Mesalazine Prolonged-release Granules from different manufacturers, whilst complying with the requirements of the monograph, are not interchangeable unless otherwise justified and authorised.
Action and use
Aminosalicylate; treatment of ulcerative colitis.
DEFINITION
Mesalazine Prolonged-release Granules contain Mesalazine. They are formulated so that the medicament is released over a period of several hours.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the appropriate release of Mesalazine. The dissolution profile reflects the in vivo performance which in turn is compatible with the dosage schedule recommended by the manufacturer.
The granules comply with the requirements stated under Granules and with the following requirements.
Content of mesalazine, C7H7NO3
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Boil a quantity of the powdered granules containing 1.0 g of Mesalazine with 50 mL of water for 1 minute and filter the hot supernatant fluid. Cool the solution to room temperature, allow to stand, filter and dry the crystals at 110°. The infrared absorption spectrum of the crystals, Appendix II A, is concordant with the reference spectrum of mesalazine (RS 454).
TESTS
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use.
(1) Mix for 10 minutes with the aid of ultrasound a quantity of the powdered granules containing 50 mg of Mesalazine in 30 mL of 0.01M hydrochloric acid, add sufficient 0.01M hydrochloric acid to produce 50 mL, mix using a vortex mixer and filter through a 0.45-μm membrane filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with 0.1M hydrochloric acid. Dilute 1 volume of the resulting solution to 10 volumes with 0.1M hydrochloric acid.
(3) 0.1% w/v of mesalazine for system suitability EPCRS in 0.01M hydrochloric acid.
(4) 0.0001% w/v each of 4-aminosalicylic acid (impurity E), 2,5-dihydroxybenzoic acid (impurity G), 2-chlorobenzoic acid (impurity L), 2-chloro-5-nitrobenzoic acid (impurity M), 5-nitrosalicylic acid (impurity N), sulfanilic acid (impurity O), 3- nitrosalicylic acid (impurity R) and 0.0003% w/v of salicylic acid (impurity H) in 0.01M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl amorphous organosilica polymer (5 μm) (XTerra MS 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 40°.
(e) Use a detection wavelength of 240 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A: A 0.69% w/v solution of sodium dihydrogen orthophosphate monohydrate, adjusted to pH 6.2 with dilute sodium hydroxide.
Mobile phase B: 40 volumes of acetonitrile and 60 volumes of mobile phase A.
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to mesalazine (retention time about 6 minutes) are: impurity O, about 0.55; impurity J, about 0.6; impurity E, about 0.8; impurity F, about 1.36; impurity G, about 1.4; impurity P, about 1.5; impurity L, about 2.0; impurity M, about 3.3; impurity H, about 3.5; impurity R, about 5.1 and impurity N, about 5.5.
SYSTEM SUITABILITY
In the chromatogram obtained with solution (3) the peak-to-valley ratio is at least 3.0, where Hp is the height above the baseline of the peak due to impurity F and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to mesalazine.
LIMITS
Use the chromatogram supplied with mesalazine for system suitability EPCRS and the chromatogram obtained with solution (3) to identify any peaks due to impurities F, J and P and the chromatogram obtained with solution (4) to identify any peaks due to impurities E, G, H, L, M, N, O and R, in the chromatogram obtained in solution (1). Multiply the area of these peaks by the corresponding correction factors: impurity E, 1.3; impurity G, 1.4; impurity H, 1.4; impurity J, 2.0; impurity L, 4.5; impurity M, 1.7; impurity O, 0.6; impurity P, 0.6; impurity R, 1.3.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity H 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 peak corresponding to impurity E, F, G, J, L, M, P or R is not greater than 1.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.15% of each);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.1%);
the sum of the areas of any secondary peaks is not greater than 5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5 %).
Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).
Impurities A and C
Carry out the method for liquid chromatography, Appendix III D, using the following solutions and freshly prepared mobile phases.
