- British Pharmacopoeia Volume III
- Formulated Preparations: Specific Monographs
Clozapine Oral Suspension |
Dopamine D4 receptor antagonist; neuroleptic.
Clozapine Oral Suspension is a suspension of Clozapine in a suitable flavoured vehicle.
The oral suspension complies with the requirements stated under Oral Liquids and with the following requirements.
95.0 to 105.0% of the stated amount.
Shake the oral suspension vigorously before carrying out the following tests.
A. Shake a quantity of the oral suspension containing 100 mg of Clozapine with 20 mL of dichloromethane for 15 minutes, filter (Whatman GF/C is suitable) and evaporate the filtrate to dryness under a stream of nitrogen. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of clozapine (RS 444).
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).
pH, 4.0 to 6.0, Appendix V L.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the oral suspension containing 80 mg of Clozapine with 80 mL of methanol for 20 minutes, dilute to 100 mL with water and filter (Whatman GF/C is suitable followed by a 0.45-μm nylon filter).
(2) Dilute 1 volume of solution (1) to 10 volumes with methanol (80%) . Dilute 1 volume of this solution to 100 volumes with methanol (80%) .
(3) Dissolve the contents of a vial of clozapine for peak identification EPCRS in 1.0 mL of methanol (80%).
(4) Dilute 1 volume of solution (2) to 2 volumes with a mixture of 20 volumes of methanol (80%).
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 µm) (Phenomenex Luna C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 257 nm.
(f) Inject 20 µL of each solution.
Mobile phase A 25 volumes of methanol and 75 volumes of a solution prepared by dissolving 2.04 g of potassium dihydrogen orthophosphate in 1000 mL of water and adjusting the pH to 2.0 with dilute orthophosphoric acid (solution A).
Mobile phase B 15 volumes of solution A and 85 volumes of methanol.
The test is not valid unless:
in the chromatogram obtained with solution (3), the resolution factor between the peaks due to clozapine and impurity C is at least 2.5;
the chromatogram obtained with solution (3) closely resembles the reference chromatogram supplied with clozapine for peak identification EPCRS.
Identify any peaks in the chromatogram obtained with solution (1) corresponding to impurities A, B, C and D using solution (3). Multiply the area of any peak due to impurity D by the following correction factor: 2.7.
In the chromatogram obtained with solution (1):
the areas of any peaks corresponding to impurities A, B and D are not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2% of each);
the area of any peak corresponding to impurity C is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (0.3%);
the area of any other secondary peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of all the secondary peaks is not greater than 6 times the area of the principal peak in the chromatogram obtained with solution (2) (0.6%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.05%).
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Add 180 mL of ethanol (96%) to a weighed quantity of the oral suspension containing 20 mg of Clozapine, shake for 15 minutes and mix with the aid of ultrasound for 15 minutes. Add sufficient ethanol (96%) to produce 200 mL and mix; filter the final solution, if necessary, discarding the first 10 mL of filtrate.
(2) Add 90 mL of ethanol (96%) to 20 mg of clozapine BPCRS and shake for 15 minutes; mix with the aid of ultrasound for a further 15 minutes and add sufficient ethanol (96%) to produce 200 mL.
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped base-deactivated octadecylsilyl silica gel for chromatography (5 µm) (Hypersil BDS is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 µL of each solution.
33 volumes of a 1.36% w/v solution of sodium acetate, adjusted to pH 5.5 with glacial acetic acid, and 67 volumes of methanol.
Determine the weight per mL of the oral suspension, Appendix V G, and calculate the content of C18H19ClN4, weight in volume, using the declared content of C18H19ClN4 in clozapine BPCRS.
Clozapine Oral Suspension should be protected from light.