(Ph. Eur. 11.6 update)
DEFINITION
Glyceryl Trinitrate Sublingual Spray contains Glyceryl Trinitrate Solution in a suitable vehicle either in a suitable
pressurised container or in a container fitted with a spray device.
PRODUCTION
A suitable test is carried out to demonstrate the uniformity of dose.
The oromucosal spray complies with the requirements stated under Oromucosal Preparations and with the following requirements.
Content of glyceryl trinitrate, C3H5N3O9
80.0 to 120.0% of the amount stated to be delivered per metered dose.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using a TLC silica gel plate (Merck silica gel plates are suitable) and a mixture of 20 volumes of ethyl acetate and 80 volumes of toluene as the mobile phase. Apply. separately to the plate 5 μL of each of the following solutions. For solution (1) expel a number of metered doses containing the equivalent of about 4 mg of glyceryl trinitrate into a beaker, add 5 mL of acetone, transfer to a graduated flask and add sufficient acetone to produce 10 mL. For solution (2) dilute a quantity of glyceryl trinitrate solution BPCRS with methanol (50%) to produce a solution containing 0.04% w/v of glyceryl trinitrate. Solution (3) is a mixture of equal volumes of solutions (1) and (2). After removal of the plate, allow it to dry in air and spray with freshly prepared potassium iodide and starch solution. Expose the plate to ultraviolet light (254 nm) for 15 minutes and examine in daylight. The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2). The principal spot in the chromatogram obtained with solution (3) appears as a single compact spot.
B. In the Assay, the chromatogram obtained with solution (1) shows a peak with the same retention time as the principal
peak in the chromatogram obtained with solution (2).
TESTS
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) expel a number of metered doses containing the equivalent of about 5 mg of glyceryl trinitrate into a beaker, dilute to 5 mL with methanol, mix well and add sufficient water to produce 10 mL. For solution (2) dilute 1 volume of solution (1) to 100 volumes with methanol (50%). For solution (3) dilute a quantity of glyceryl trinitrate solution BPCRS with sufficient 1M hydrochloric acid to produce a solution containing 0.05% w/v of glyceryl trinitrate and heat in a reaction vial at 100° for 30 minutes.
The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Nucleosil C18 is suitable), (b) as the mobile phase with a flow rate of 1.0 mL per minute a mixture of 50 volumes of acetonitrile and 50 volumes of water and (c) a detection wavelength of 210 nm.
The test is not valid unless the chromatogram obtained with solution (3) resembles the reference chromatogram supplied with glyceryl trinitrate solution BPCRS in that it shows a principal peak due to glyceryl trinitrate and two clearly separated peaks due to the dinitrate impurities with retention times relative to glyceryl trinitrate of approximately 0.5.
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) (1%) and the sum of areas of any secondary peaks is not greater than three times the area of the principal peak in the chromatogram obtained with solution (2) (3%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) collect 10 metered doses in a vessel avoiding loss of material, dissolve the expelled material in methanol and dilute with sufficient methanol to produce a solution containing the equivalent of 0.04% w/v of glyceryl trinitrate. For solution (2) dilute a quantity of glyceryl trinitrate solution BPCRS with sufficient methanol (50%) to produce a solution containing 0.04% w/v of
glyceryl trinitrate.
The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Nucleosil C18 is suitable), (b) as the mobile phase with a flow rate o 1.3 mL per minute a mixture of 50 volumes of methanol and 50 volumes of water and (c) a detection wavelength of 225 nm.
Calculate the content of C3H5N3O9 per metered dose using the declared content of C3H5N3O9 in glyceryl trinitrate solution BPCRS.
