EP3413716A1

EP3413716A1 - Synthesis and application of an antimicrobial active

Info

Publication number: EP3413716A1
Application number: EP16782090.1A
Authority: EP
Inventors: Rakesh Ratnam K; Samir SARVIYA; Mohana Narayanan N.; Raviraj S P; Prithviraj VASANTRAO PATIL
Original assignee: Salicylates & Chemicals Pvt Ltd
Current assignee: Salicylates & Chemicals Pvt Ltd
Priority date: 2016-02-12
Filing date: 2016-08-19
Publication date: 2018-12-19
Also published as: WO2017137818A1; CO2018009513A2

Abstract

The disclosure Synthesis & Application of a Novel Antimicrobial active provides a method of synthesis of organic complex starting from fatty acid with a free base bioactive molecule containing nitrogen atoms. The reaction is usually conducted in refluxing alcohol. The product is synthesized by a acid-base reaction whereby the acid molecule is capable of donating a proton, to the free base molecule resulting in the formation of the desired complex. These complexes are very effective antimicrobial active against a variety of bacteria, fungi, protozoa, helminths and viruses. The process is suitable for large-scale synthesis and involves simple and high-yielding techno feasible chemical transformations using low-cost commercially available raw materials. The complex has wide spread use in human personal care, industries and household applications, as the disclosed chemical has antimicrobial activity against gram positive, gram negative bacteria, yeast, mold, fungi.

Description

SYNTHESIS AND APPLICATION OF AN ANTIMICROBIAL ACTIVE

F ield of Invention

Present invention discloses Synthesis and Application of a Novel Antimicrobial active Particularly the invention provides an organic amino- salt ingredient as an efficient antimicrobial agent for personal care, oral care; home care and topical pharmaceutical formulation.

Background of Invention

Antimicrobial ingredients are materials that protect against the growth of microorganisms in personal care products, including bacteria, viruses and fungi. Antimicrobial personal care products, which are sometimes referred to as antibacterial products, provide an important extra measure of protection for consumers at home and doctors and nurses in hospitals seeking to prevent spread of germs. These products, depending on their formulation and application, kill or inhibit the growth of bacteria that cause skin infections, intestinal illnesses or other commonly transmitted diseases. These include potentially fatal illnesses caused by bacteria such as S almonella and E .coli.

Antimicrobial ingredients play an important role in making sure that personal care products are free of microorganisms during storage and after they are opened. They are effective at low levels so that it doesn^'t take much of the ingredient to work. There are many different types of materials that can be used in products and they are selected based on the specific type of product. A water-based product may use a different type of ingredient (or combination of ingredients) than an oil-based product. The same ingredients that are used to protect cosmetic product integrity may also be used in OTC Antimicrobial drug products, although the amount added may be different

Anti microbial protection and the related biotechnologies are more relevant today than ever before. C hlorhexidine and its salts are reported as being used in cosmetics as an active ingredient to give the desired effect or as a preservative in concentrations of 0.1 % to 0.3 %. S uch products include mouthwashes, hair dying and bleaching formulations, shampoos, anti hair aging_ products and exfoliants, body lotions, eye creams, face cleansers, sun cream, after-sun lotions, eye makeup removers, and facial masks.

Within the health sector, chlorhexidine is used in formulations for preoperative skin disinfection, in treatment of wounds and burns, for urinary bladder flushing, for catheter disinfection, and in ophthalmology and gynecology. In cosmetic products, chlorhexidine is commonly used in combination with other agents with antimicrobial activity in order to improve the biocidal effect

E uropean patent application No E P0807440A2 teaches synthesis of aqueous C hlorhexidine gluconate-containing stabilized aqueous pharmaceutical preparations. The disclosure essentially teaches use of the chemical for eye care and nasal care. It further teaches use of preparation further contains at least one pharmaceutical acceptable polycarboxylic acid.