(1) Mix for 10 minutes with the aid of ultrasound, a quantity of the powdered granules containing 50 mg of Mesalazine in 30 mL of mobile phase A, add sufficient mobile phase A to produce 50 mL, mix using a vortex mixer and filter through a 0.45-μm membrane filter.
(2) Mix 1 volume of a 0.002% w/v solution of 4-aminophenol (impurity A) in mobile phase A with 1 volume of 0.002% w/v of 2-aminophenol (impurity C) in mobile phase A, add sufficient mobile phase A to produce 100 volumes and mix.
(3) To 1 volume of solution (1) add sufficient of mobile phase A to produce 200 volumes, mix 1 volume of this solution with 1 volume of 0.0005% w/v of 2-aminophenol in mobile phase A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with spherical end-capped octadecylsilyl silica gel for chromatography (3 μm) (Nucleosil 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 an ambient column temperature.
(e) Use a detection wavelength of 220 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A 0.22% w/v of perchloric acid and 0.1% w/v of orthophosphoric acid in water.
Mobile phase B 0.17% w/v of perchloric acid and 0.1% w/v of orthophosphoric acid in acetonitrile R1.
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to mesalazine (retention time about 9 minutes) are: impurity A, about 0.5 and impurity C, about 0.9.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the two principal peaks is at least 3.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity A is not greater than
the area of any corresponding peak in the chromatogram obtained with solution (2) (200 ppm);
the area of any peak corresponding to impurity C is not greater than the area of any corresponding peak in the chromatogram obtained with solution (2) (200 ppm).
Impurity K
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Add 2 mL of 0.01M sodium hydroxide and 5 drops of 1M sodium hydroxide to a quantity of the powdered granules containing 50 mg of Mesalazine, add 15 mL of the mobile phase and mix for 20 minutes with the aid of ultrasound, add sufficient of the mobile phase to produce 25 mL and filter through a 0.45 μm membrane filter.
(2) 0.00000278% w/v of aniline hydrochloride in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (Lichrospher RP18e is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 205 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
15 volumes of methanol and 85 volumes of a solution containing 0.141% w/v of potassium dihydrogen orthophosphate and 0.047% w/v of disodium hydrogen orthophosphate dihydrate previously adjusted to pH 8.0 with 4.2% w/v of sodium hydroxide.
When the chromatograms are recorded under the prescribed conditions, the retention time of aniline is about 15 minutes.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to aniline (impurity K) is not greater than the area of any corresponding peak in the chromatogram obtained with solution (2) (10 ppm).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Mix a quantity of the powdered granules containing 25 mg of Mesalazine in 15 mL of 0.1M hydrochloric acid for 50 minutes with the aid of ultrasound, with additional vortex mixing at 10 minute intervals; add sufficient 0.1M hydrochloric acid to produce 25 mL, mix and filter. To 1 volume of the filtrate add sufficient 0.1M hydrochloric acid to produce 50 volumes.
(2) 0.002% w/v of mesalazine BPCRS prepared by dissolving in 0.1M hydrochloric acid with the aid of ultrasound.
(3) Prepare a 0.01% w/v of 3-aminosalicylic acid (impurity F) in 0.1M hydrochloric acid and dilute 1 volume of this solution to 100 volumes with a 0.1% w/v solution of mesalazine BPCRS in 0.01M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl amorphous organosilica polymer (5 μm) (XTerra MS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 240 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
A 0.69% w/v solution of sodium dihydrogen orthophosphate monohydrate, adjusted to pH 6.2 with dilute sodium hydroxide solution.
SYSTEM SUITABILITY
In the chromatogram obtained with solution (3) the peak-to-valley ratio is at least 3.0, where Hp is the height above the baseline of the peak due to impurity F and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to mesalazine.
DETERMINATION OF CONTENT
Calculate the content of C7H7NO3 in the granules using the declared content of C7H7NO3 in mesalazine BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Mesalazine.
