(Ph. Eur. 11.6 update)
Action and use
Local anaesthetic; class I antiarrhythmic and antiseptic.
DEFINITION
Lidocaine and Chlorhexidine Gel is a sterile solution of Lidocaine Hydrochloride Monohydrate containing 0.25% v/v of Chlorhexidine Gluconate Solution in a suitable water-miscible basis.
The gel complies with the requirements stated under Topical Semi-solid Preparations and with the following requirements.
Content of anhydrous lidocaine hydrochloride, C14H22N2O,HCl
95.0 to 105.0% of the stated amount.
Content of chlorhexidine gluconate solution
0.225 to 0.275% v/v.
IDENTIFICATION
To a quantity of the gel containing the equivalent of 80 mg of anhydrous lidocaine hydrochloride add 4 mL of hydrochloric acid and heat on a water bath for 10 minutes.
Allow to cool, transfer to a separating funnel with the aid of 20 mL of water, add 5M sodium hydroxide until precipitation is complete and extract with two 20-mL quantities of chloroform. Filter the chloroform extracts through anhydrous sodium sulfate and evaporate the filtrate to dryness on a water bath using a current of nitrogen. The residue complies with tests A, B and C.
A. The infrared absorption spectrum, Appendix II A, is concordant with the reference spectrum of lidocaine (RS 202).
B. Dissolve 20 mg in 1 mL of ethanol (96%), add 0.5 mL of a 10% w/v solution of cobalt(II) chloride and 0.5 mL of 5M sodium hydroxide and shake for 2 minutes. A bluish-green precipitate is produced.
C. Dissolve 40 mg in 5 mL of a 1% w/v solution of cetrimide and add 1 mL of 5M sodium hydroxide and 1 mL of bromine water. An orange colour is produced.
D. In the Assay for chlorhexidine gluconate solution, the chromatogram obtained with solution (2) shows a peak with the same retention time as the peak due to chlorhexidine acetate in the chromatogram obtained with solution (1).
TESTS
Aromatic amines
Not more than 8 ppm of 2,6-dimethylaniline and not more than 1.5 ppm of 4-chloroaniline when determined in the following manner.
Carry out the method for gas chromatography, Appendix III B, using the following solutions.
(1) Shake 0.2 g of the gel with 20 mL of a mixture of 20 volumes of ether and 80 volumes of hexane and 5 mL of a buffer solution prepared by adjusting the pH of 0.1M sodium citrate to 5.0 with 0.2M sodium hydroxide, allow to separate and discard the aqueous layer. Shake the organic layer with anhydrous sodium sulfate and filter through silica-treated filter paper (Whatman 1PS is suitable), add 100 μL of heptafluorobutyric anhydride and shake for 30 seconds. Allow the solution to stand for 2 minutes, add 5 mL of 0.6M sodium hydrogen carbonate solution, shake, allow to separate and use the upper layer.
(2) Dissolve 80 mg of 2,6-dimethylaniline in 1 mL of 1M hydrochloric acid with the aid of ultrasound, add sufficient water to produce 100 mL, dilute 1 volume of this solution to 50 volumes with 0.01M hydrochloric acid and further dilute 1 volume to 20 volumes with the same solvent. Shake 2 mL of this solution with 20 mL of a mixture of 20 volumes of ether and 80 volumes of hexane and 5 mL of 0.6M sodium hydrogen carbonate solution and continue in the same manner as for solution (1) beginning at the words ‘allow to separate …’.
(3) Dissolve 30 mg of 4-chloroaniline in 1 mL of 1M hydrochloric acid with the aid of ultrasound, add sufficient water to produce 200 mL and dilute 1 volume to 50 volumes with the same solvent; further dilute 1 volume to 20 volumes with the same solvent. Shake 2 mL of this solution with 20 mL of a mixture of 20 volumes of ether and 80 volumes of hexane and 5 mL of 0.6M sodium hydrogen carbonate solution and continue in the same manner as for solution (1) beginning at the words ‘allow to separate …’.
CHROMATOGRAPHIC CONDITIONS
(a) Use a glass column (1.5 m × 4 mm) packed with acid-washed, silanised diatomaceous support (100 to 120 mesh) coated with 15% w/w of cyanopropylmethylphenyl methyl silicone fluid (OV-225 is suitable).
(b) Use nitrogen as the carrier gas at a flow rate of 50 mL per minute.
(c) Use isothermal conditions maintained at 190°.
(d) Use an inlet temperature of 200°.
(e) Use an electron capture detector at a temperature of 270°.
(f) Inject 1 μL of each solution.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to 2,6-dimethylaniline is not greater than the area of the principal peak in the chromatogram obtained with solution (2);
the area of any peak corresponding to 4-chloroaniline is not greater than the area of the principal peak in the chromatogram obtained with solution (3).
Sterility
Complies with the test for sterility, Appendix XVI A.
ASSAY
For anhydrous lidocaine hydrochloride
Disperse a quantity containing the equivalent of 10 mg of anhydrous lidocaine hydrochloride in 20 mL of water. Add 5 mL of acetate buffer pH 2.8, 120 mL of chloroform and 5 mL of dimethyl yellow and oracet blue 2R solution and titrate with 0.005M dioctyl sodium sulfosuccinate VS, swirling vigorously. Near the end point add the titrant dropwise and, after each addition, swirl vigorously, allow to separate and swirl gently for 5 seconds. The end point is indicated when the colour of the chloroform layer changes from green to pinkish-grey. Repeat the operation without the preparation being examined. The difference between the titrations represents the amount of dioctyl sodium sulfosuccinate required. Each mL of 0.005M dioctyl sodium sulfosuccinate VS is equivalent to 1.354 mg of C14H22N2O,HCl Determine the weight per mL of the gel, Appendix V G, and calculate the percentage of C14H22N2O,HCl, weight in volume.
For chlorhexidine gluconate solution
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Add 5 mL of a 0.080% w/v solution of diphenylamine (internal standard) in the mobile phase to 5 mL of a 0.070% w/v solution of chlorhexidine acetate BPCRS in the mobile phase and dilute to 100 mL with the mobile phase.
(2) Mix 10 g of the gel with sufficient of the mobile phase to produce 100 mL.
(3) Prepare solution (3) in the same manner as solution (2) but adding 5 mL of the internal standard solution before diluting to 100 mL.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (20 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (10 μm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
0.01M sodium octanesulfonate in methanol (73%) adjusted to pH 3.0 with glacial acetic acid
DETERMINATION OF CONTENT
Calculate the content of C22H30Cl2N10,2C6H12O7 from the declared content of C22H30Cl2N10 in chlorhexidine acetate BPCRS. Each mg of C22H30Cl2N10 is equivalent to 1.776 mg of C22H30Cl2N10,2C6H12O7. Determine the weight per mL of the gel, Appendix V G, and express the result as the percentage volume in volume of Chlorhexidine Gluconate Solution, which contains 20% w/v of C22H30Cl2N10,2C6H12O7
LABELLING
The quantity of Lidocaine Hydrochloride is stated in terms of the equivalent amount of anhydrous lidocaine hydrochloride.