C hlorhexidine gluconate, a salt of chlorhexidine with gluconic acid and salts of chlorhexidine base with other organic and inorganic acid, are used as local disinfectants for disinfection of fingers and skin, and disinfection of the site of surgery, disinfection of surgical tools and in the areas of personal care. C hlorhexidine gluconate and other acid salts are also widely used as a preservative to prevent growth of microorganisms in cosmeceuticals and pharmaceutical preparations for external use and preparations for topical use such as, eye drops and nasal drops.

A US patent publication No2004/0234496A1 on the other hand, teaches a biocidal compositions formed by metathesis of either mono meric or polymeric bioactive cations with either monomeric or polymeric bioactive anions to from an essentially water insoluble complexes. The salts of chlorhexidine base with the organic acids have been reported earlier. S ome references are there for chlorohexidene base and the saturated fatty acids of the base. Fatty acids are known to possess antibacterial, antimalarial and antifungal activity. Fatty acids pose less environmental risks. They are not only biodegradable, but exhibit a high degree of specificity. In addition, fatty acids are accepted food additives and importantly, pathogenic fungi are less likely to become resistant to antifungal fatty acids. The most important target of antifungal fatty acids is the cell membrane. They cause an increase in membrane fluidity, which will result in leakage of the intracellular components and cell death.

Unsaturated fatty acids contain fixed bend C=C bonds and will therefore occupy a greater cross section when inserted into the membrane as disclosed in Applied and E nvironmental Microbiology. 2001 ;67:956-960. They are proposed to have increased fungicidal activity due to their increased motional freedom inside the membrane. It must however be noted that increased oxidative stress caused by incorporation of polyunsaturated lipids in the membrane, may contribute to the antifungal activity of these fatty acids as disclosed in Marine Drugs. 2010;8:2597-2604

Undecylenic acid (C 1 1 ) or also called 10-undecenoic acid is an organic unsaturated fatty acid derived from castor oil by cracking. Undecylenic acid is an F DA approved active ingredient in medications for skin infections, and relieves itching, burning, and irritation. In technical applications it is used because of its antifungal properties. Undecenoic acid is known to inhibit growth of the Myrothecium verrucaria as disclosed in American Oil C hemists ^" S ociety; 1978:51 -62. , S accharomyces cerevisiae as discloaed in Biochimica et Biophysica Acta. 2002;1581 :109-1 18.

For last four decades TRIC LOSAN has been synonymous with the personal care & product based hygienic Industry, enduring successfully a time-tested path for its activity as well as safety. The twin driving forces apart from creating a unique anti microbial also have paved ways into cutting edge markets catering not just to curative but also to prophylactic and preventive segments. The chemical, triclosan, is a synthetic, broad- spectrum antimicrobial agent that in recent years has exploded onto the consumer market in a wide variety of antibacterial soaps, deodorants, toothpastes, cosmetics, fabrics, plastics, and other products.

However; recently many studies have increasingly linked triclosan to a range of health and environmental effects, from skin irritation, allergy susceptibility, bacterial and compounded antibiotic resistant, and dioxin contamination to destruction of fragile aquatic ecosystems.. According to the American Medical Association, ^'Despite their recent proliferation in consumer products, the use of antimicrobial agents such as triclosan in consumer products has not been studied extensively. No data exist to support their efficacy when used in such products or any need for themu it may be prudent to avoid the use of antimicrobial agents in consumer productsu _2(Ref 5 American Medical Association. 2000. Use of Antimicrobials in Consumer Products. Report 2 of the Council on S cientific Affairs (A-OO).The other drawback of triclosan is that it is not biodegradable.

Consumers are concerned about the recent studies that have prompted further F DA and E PA review of Triclosan. For formulators seeking Triclosan alternatives, there is a need to provide a suitable replacement with similar efficacy.

