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Category Anti-emetic; dopaminergic blocking agent.

          Domperidone contains not less than 99.0 per cent and not more than 101.0 per cent of C₂₂H₂₄ClN₅O₂, calculated on the dried basis.

Description White or almost white powder. 

Solubility Practically insoluble in water; soluble in dimethylformamide; slightly soluble in ethanol and in methanol.

Contra-indication

         1. It is contra-indicated in patients with a prolactinreleasing pituitary tumour (prolactinoma).

         2. It should not be used whenever stimulation of gastric motility is to be avoided or could be harmful, e.g. in the presence of gastro-intestinal hemorrhage, obstruction or perforation.

Warning

         1. It should be used with caution in patients with hepatic impairment.

         2. It may cause allergic reactions such as rash or urticaria, abdominal cramps, dystonic reactions (extrapyramidal phenomena), reversible raised serum prolactin levels which may lead to galactorrhea and gynecomastia, or hypertensive crises in patients with pheochromocytoma. Neurological side-effects may occur in young babies or in patients with impaired blood brain barrier.

         3. Caution should be exercised if it is to be used concomitantly with anticholinergic, antimuscarinic agents, opioid analgesics, CYP3A4 inhibitors (e.g., azole antifungals, macrolide antibiotics, HIV protease inhibitors and nefazodone) or MAO inhibitors.

         4. Risk-benefit should be considered if it is to be used in pregnant or nursing women.

Additional information

         1. As the drug interferes with serum prolactin levels, it may interfere with other hypoprolactinemic agents and with some diagnostic tests. 

         2. Antacids and antisecretory agents lower the oral bioavailability of domperidone. They should not be taken simultaneously with this medicine.

Packaging and storage Domperidone shall be kept in well-closed containers, protected from light.

Identification

         A. The infrared absorption spectrum is concordant with the spectrum obtained from Domperidone RS (Appendix 2.1) or with the reference spectrum of Domperidone

         B. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using suitable octadecylsilyl silica gel as the coating substance and a mixture of 20 volumes of ammonium acetate TS, 40 volumes of dioxane and 40 volumes of methanol as the mobile phase. Apply separately to the plate, 5 μl of each of the following solutions. For solution (A) dissolve 20 mg of the test substance in methanol and dilute to 10 ml with the same solvent. For solution (B) dissolve 20 mg of Domperidone RS in methanol and dilute to 10 ml with the same solvent. For solution (C) dissolve 20 mg of Domperidone RS and 20 mg of Droperidol RS in methanol and dilute to 10 ml with the same solvent. After removal of the plate, dry it for 15 minutes, expose it to iodine vapour until the spots appear and examine in daylight: the principal spot in the chromatogram obtained from solution (A) is similar in position and size to the principal spot in the chromatogram obtained from solution (B). The test is not valid unless the chromatogram obtained from solution (C) shows two clearly separated spots.

        C. Dissolve 5 mg of the test substance in 3 ml of methanol, add 2 drops of a solution containing 10 per cent w/v of cobalt(II) nitrate and 10 per cent w/v of calcium chloride, mix and add, with shaking, 2 drops of 2 M sodium hydroxide: a violet-blue colour and precipitate are produced.

Clarity of solution A 1.0 per cent w/v solution in dimethylformamide is clear (Appendix 4.1).

Loss on drying Not more than 0.5 per cent w/w after drying at 105º to constant weight (Appendix 4.15).

Heavy metals Not more than 20 ppm (Method II, Appendix 5.2). Use 1.0 g; for the Standard Preparation, use 2 ml of lead standard solution (10 ppm Pb).

Sulfated ash Not more than 0.1 per cent w/w (Appendix 5.3).

Related substances Carry out the test as described in the “High-pressure Liquid Chromatography” (Appendix 3.5). Prepare the solutions immediately before use. 

Mobile phase Mix 3 volumes of methanol and 7 volumes of a 0.5 per cent w/v solution of ammonium acetate.

Reference solution (a) Dissolve 10.0 mg of Domperidone RS and 15.0 mg of Droperidol RS in dimethylformamide and dilute to 100.0 ml with the same solvent.

Reference solution (b) Dilute 1.0 ml of Test solution to 100.0 ml with dimethylformamide. Dilute 5.0 ml of this solution to 20.0 ml with the same solvent.

Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (10 cm × 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (3 μm), (b) Mobile phase at a flow rate of 1.5 ml per minute, changing by linear gradient to methanol over 10 minutes, followed by elution with methanol for 2 minutes, and (c) an ultraviolet photometer set at 280 nm.

         Procedure Inject 10 μl of Reference solution (a). When the chromatogram is recorded in the prescribed conditions, the retention times are: domperidone, about 6.5 minutes and droperidol, about 7 minutes. The test is not valid unless the resolution between the peaks due to domperidone and droperidol is at least 2.0. If necessary, adjust the concentration of methanol in the mobile phase or adjust the time program for the linear gradient.

Separately inject equal volumes (about 10 μl) of dimethylformamide as a blank, Test solution and Reference solution (b).

         In the chromatogram obtained from Test solution: the area of any peak, apart from the principal peak, is not more than the area of the principal peak in the chromatogram obtained from Reference solution (b) (0.25 per cent); the sum of the areas of all peaks, apart from the principal peak, is not more than twice the area of the principal peak in the chromatogram obtained from Reference solution (b) (0.5 per cent). Disregard any peak in the chromatogram obtained from the blank run and any peak with an area less than 0.2 times that of the principal peak in the chromatogram obtained from Reference solution (b).

Assay Dissolve about 300 mg of Domperidone, accurately weighed, in 50 ml of a mixture of 1 volume of anhydrous glacial acetic acid and 7 volumes of 2-butanone. Titrate with 0.1 M perchloric acid VS until the colour changes from orange-yellow to green, using naphtholbenzein TS as indicator (Appendix 6.1). Performa blank determination, and make any necessary correction. Each ml of 0.1 M perchloric acid is equivalent to 42.59 mg of C₂₂H₂₄ClN₅O₂.