Lidocaine

Chemical Names
2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide 2-Diethylamino-2,6-acetoxylidide

Other Names
Lignocaine, Xylocaine Form Lidocaine Lidocaine hydrochloride Molecular Formula C14H22N2O C14H22N2O.HCl.H2O MW 234.3 288.8 CAS 137-58-6 6108-05-0

Appearance
Lidocaine is a white to slightly yellow crystalline powder. Lidocaine hydrochloride is a white odorless crystalline powder.

Solubility
Lidocaine is practically insoluble in water; it is very soluble in alcohol, chloroform, and methylene chloride. It is freely soluble in ether. Lidocaine hydrochloride is very soluble in water and alcohol and soluble in chloroform, but it is insoluble in ether.

pKa
Lidocaine hydrochloride has a pKa of 7.86.

Method 1
Gebauer et al. developed a method for the study of lidocaine and oxycodone stability in a rectal gel. The HPLC instrument consisted of a Waters model 510 pump, a model W717 autoinjector, and a model 996 photodiode-array detector and was managed by Waters Millenium 32 software. The stationary phase was a Hewlett-Packard Zorbax SB-C8 reversed-phase column (250 4.6 mm, 5-m particle size). The mobile phase was a mixture of 350 mL of methanol, 150 mL of water, 10 mL of acetic acid, and 1.60 g of sodium dodecyl sulfate. The flow rate was 1.5 mL/min. The eluant was monitored by a photodiode-array detector from 250 to 300 nm. A chromatogram was extracted from the contour plot at 264 nm for lidocaine. A 0.5-mL sample of the gel was placed in a disposable filtration tube and centrifuged at 2600 g for 30

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min at 10 C. The filtrate was collected and assayed. Under these conditions, retention times for the preservative methyl 4-hydroxybenzoate and for oxycodone and lidocaine were about 2.8, 5.1, and 8.0 minutes, respectively. The method was demonstrated to be stability indicating by intentional degradation of lidocaine. Aqueous solutions of lidocaine hydrochloride were heated to dryness or mixed with hydrogen peroxide. The peak of the intact lidocaine hydrochloride was resolved from its degradation product peaks on the chromatogram. A calibration curve for lidocaine was constructed in the concentration range from 0.1 to 5.0% (wt/wt). The correlation coefficient was greater than 0.998. The interday coefficient of variation for the analysis was 3.0%. Reference Gebauer M G, McClure A F, Vlahakis T L. Stability indicating HPLC method for the estimation of oxycodone and lidocaine in rectal gel. Int J Pharm. 2001; 223: 4954.

Method 2
Wilson and Forde determined the stability of lidocaine hydrochloride using an HPLC method. The liquid chromatograph consisted of a Varian model 5000 pump and an autosampler, a Waters model 441 UV detector, a Fisher Scientific model 5000 stripchart recorder, and a Hewlett-Packard model 3354 laboratory automation system. The stationary phase was a Whatman PXS ODS-3 stainless steel column (250 4.6 mm, 10-m particle size). The mobile phase consisted of 5% acetic acid in water adjusted to pH 3.0 with 1 N sodium hydroxide and acetonitrile (800:200, vol/vol). The flow rate was 2.0 mL/min. UV detection was performed at 254 nm and 0.1 AUFS. Samples were diluted to about 0.8 mg/mL with a mixture of water, methanol, and 0.5 M sodium borate (pH 7.0) (650:350:20, vol/vol/vol). The injection volume was 20 L. Retention times for milrinone and lidocaine were about 3 and 5 minutes, respectively. The method was stated to be stability indicating. A standard curve for lidocaine was constructed from 0 to 7.668 mg/mL. Reference Wilson T D, Forde M D. Stability of milrinone and epinephrine, atropine sulfate, lidocaine hydrochloride, or morphine sulfate injection. Am J Hosp Pharm. 1990; 47: 25047.

Method 3
Gupta and Stewart investigated the stabilities of lidocaine hydrochloride and phenylephrine hydrochloride in combination in the most commonly used concentrations. A Waters ALC 202 high-pressure liquid chromatograph was equipped with a Kratos SF 770 multiple-wavelength detector, a Houston Omniscribe recorder, and a Waters Bondapak C18 nonpolar column (300 3.9 mm). The mobile phase was an aqueous solution of 54% (vol/vol) acetonitrile containing 0.01 M monobasic potassium phosphate, adjusted to pH 7.05 0.05 with phosphoric acid. The flow rate was 2.0 mL/min.

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UV detection was performed at 261 nm and 0.04 AUFS. An aqueous solution of verapamil hydrochloride 0.16% was used as the internal standard. Samples were diluted with water. The injection volume was 20 L. The retention time for lidocaine was about 3.3 minutes (estimated from the published chromatogram). The analytical method was stated to be stability indicating. Reference Gupta V D, Stewart K R. Chemical stabilities of lignocaine hydrochloride and phenylephrine hydrochloride in aqueous solution. J Clin Hosp Pharm. 1986; 11: 44952.

Method 4
Waraszkiewicz et al. developed a stability-indicating HPLC method for analysis of lidocaine hydrochloride and lidocaine hydrochloride with epinephrine injectable solutions. A Waters model ALC/GPC 204 liquid chromatograph was equipped with a Waters model U6K septumless injector, a Waters model 440 dual-channel fixed-wave-length UV detector, and a Waters Bondapak CN column (300 4 mm, 10-m particle size). The mobile phase consisted of 0.01 M 1-octanesulfonic acid sodium salt, 0.1 mM edetate disodium, 2% (vol/vol) acetic acid, 2% (vol/vol) acetonitrile, and 1% (vol/vol) methanol in high-quality distilled water. The flow rate was 2.0 mL/min. UV detection was performed at 254 nm. The sample injection volume was 2 L. Under these conditions, the retention time for lidocaine was 6.8 minutes. The assay was determined to be stability indicating. Samples of lidocaine hydrochloride were spiked with the potential degradation products and chromatographed. Other samples of lidocaine with epinephrine were subjected to various conditions of stress such as autoclaving for 5, 10, and 20 cycles, storage for 1 month at 80 and 110 C, exposure to atmospheric oxygen, addition of 12 ppm of aluminum, and an increase in the pH of the solution. Degradation products did not interfere with the analysis of the intact lidocaine. These along with other compounds follow, with their retention times in parentheses in minutes: epinephrine sulfonic acid (1.8), adrenochrome (2.2), epinephrine (3.0), p-hydroxybenzoic acid (3.2), methylparaben (4.4), and 2,6-xylidine (5.0). Standard curves were constructed from 5 to 20 mg/mL. Correlation coefficients were greater than 0.99. Reference Waraszkiewicz S M, Milano E A, DiRubio R. Stability-indicating high-performance liquid chromatographic analysis of lidocaine hydrochloride and lidocaine hydrochloride with epinephrine injectable solutions. J Pharm Sci. 1981; 70: 12158.

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