U.S . Patent (No. 2,684,924 ) describes the preparation of the dihydrochloride, digluconate and diacetate salts of chlorhexidine base. All the three salts are derived by either using an inorganic acid or a small molecular weight organic acid. Higher molecular saturated acid also have been reported to form salt with the chlorhexidene base. S ome are reported in Pat E P0707794A1 wherein salt with acetic lactic acid, malic acid, salicylic acid, and palmitic lactic acid are described. S ome of the salts are presumed to be made insitu with appropriate ratios of the ingredient in a desired solvent and used as such for the antimicrobial application.

There is need for a broad spectrum, biodegradable microbial agent which will work across for the control of gm+ve, gm ^"ve bacteria, yeast mold and fungi Objectives of Invention

Principal objective of the present invention is to provide synthesis of chlorhexidine based organic complex and its application as an efficient antimicrobial active for various industrial, cosmeceutical, and pharmaceutical formulations. .

Another objective of the invention is to provide the active antimicrobial ingredient to be used in the preparation of personal care formulations.

Another objective of the invention is to provide the active antimicrobial ingredient to be used in the preparation of industrial substances such as Plasticjextiles and Polymers . Another objective of the invention is to provide the active antimicrobial ingredient to be used in the preparation of oral care preparations such as toothpaste and mouthwash rinses.

Another objective is to isolate and characterize the novel antimicrobial active

Another objective is to show the efficacy of the novel antimicrobial active in cosmeceutical skin car, hair care formulation, oral care cosmeceutical and pharmaceutical formulation and pharmaceutical topical formulation.

Another objective is to show the efficacy of the novel antimicrobial active as a disinfectant in home care and pharmaceutical formulation.

Another objective is to show the efficacy of the antimicrobial active for its application in the soaps and detergents including the dish washing detergents.

Drawings

An embodiment of the complex is shown in the figure 1.

NMR spectra of chlorhexidine base complex is shown in F ig 2

S ummarv of Invention

According to the main aspect of the invention there is provided synthesis of chlorhexidine based organic complex which comprises the steps of :

heating up slowly the mixture of rectified spirit and fatty acid having with C n in a temperature range of 20 to 50° C to get a clear solution, clear solution further being maintained under stirring for homogenization leading to complete solid precipitation and the mass cooled further to room temperature , solid precipitate being then filtered suck dry, to collect wet cake,

the solid wet cake then dissolved in alcoholic or alkyl ,aryl solvent, ketonic solvent, the solution is heated to a temperature range of 40 to 80 degrees preferably between 40 to 60 degrees and most preferable temperature 45 ^"50°C, the solution of wet cake in acetone charged with activated charcoal and heating up to reflux, collecting mother liquor slowly and cooling down to room temp and chilled to about 4 to 6 degree for complete precipitation of the product, the wet cake after filtration was washed with chilled solvent preferably acetone, squeeze out main mother liquor and collecting the wet cake followed by drying to get chlorhexidine based organic complex.

According to another aspect of the invention wherein, preferred fatty acid is undecylenic acid.

According to a further aspect of the invention wherein alcoholic or alkyl ,aryl solvent are selected from a group of methanol, isopropanol or any low boiling alcoholic solvent

According to a further aspect of the invention wherein, ketonic solvent is selected from a group of methyl ethyl ketone, acteophenone , acetone, preferably low boiling alkyl ketones.

According to a still further aspect of the invention wherein, organic complex has negligible oral toxicity. According to a yet another aspect of the invention wherein, organic complex has negligible dermal toxicity .

According to a still another aspect of the invention wherein, organic complex has antimicrobial efficacy for the hand wash.

According to a still another aspect of the invention wherein the organic complex is useful in oral health, dental care.

According to still another aspect of the invention wherein, the organic complex is useful in hair care, skin care formulations.

According to still another aspect of the invention wherein, hair care formulations comprise, hair oil, hair creams shampoo, a ntidandruff applications.

According to still another aspect of the invention wherein, , skin care formulations comprise powders, sun screens, lotions, lipsticks and the like.

