Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Osmotic laxative.
DEFINITION
Lactulose Oral Powder consists of Lactulose with or without lesser amounts of other sugars including lactose and galactose.
The oral powder complies with the requirements stated under Oral Powders and with the following requirements.
Content of lactulose, C12H22O11
95.0 to 102.0%.
Dissolve 3 g in carbon dioxide-free water and dilute to 50 mL with the same solvent (solution S).
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using silica gel G as the coating substance and a mixture of 10 volumes of glacial acetic acid, 15 volumes of a 5% w/v solution of boric acid, 20 volumes of methanol and 55 volumes of ethyl acetate as the mobile phase. Apply separately to the plate 2 μL of each of the following solutions. For solution (1) dissolve 50 mg of the oral powder in water and dilute to 10 mL with the same solvent. For solution (2) dissolve 50 mg of lactulose BPCRS in water and dilute to 10 mL with the same solvent. After removal of the plate, dry it at 100° to 105° for 5 minutes and allow to cool. Spray the plate with a 0.1% w/v solution of 1,3-dihydroxynaphthalene in a mixture of 10 volumes of sulfuric acid and 90 volumes of methanol. Heat the plate at 110° for 5 minutes. The principal spot in the chromatogram obtained with solution (1) is similar in position, colour and size to the principal spot in the chromatogram obtained with solution (2).
B. In the Assay, the principal peak in the chromatogram obtained with solution (1) is similar in position and size to the principal peak in the chromatogram obtained with solution (3).
C. Dissolve 0.05 g in 10 mL of water. Add 3 mL of cupri-tartaric solution and heat. A red precipitate is formed.
D. Dissolve 0.125 g in 5 mL of water. Add 5 mL of ammonia. Heat on a water bath at 80° for 10 minutes. A red colour develops.
E. Complies with the test for Specific optical rotation.
TESTS
Clarity and colour of solution
Solution S is clear, Appendix IV A, and not more intensely coloured than reference solution BY5, Appendix IV B, Method II.
pH
To 10 mL of solution S add 0.1 mL of a saturated solution of potassium chloride. The pH of the solution is 3.0 to 7.0, Appendix V L.
Specific optical rotation
Dissolve 1.25 g in water, add 0.2 mL of 13. 5M ammonia and dilute to 25 mL with water. The specific optical rotation is – 46.0° to –50.0°, Appendix V G.
Related substances
In the Assay, in the chromatogram obtained with solution (1), the sum of the areas of any peaks corresponding to the principal peaks in the chromatograms obtained with solutions 5, 6, 7, 8 and 9 respectively (galactose, lactose, epilactose, tagatose and fructose) is not greater than the area of the peak corresponding to lactulose in the chromatogram obtained with solution (2) (3%).
Methanol
Carry out the method for head-space gas chromatography, Appendix III B, Method II. Mix 0.5 mL of propan-1-ol with 100 mL of water. Dilute 1 mL to 100 mL with water. Dilute 5 mL to 50 mL with water (internal standard solution). For solution (1) add 1 mL of the internal standard solution and 5 μL of a 0.1% v/v solution of methanol to 79 mg of the oral powder in a 20 mL vial. For solution (2) add 5 μL of a 0.1% v/v solution of methanol to 1 mL of the internal standard solution in a 20 mL vial.
The chromatographic procedure may be carried out using (a) a column (2 m × 2 mm) packed with ethylvinylbenzene– divinylbenzene co-polymer (180 μm), (b) helium for chromatography as the carrier gas at a flow rate of 30 mL per minute and (c) a flame-ionisation detector, maintaining the temperature of the column at 140°, that of the injection port at 200° and that of the detector at 220°. Maintain each solution at 60° for 1 hour, pressurise for 1 minute and transfer onto the column 1 mL of the gaseous phase.
In the chromatogram obtained with solution (1), the ratio of the area of the methanol peak to that of the internal standard peak is not greater than twice the corresponding ratio for the chromatogram obtained with solution (2) (50 ppm, calculated assuming the density of methanol to be 0.79 g/mL at 20°).
