Edition: BP 2025 (Ph. Eur. 11.6 update)
NOTE: This monograph has been developed to cover unlicensed formulations.
Action and use
Anaesthetic; treatment of chronic pain.
DEFINITION
Ketamine Nasal Spray is an aqueous solution of Ketamine Hydrochloride in a suitable container fitted with an appropriate nasal delivery system.
The nasal spray complies with the requirements stated under Nasal Preparations and with the following requirements.
Where appropriate, the nasal spray also complies with the requirements stated under Unlicensed Medicines.
Content of ketamine, C13H16ClNO
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Dilute a quantity of the nasal spray with a mixture of 1 volume of 1M sodium hydroxide and 49 volumes of methanol to produce a solution containing the equivalent of 0.1% w/v of ketamine. The light absorption, Appendix II B, in the range 230 to 350 nm of this solution exhibits a maximum at 301 nm and shoulders at 274, 268 and 261 nm.
B. Dilute a quantity of the nasal spray with 0.1M hydrochloric acid to produce a solution containing the equivalent of 0.025% w/v of ketamine. The light absorption, Appendix II B, in the range 230 to 350 nm of this solution exhibits two maxima at 276 nm and at 269 nm and a shoulder at 260 nm.
C. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
D. Complies with the test for Specific optical rotation.
TESTS
Acidity
pH, 3.5 to 5.5, Appendix V L.
Specific optical rotation
Dilute a quantity of the nasal spray with carbon dioxide-free water to produce a solution containing the equivalent of 2% w/v of ketamine. The specific optical rotation is -0.2 to +0.2, Appendix V F.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in the mobile phase.
(1) Dilute a quantity of the nasal spray, if necessary, to produce a solution containing the equivalent of 0.1% w/v of ketamine.
(2) Dilute 1 volume of solution (1) to 200 volumes.
(3) Dilute 1 volume of solution (2) to 2 volumes.
(4) Add 2 volumes of a 0.05% w/v solution of ketamine impurity A EPCRS in methanol to 1 volume of solution (1) and dilute the resulting solution to 100 volumes with the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Kromasil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 215 nm.
(f) Inject 20 μL of each solution.
(g) Allow the chromatography to proceed for 10 times the retention time of ketamine.
When the chromatograms are recorded under the prescribed conditions, the retention time of ketamine is about 5 to 6 minutes and the relative retention of the peak due to impurity A is about 1.6.
MOBILE PHASE
25 volumes of acetonitrile R1 and 75 volumes of a 0.1% w/v solution of sodium hexanesulfonate containing 0.05% w/v of glacial acetic acid.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to ketamine and ketamine impurity A is at least 1.5.
LIMITS
In the chromatogram obtained with solution (1):
the area of any secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%); not more than one such peak has an area greater than the area of the principal peak in the chromatogram obtained with solution (3) (0.25%);
the sum of the areas of all the secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (1.0%).
Disregard any peak with an area less than 0.4 times the area of the principal peak in the chromatogram obtained with solution (3) (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in water.
(1) Dilute the nasal spray, if necessary, to produce a solution containing the equivalent of 0.005% w/v of ketamine.
(2) 0.005% w/v of ketamine hydrochloride BPCRS.
(3) Mix equal volumes of a 0.0025% w/v solution of ketamine hydrochloride BPCRS in water and a 0.0025% w/v solution of ketamine impurity A EPCRS in methanol.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Kromasil 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 220 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
35 volumes of methanol and 65 volumes of a 0.575% w/v solution of ammonium dihydrogen orthophosphate adjusted to pH 3.0 using orthophosphoric acid.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to ketamine and ketamine impurity A is at least 2.0.
DETERMINATION OF CONTENT
Calculate the content of C13H16ClNO in the nasal spray using the declared content of C13H16ClNO in ketamine hydrochloride BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include impurity A listed under Ketamine Hydrochloride.
STORAGE
Ketamine Nasal Spray should be protected from light.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of ketamine.