According to still another aspect of the invention wherein, the organic complex is used in disinfectants in pharmaceutical disinfectant for instruments, hand washes.

According to one aspect of the invention wherein, the organic complex is used as antifungal and antifouling agent in Paints , coatings.

According to one more aspect of the invention wherein, the organic complex has antimicrobial activity against gram positive, gram negative bacteria , yeast, mold, fungi.

Detailed Description of the Invention

This present disclosure describes the technique of the preparation of the acid salt of the chlorhexidine base. C hlorhexidine is a guanidine derivative which has a potential to form a salt with one or more moles of acid per mole of the base. The technique in making the desired product depends on the various factors like the mole ratio of the raw materials, temperature, selection of the reaction medium and reaction time.

The base materials used in the present invention are as given in table-1 below Table -1

F ollowing examples are given for illustration and do not limit the scope of invention

E xamples E xample 1

Synthesis of chlorhexidine based organic complex is achieved by first cha rging 500g of rectified spirit at room temperature. To this 75 g undecylenic acid is added under stirring. This reaction mixture is then heated up slowly to 40oC to get a clear solution. Then C hlorohexedine base is charged lot wise within 1 hr under controlled temp parameter. The reaction mass is maintained at 40° C for 2hrs during which a solid precipitation is obtained . The reaction mass was further mainta ined for 1 hr to effect completing precipitation of product and cooled to room temperature. S olid precipitated is then filtered and suck dried to collect the wet cake. The solid wet cake then dissolved in alcoholic solvent, To purify the wet cake, the solid wet cake was then dissolved in acetone and heated to 45 ^" 50° C . To this solution was charged 5g activated cha rcoal and heated up to reflux for 30 mins and filtered over super cell bed to get a clear colorless solution. F inally, the clea r colorless filtrate was cooled down to room temperature first and chilled up to 5-6° C over a period of couple of hours. The product was filtered to get the wet cake. The wet cake was washed with 50 X 2 chilled acetone and suck dried. F inally, crystallized cake is dried by VTD for 4- 5hrs to get 55g chlorhexidine undecylinate..

E xample ^" 2

Synthesis of chlorhexidine based organic complex is achieved by first charging 500g of rectified spirit at room temperature. To this 75 g undecylenic acid is added under stirring. This reaction mixture is then heated up slowly to 40°C to get a clear solution. Then C hlorohexedine base is charged lot wise within 1 hr under controlled temp parameter. The reaction mass is maintained at 40° C for 2hrs during which a solid precipitation is obtained . The reaction mass was further maintained for 1 hr to effect completing precipitation of product and cooled to room temperature. S olid precipitated is then filtered and suck dried to collect the wet cake. The solid wet cake then dissolved in an aryl solvent. To purify the wet cake, the solid wet cake was then dissolved in acetone and heated to 45 °C To this solution was charged 5g activated charcoal and heated up to reflux for 30 mins and filtered over super cell bed to get a clear colorless solution. F inally, the clear colorless filtrate was cooled down to room temperature first and chilled up to 5-6oC over a period of couple of hours. The product was filtered to get the wet cake. The wet cake was washed with 50 X 2 chilled acetone and suck dried. F inally, crystallized cake is dried by VTD for 4- 5hrs to get 55g chlorhexidine undecylinate.