Boron
Avoid where possible the use of glassware. Prepare a reference solution as follows. Dissolve 50 mg of boric acid in water and dilute to 100 mL with the same solvent. Dilute 5 mL of this solution to 100 mL with water. Keep in a well-closed polyethylene container. In four polyethylene 25 mL flasks, place 0.50 g of the oral powder dissolved in 2 mL of water (solution A), 0.50 g of the oral powder dissolved in 1 mL of the reference solution and 1 mL of water (solution B), 1 mL of the reference solution and 1 mL of water (solution C) and 2 mL of water (solution D). To each flask, add 4 mL of acetate- edetate buffer solution pH 5.5. Mix and add 4 mL of freshly prepared azomethine H solution. Mix and allow to stand for 1 hour. Measure the absorbance, Appendix II B, of solutions A, B and C at 420 nm, using solution D as the compensation liquid. The test is not valid unless the absorbance of solution C is at least 0.25. The absorbance of solution B is not less than twice that of solution A (9 ppm of boron).
Lead
Complies with the limit test for lead in sugars, Appendix VII (0.5 ppm).
Water
Not more than 2.5%, Appendix IX C, Method I. Use 0.5 g.
Sulfated ash
Not more than 0.1%, Appendix IX A, Method II. Use 1 g.
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) dissolve 1 g of the oral powder in 10 mL of water, add 12.5 mL of acetonitrile with gentle heating and dilute to 25 mL with water. For solution (2) add 47.5 mL of acetonitrile to 3 mL of solution (1) with gentle heating and dilute to 100 mL with water. For solution (3) dissolve 1 g of lactulose BPCRS in 10 mL of water, add 12.5 mL of acetonitrile with gentle heating and dilute to 25 mL with water. For solution (4) dissolve 20 mg of lactulose BPCRS and 20 mg of epilactose EPCRS in 2 mL of water, add 2.5 mL of acetonitrile with gentle heating and dilute to 5 mL with water. For solution (5) dissolve 0.2 g of galactose in 20 mL of water, add 25 mL of acetonitrile with gentle heating and dilute to 50 mL with water. For solution (6) dissolve 0.2 g of lactose in 20 mL of water, add 25 mL of acetonitrile with gentle heating and dilute to 50 mL with water. For solution (7) dissolve 20 mg of epilactose EPCRS in 2 mL of water, add 2.5 mL of acetonitrile with gentle heating and dilute to 5 mL with water. For solution (8) dissolve 0.2 g of tagatose in 20 mL of water, add 25 mL of acetonitrile with gentle heating and dilute to 50 mL with water. For solution (9) dissolve 0.2 g of fructose in 20 mL of water, add 25 mL of acetonitrile with gentle heating and dilute to 50 mL with water.
The chromatographic procedure may be carried out using (a) a stainless steel column (5 cm × 4.6 mm) followed by a stainless steel column (15 cm × 4.6 mm), both packed with aminopropylsilyl silica gel for chromatography (3 μm) and maintained at 37° to 39°, (b) as mobile phase with a flow rate of 1.0 mL per minute a mixture prepared as follows: dissolve 0.253 g of sodium dihydrogen orthophosphate in 220 mL of water and add 780 mL of acetonitrile, and (c) as detector a refractometer maintained at a constant temperature.
When the chromatograms are recorded in the prescribed conditions, the retention time of lactulose is about 18.3 minutes and retention times relative to lactulose are about 0.38 for tagatose, 0.42 for fructose, 0.57 for galactose, 0.90 for epilactose and 1.17 for lactose.
Inject 20 μL of solution (4). The test is not valid unless the resolution factor between the peaks corresponding to lactulose and epilactose is at least 1.3. If necessary, adjust the concentration of acetonitrile in the mobile phase to between 75.0% and 82.0% v/v to achieve the prescribed resolution.
Inject separately 20 μL of solution (1) and 20 μL of solution (3) and continue the chromatography for 2.5 times the retention time of lactulose. Calculate the percentage content of C12H22O11 (lactulose) from the areas of the peaks and from the declared content of C12H22O11 in lactulose BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed in the monograph for Lactulose.
