isolates. 
After 1 minute of exposure, chlorhexidine digluconate solutions as well as the essential oil and the amine/stannous fluoride-containing solutions showed a high activity against the tested microorganisms. 
Commercially available chlorhexidine digluconate formulations (ie, those with antidiscoloration systems) were partly less efficient than the corresponding manually prepared chlorhexidine digluconate preparation. 
The determination of MTT resulted in a strong cytotoxicity of all tested preparations to gingival fibroblasts. 
Conclusion: The results indicate that most of the chlorhexidine digluconate formulations as well as essential oil and the amine fluoride/stannous fluoride solutions are active against oral microbes. 
Long-term use of these agents would not result in emergent antimicrobial resistance.
Keywords: chlorhexidine, mouthrinse, periodontopathogenic bacteria


Chlorhexidine digluconate, 20 % soln.
CAS name: D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (2:1)
CAS number: 18472-51-0
Formula: C22H30Cl2N10 x 2 C6H12O7
Product Groups: Amino Acids for Pharma
Markets: Pharma & Healthcare
Applications: Anti-parasitic
Dermatological Products
Code: Chlorhexidine digluconate
Synonyms: 2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, di-D-gluconate
Biguanide, 1,1'-hexamethylenebis[5-(p-chlorophenyl)-, di-D-gluconate D-Gluconic acid, compd. with 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide] (2:1) Gluconic acid, compd. with 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide] (2:1), D- 1,1'-Hexamethylenebis[5-(p-chlorophenyl)biguanide] digluconate 1,6-Bis(4-chlorophenyldiguanino)hexane digluconate 1,6-Bis(p-chlorophenyldiguanido)hexane digluconate 1,6-Bis[N5-(p-chlorophenyl)biguanido]hexane digluconate 4-Chlorhexidine digluconate Bis(p-chlorophenyl)diguanidohexane digluconate Chlorhexidine bigluconate Chlorhexidine di-D-gluconate Chlorhexidine digluconate Chlorhexidine gluconate
Molecular weight: 897.77 g/mol 
 
Chlorhexidine Dihydrochloride
CAS name: N,N''-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide dihydrochloride
CAS number: 3697-42-5
Formula: C22H30Cl2N10 x 2HCl
Product Groups: Amino Acids for Pharma
Markets: Pharma & Healthcare
Applications: vetinary
Synonyms: Biguanide, 1,1'-hexamethylenebis[5-(p-chlorophenyl)-, dihydrochloride
1,1'-Hexamethylenebis[5-(p-chlorophenyl)biguanide] dihydrochloride Arlacide H AY 5312 Chlorhexidine dihydrochloride Chlorhexidine hydrochloride Chlorhexidinium dichloride
Molecular weight: 578.38 g/mol 

Chlorhexidine digluconate has low toxicity if swallowed or in skin contact.
There is no data available for inhalation exposure. Due to the chemical character of the substance eye and skin irritation / damage may occur after contact. 
It is not a skin sensitizer. Standard tests indicate Chlorhexidine digluconate is neither mutagenic nor genotoxic. 
Data shows no evidence that Chlorhexidine digluconate is a reproductive toxin. 
Data available show no evidence of carcinogenicity.


Human health Personnel exposure to this chemical in the manufacturing facilities is low because the process, storage and handling operations are enclosed. 
Normal industrial practices assure limited workplace exposures. These practices include handling with good ventilation. 
When containers and tanks are cleaned, residues are captured and treated. 
All workers are trained in the properties and safe practices of using chemicals including using personal protective clothing. 
It is concluded that there is no risk for any of the exposures considered for Chlorhexidine digluconate containing products for professional users and consumers. 
Therefore, it can be used safely within its low concentrations in medicinal, biocidal or consumer products.

Hazard statement(s) H318 - Causes serious eye damage.
H410 - Very toxic to o aquatic life with long lasting effects 


Clorhexidine (CHD), chemically identified as 1,1′-hexamethylenebis[5-(p -chlorophenyl)biguanide], is a substance having a strongly basic action with only very low water solubility. 
By reacting the chlorhexidine base with acids, a large number of salts that are also sparingly water-soluble can be obtained. 
However, some salts of chlorhexidine with sugar acids are water-soluble. 
Chlorhexidine base, and especially the water-soluble chlorhexidine digluconate, a salt of D(+)-gluconic acid with chlorhexidine, represent important antibacterial substances for use in both the human and the animal sector. 
Their low toxicity and compatibility with cationic and non-ionic detergents should be highlighted. 
Chlorhexidine digluconate (CHD-gluc) is commercially available as a 20 wt. % aqueous solution. 
Liquid formulations containing chlorhexidine are modified in many different ways and used as an antibacterial additive in cosmetics, for skin disinfection, treatment of wounds, in veterinary medicine as an udder disinfectant, and also for disinfecting surfaces.


Chlorhexidine HCl
Chlorhexidine HCL is a high quality antispetic, disinfectant and preservative used for a broad field of indications

Chlorhexidine Acetate
Chlorhexidine Acetate is a high quality antiseptic used for a broad field of indications.


 

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