E xample -3

Synthesis of chlorhexidine based organic complex is achieved by first charging 500g of rectified spirit at room temperature. To this 75 g undecylenic acid is added under stirring. This reaction mixture is then heated up slowly to 400C to get a clear solution. Then C hlorohexedine base is charged lot wise within 1 hr under controlled temp parameter. The reaction mass is maintained at 400 C for 2hrs during which a solid precipitation is obtained . The reaction mass was further maintained for 1 hr to effect completing precipitation of product and cooled to room temperature. S olid precipitated is then filtered and suck dried to collect the wet cake. The solid wet cake then dissolved in a ketonic solvent. To purify the wet cake, the solid wet cake was then dissolved in acetone and heated to 45 °C To this solution was charged 5g activated charcoal and heated up to reflux for 30 mins and filtered over super cell bed to get a clear colorless solution. F inally, the clear colorless filtrate was cooled down to room temperature first and chilled up to 5-6° C over a period of couple of hours. The product was filtered to get the wet cake. The wet cake was washed with 50 X 2 chilled acetone and suck dried. F inally, crystallized cake is dried by VTD for 4- 5hrs to get 55g chlorhexidine undecylinate.

The above produced product is analyzed by using the following HP LC method.

HP LC Column

Column :

The liquid chromatograph is equipped with a 239nm detector and a 4.6mm B 25cm column that contains base deactivated 5i m packing L1 .

Column Temperature : About 40 .

F low rate : About 1.5 mL per minute.

C hromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between chlorhexidine and pchloroaniline is not less than 3; and the relative standard deviation for replicate injections is not more than 2% determined from the chlorhexidine peak and not more than 5% determined from the pchloroaniline peak. Procedure ^' S eparately inject equal volumes (about 50 I L) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the peak areas for chlorhexidine. Calculate the percentage (w/v) of C22H30C I2N10X2C6H12O7 in the portion of S olution taken by the formula: (897.77/625.66)(0.25C)(rU / rS ), in which 897.77 and 625.66 are the molecular weights of chlorhexidine gluconate and chlorhexidine acetate, respectively; C is the concentration, in ι g per mL, of US P C hlorhexidine Acetate RS in the Standard preparation; and rU and rS are the peak areas for chlorhexidine obtained from the Assay preparation and the Standard preparation, respectively NMR S pectral analysis.

1

P roton nuclear magnetic resonance ( H NMR) spectroscopy was used to analyze the structure of

1

chlorhexidine undecylinate. T he H NMR spectrum of chlorhexidine had peaks at 7.26, 7.23, 6,86,

5.84,5.82, 5.81 , 5.80, 4.99, 4.94, 4.92, 3.72, 3.70, 3.69, 2.10, 2,16, 2.14 1.98, and 1 .25 ppm similar to that of chlorhexidine. The intensities, however, were different,

^Ί Η NMR (400 MHz, DMS O-d6) d (ppm): 0.89-0.97(d_f 4 x 3H), 1.3-1.7 (m, 20H), 1.38- 1.41 (t, 3H), 2.58-2.6(m, 2H), 3.08-3.1 (m, 4H), 3.48 (s, 2H)_f 4.07-4.12(q, 2H), 5,37- 5.38(m_; IH), 5.5-5.57 (m, IH)_f 6.8-7.6 (m, 8H)_f 6.8-7.6 (d, 3H), 8.32-8.34(d_f IH), 8.41 - 8.44(d, IH); and

MS : m/z : 873.

The DS C Analysis is as shown below :

Peak : 1 17.92eC

Onset : 1 14.1 eC

The DS C implies that the product decomposes between the said temperature indicating that is a salt and not a mixture of two individual organic molecule.

Applications of the chlorhexidine base complex are described below

In order to substantiate the efficacy of the complex was subjected to kill test of on Oral Care Bacteria. This test is essential to be able to be used in oral care like toothpaste and hand wash care.

