Nimodipine

C21H26N2O7                                                            Mol.Wt.418.4   

Nimodipine is 2-methoxyethyl 1-methylethyl (4RS)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Nimodipine contains not less than 98.5 per cent and not more than 101.5 per cent of C21H26N2O7, calculated on the dried basis.

Category. Calcium channel blocker.

Dose. Oral, 360 mg daily; intravenous, 1 mg per hour initially, increased to 2 mg per hour after 2 hour.

Description. A light yellow or yellow, crystalline powder. It shows polymorphism (2.5.11). Exposure to ultraviolet light leads to the formation of a nitrophenylpyridne derivative.

Identification  

Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained with nimodipine RS or with the reference spectrum of nimodipine. If the spectra obtained in the solid state show differences, dissolve the substance under examination and the reference substance separately in the 2.0 per cent w/v solution of methylene chloride and using 0.2 mm cell for recording new spectra.

Tests

NOTE: Prepare solutions immediately before use either protected from light or under long-wavelength light (> 420 nm).

Solution A.A 5.0 per cent w/v solution in acetone. 

Appearance of solution. Solution A is clear (2.4.1).

Specific optical rotation (2.4.22). -0.10º to +0.10º, determined in solution A.

Related substances. Determine by liquid chromatography (2.4.14).  

Test solution. Dissolve 40 mg of the substance under examination in 2.5 ml of tetrahydrofuran and dilute to 25.0 ml with the mobile phase.

Reference solution (a). Dilute 1.0 ml of the test solution to 100.0 ml with the mobile phase. Dilute 1.0 ml of this solution to 10.0 ml with the mobile phase.

Reference solution (b). Dissolve 8 mg of nimodipine for peak identification RS (containing impurity C) [bis(2-methoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] in 0.5 ml of tetrahydrofuran and dilute to 5.0 ml with the mobile phase.

Reference solution (c). Dilute 0.5 ml of the test solution to 25.0 ml with the mobile phase. Mix 0.5 ml of this solution with 0.5 ml of nimodipine impurity A RS [2-methoxyethyl 1-methylethyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate] and dilute to 10.0 ml with the mobile phase.

Chromatographic system

     –   a stainless steel column 12.5 cm x 4.6 mm, packed with octadecylsilane bonded to porous silica (5 µm),

    –    column temperature: 40º,

     –   mobile phase: a mixture of  20 volumes of methanol, 20 volumes of tetrahydrofuran and 60 volumes of water,

     –   flow rate: 2.0 ml per minute,

     –   spectrophotometer set at 235 nm,

     –   injection volume: 20 µl.

NOTE: Use the chromatogram supplied with nimodipine for peak identification RS and the chromatogram 

            obtained with reference solution (b) to identify the peak due to impurity C; use the chromatogram  

            obtained with reference solution (c) to identify the peak due to impurity A.

The relative retention time with reference to nimodipine (retention time about 7 minutes) for nimodipine impurity C is about 0.5 and for nimodipine impurity A is about 0.9.  

Inject reference solution (c). The test is not valid unless the peak to valley ratio is not less than 4.0, where Hp is the height above the baseline of the peak due to nimodipine  impurity A and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to nimodipine.

Inject reference solutions (a), (b) and the test solution. Run the chromatogram 4.5 times the retention time of the principal peak. In the chromatogram obtained with the test solution, the area of peak corresponding to nimodipine impurity C is not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent),  the area of any secondary peak is not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent). The sum of the areas of all the secondary peaks is not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5per cent). Ignore any peak with an area less than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).

Loss on drying (2.4.19). Not more than 0.5 per cent, determined on 1.0 g by drying in an oven at 105°.

Sulphated ash (2.3.18). Not more than 0.1 per cent, determined on 1.0 g.

Assay. Weigh accurately about 0.18 g and dissolve with gentle heating in a mixture of 25 ml of 2-methyl-2-propanol and 25 ml of perchloric acid solution. Add 0.1 ml of ferroin and titrate with 0.1 M cerium sulphate, determining the end-point potentiometrically (2.4.25). Carry out a blank titration.

1 ml of 0.1 M cerium sulphate is equivalent to 0.02092 g of C21H26N2O7.

Storage: Protected from light.

Solubility: Freely soluble in ethyl acetate, sparingly soluble in anhydrous ethanol, practically insoluble in water.