Time Kill Test by ASTM E 2315 03 (Re 2008 Test Inoculum used is:

1. E scherichia coli ATCC 1 1229

2. Staphylococcus aureus ATCC 6538

3. Pseudomonas aeruginosa ATCC 10145 4. Streptococcus mutans ATCC 25175

5. E nterococcus faecalis ATCC 29212

6. Candida albicans ATCC 10231

7. Candida tropicalis ATCC 13803

Test Conditions:

Test P roduct: Hand Wash as it is

Contact Time: 30 seconds, 60 seconds and 2 minutes

Contact Temperature: Room Temperature

Diluent / Neutralizer: Lecithin, Polysorbate 80, and S od. Thiosulphate, Histidine,

S aponin in

Phosphate buffer 0.0025 mol/l

Media and Reagent S oyabeancasein digest agar for bacteria

Incubation condition: 37 C

Test product was inoculated with test organisms individually (approximately 108 C F U/ ml). After the specified exposure time of 30 seconds, 60 seconds & 2 minutes surviving microorganisms were recovered by drawing an aliquot, neutralizing it and performing Standard Pour plate Technique. C ulture count was ascertained by dilution Blank. Adequate Validation of Neutralizing agent was also carried with both the test bacteria. Test was carried out in duplicate and average count was taken as C FU/ ml.

Table - 2

Test product hand wash with 0.1 % C HUA

Test Organism Expos Initial After Log Percentage ure Count exposure reduction reduction

Time C FU/ml

C FU/ml Log

E sch.Coli 30 3.5x10^b <10 <1 >4.53 >99.999 sees

Log=5.53

60 <10 <1 >4.53 >99.999 sees

2 mins <10 <1 >4.53 >99.999

Staph aureus 30 1.93x10 <10 <1 >4.28 >99.999 sees 60 Log=5.28 <10 <1 >4.28 >99.999 sees

2 mins <1 0 <1 >4.28 >99.999

Pseudo.aeruginosa 30 1 .80 <10 <1 >4.25 >99.999 sees x10⁵

60 Log=5.25 <10 <1 >4.25 >99.999 sees

2 mins <1 0 <1 >4.25 >99.999

S trepto.mutans 30 1 .78x10 <10 <1 >4.25 >99.999 sees

Log=5.25

60 <10 <1 >4.25 >99.999 sees

2 mins <1 0 <1 >4.22 >99.999

E ntero.faecalis 30 1 .27x10 <10 <1 >4.10 >99.999 sees

Log=5.10

60 <10 <1 >4.10 >99.999 sees

2 min <10 <1 >4.10 >99.999

Can.albicans 30 4.80x10⁴ <10 <1 >3.68 >99.99 sees

Log

60 =4.68 <10 <1 >3.68 >99.99 sees

2 min <10 <1 >3.68 >99.99

Can.Tropicalis 30 2.1 0x10 <10 <1 >4.32 >99.999

S ees

Log=5.32

60 <10 <1 >4.32 >99.999

S ees

2 min <10 <1 >4.32 >99.999

F ollowing F ormulae was used in computing test results:

Percentage R eduction of Microorganism = 100 (Initial ^" After E xposure)/ Initial

Log R eduction = Log Initial ^" Log after E xposure Handwash with 0.1 % C HUA has shown >99.999% reduction of E scherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa,

Streptococcus mutans, E nterococcus faecalis, Candida albicans and Candida tropicalis in 30 seconds when analysed as per ASTM E 2315 ^" 03 (Re. 2008) Method

Hand wash formulation using the chlorhexidine base complex

Table 3

A general preferred process but without limiting the scope of the invention is Add ingredients from (1 ) to (6) in one vessel add one by one. S lowly stirring the system. Premix P ropylene G lycol & Anti microbial agent (C HUA) and add it into system and stir it Then added the desired perfume, followed by addition of salt to the system to get the desired viscocity Stir the content and check the pH & if the desired pH is not attained add C itric acid to adjust the pH.. The product was tested for stability and it was found to be stable at 45°C for a minimum of one month. The efficacy of the disclosed C HUA molecule in had wash was compared with an Triclosan an antibacterial used widely in the market in the personal care and pharma formulation. Table- 4 shows the ingredients for hand wash with Triclosan The comparison as shown in Table -5

Table-4

Kill test were performed by both these formulation on both gram ^"ve and gram +ve bacterial.

Results of comparison between C HUA and Triclosan are shown in Table -5 .The tests were performed as per Manual of Microbiology Methods Table ^" 5

By above test result shows 0.1 % C hlorhexidine Undecylenate is more effectively working against microorganisms as compared to a higher required concentration of 0.3% Triclosan

The efficacy of the C HUA ingredient as an efficient and effective antimicrobial agent for both pharma and personal/oral care formulations have also been established .

Handwash with 0.1 % S alibact and Handwash with 0.2% S alibact have shown >99.999% reduction of E scherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus mutans, E nterococcus faecalis, Candida albicans and Candida tropicalis in 30 seconds when analysed as per ASTM E 2315 03 (Re. 2008) Method The initial studies and observation reveals that this ingredient is effective against both gm+ve,gram ^"ve ,yeast, molds and oral care bacteria and is also active against the protozoan and helminthes. CHUA of the present disclosure been used in oral care formulations as well as topical formulations like skin care and hair care. Some of the formulation made for the stability, efficacy and compatibility are shown as below.

on Deo with CHUA Formulati

Phases Ingredients INCI Name Percentage Functions

Eumulgin B2 C etea reth20 2.5 Emulsifier

GMS SE Glycero 1 Emulsifier/Emollient

Monostearate

A

Cetostearyl Cetostearyl 15 Emulsion stabilizer Alcohol Alcohol

Xia meter Cyclopentasil 3 E mollient PMX0245 oxane

Montanov L C1422 2 E mulsifier

Alcohols (and)

C1220 Alkyl

Glucoside

B Water Aqua Upto 100 Solvent

C Propylene Glycol Propylene 3 Humectent

Glycol

Salibact(CHUA) - 0.1 AntiBacterial

D Saliguard EHGP Ethylhexylglyc 0.8 Preservative

erin(and)Phen oxy etha nol

Perfume Fragrance 0.4 Fragrance

Procedure to prepare the Deodorant with CHUA is given below :

1) Add Phase A ingredients in one vessel one by one, heat it up to 80° C.

2) Heat Phase B vessel up to 80° C.

3) Add phase A into Phase B at same temperature (around 80° C) and stir both phase till the emulsion gets complete.

4) At the time of stirring add premix phase C.

5) When emulsion of temperature comes at room temperature add Phase D and give final Stirring to the productpH6.0

Formulation for Toothpaste Chalk base with CHUA

S.No Ingredients INC I name Percentage Functions

1 Carrageenan Carrageenan 0.6 Binding Agent

Gum Gum

2 S orbitol 70% S orbitol 17 Humectant soln.

3 Glycerin Glycerin 10 Humectant

4 Water Water Upto 100 Solvent

5 Sodium Sodium Benzoate 0.3 Preservative

Benzoate

6 Sodium Sodium Saccharin 0.2 Sweetner

Saccharin

7 Flavour Flavour 1 Flavour

8 Calcium Calcium 46 Polishing carbonateIP/BP carbonate Agent 9 CAPB Cocoamidopropyl 5 Surfactant Betaine

10 Propylene Propylene Glycol 3 Humectant

Glycol

11 CHUA - 0.1 Anti Bacterial

Process steps to prepare toothpaste chalk based powder are given below:

1) Disperse Carrgeenan gum in glycerin.

2) Add Sorbitol and water and mix.

3) Disperse Sodium Saccharin and Sodium Benzoate in above solution.

4) Add abrasive Calcium carbonate and mix.

5) Add Flavour, mix and deaerate.

6) Add Cocoamidopropyl betaine and mix, and then add premix CHUA and Propylene glycol.

7) Give final mixing to the product under vacuum.

Formulation for Toothpaste Gel with CHUA

S.No Ingredients INCI name Percentag Functions

e

1 Carrageenan gum Carrageenan gum 0.45 Binding Agent

2 S orbitol 70% S orbitol 67 Humectant

Soln.

3 Water Water Upto 100 Solvent

4 Sodium Benzoate Sodium Benzoate 0.5 Preservative

5 Sodium Saccharin Sodium Saccharin 0.2 Sweetener

6 Absil 100 Hydrated S ilica 11 Polishing

Agent

7 MfilP Hydrated S ilica 7 Polishing Agent

8 Flavour Flavour 1 Flavour

9 CAPB Cocoa midopropl 5 S urfactant betaine

10 Propylene Glycol Propylene Glycol 3 Humectant

11 CHUA - 0.1 Anti bacterial

12 Colour 1% Soln. Colour 0.02 Colour

Procedure to make Formulation for Toothpaste Gel is detailed below

1) Disperse Carrageenan gum in Sorbitol

2) Add water and mix.

3) Disperse Sodium benzoate and Sodium Saccharin in above solution.

4) Add abrasives Hydrated Silica, disperse and mix

5) Add flavor, mix and deaerate.

6) Add Cocoamidopropyl betaine and mix, and then add premix Salibactand Propylene Glycol.

Mixing is done undervacuum.

Claims

We claim

1. Synthesis of chlorhexidine based organic complex which comprises the steps of :

heating up slowly the mixture of rectified spirit and fatty acid having with C n in a temperature range of 20 to 50 o to get a clear solution, clear solution further being maintained under stirring for homogenization leading to complete solid precipitation and the mass cooled further to room temperature ,

solid precipitate being then filtered suck dry, to collect wet cake, the solid wet cake then dissolved in alcoholic or alkyi ,aryl solvent, ketonic solvent

the solution is heated to a temperature range of 40 to 80 degress preferably between 40 to 60 degrees and most preferable temperature 45 -500C,

the solution of wet cake in acetone charged with activated charcoal and heating up to reflux,

collecting mother liquor slowly and cooling down to room temp and chilled to about 4 to 6 degree for complete precipitation of the product, the wet cake after filtration was washed with chilled solvent preferably acetone,

squeeze out main mother liquor and collecting the wet cake followed by drying to get chlorhexidine based organic complex.

2. C hlorhexidine based organic complex of claim 1 wherein , preferred fatty acid is undecylenic acid.

3. C hlorhexidine based organic complex of claim 1 wherein alcoholic or alkyi ,aryl solvent are selected from a group of methanol, isopropanol or any low boiling alcoholic solvent.

4. C hlorhexidine based organic complex of claim 1 wherein ketonic solvent is selected from a group of methyl ethyl ketone, acteophenone , acetone, preferably low boiling alkyl ketones.

5. C hlorhexidine based organic complex of claim 1 wherein , C hlorhexidine based organic complex of claim 1 wherein , organic complex has negligible oral toxicity.

6. C hlorhexidine based organic complex of claim 1 wherein , organic

complex has negligible dermal toxicity .

7. C hlorhexidine based organic complex of claims 1 and 6 wherein , organic complex has antimicrobial efficacy for the hand wash.

8. C hlorhexidine based organic complex of claims 1 and 5 wherein , the organic complex is useful in oral health, dental care.

9. C hlorhexidine based organic complex of claim 1 wherein, the organic complex is useful in hair care, skin care formulations.

10. C hlorhexidine based organic complex of claims 1 and 9 wherein, hair care formulations comprise, hair oil, hair creams shampoo, a ntidandruff applications.

11. C hlorhexidine based organic complex of claims 1 ,6 and 9 wherein, skin care formulations comprise powders, sun screens, lotions, lipsticks and the like.

12. C hlorhexidine based organic complex of claim 1 wherein the organic complex is used in disinfectants in pharmaceutical disinfectant for instruments, hand washes.

13. C hlorhexidine based organic complex of claim 1 wherein the organic complex is used as antifungal and antifouling agent in Paints , coatings.

14. C hlorhexidine based organic complex of claim 1 wherein the organic complex has antimicrobial activity against gram positive, gram negative bacteria , yeast, mold, fungi.