Edition: BP 2025 (Ph. Eur. 11.6 update)
Gastro-resistant Erythromycin Capsules
Action and use
Macrolide antibacterial.
DEFINITION
Erythromycin Gastro-resistant Capsules contain Erythromycin. They are manufactured using gastro-resistant capsule shells or prepared by filling capsules with granules or particles covered with a gastro-resistant coating.
The capsules comply with the requirements stated under Capsules and with the following requirements.
Content of erythromycins, calculated as the sum of erythromycin A (C37H67NO13), erythromycin B (C37H67NO12) and erythromycin C (C36H65NO13)
90.0 to 110.0% of the stated amount of Erythromycin.
IDENTIFICATION
Shake a quantity of the mixed capsule contents containing 0.1 g of Erythromycin with 5 mL of dichloromethane, decolourise, if necessary, with activated charcoal, filter through a 0.45-μm PTFE filter and evaporate the filtrate to dryness.
The infrared absorption spectrum of the residue, Appendix II A, after drying in vacuo at 60o for 10 minutes, is concordant with the reference spectrum of erythromycin (RS 123).
TESTS
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII B1.
Solution A A solution containing 0.68% w/v of potassium dihydrogen orthophosphate and 0.09% w/v of sodium hydroxide in water. Adjust the solution to pH 6.8, if necessary, using orthophosphoric acid or sodium hydroxide.
First stage
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 50 revolutions per minute.
(b) Use 900 mL of 0.06M hydrochloric acid, at a temperature of 37o as the medium.
PROCEDURE
After 1 hour remove the basket from the dissolution medium, and immediately lower the basket into the second dissolution medium. Discard the first medium.
Final stage
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 50 revolutions per minute.
(b) Use 900 mL of solution A, at a temperature of 37o as the medium.
PROCEDURE
After 1 hour remove the basket from the dissolution medium. Carry out the method for liquid chromatography, Appendix III D, using the following solutions, in solution A. Prepare the solutions immediately before use and protect from light.
(1) Withdraw a sample of the second medium and filter. Use the filtered medium, diluted with solution A, if necessary, to produce a solution expected to contain 0.028% w/v of Erythromycin.
(2) 0.028% w/v of erythromycin BPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions under Related substances may be used with isocratic elution using mobile phase A. Continue the chromatography for twice the retention time of erythromycin A.
When the chromatograms are recorded under the prescribed conditions, the retention time of erythromycin A is about 23 minutes.
DETERMINATION OF CONTENT
Calculate the content of erythromycin A, C37H67NO13 in the medium using the declared content of C37H67NO13 in erythromycin BPCRS.
The amount of erythromycin A released in the final stage is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in solution B. Prepare the solutions immediately before use and protect from light.
Solution B 40 volumes of a 1.15% w/v solution of dipotassium hydrogen orthophosphate adjusted to pH 8.0 using dilute phosphoric acid and 60 volumes of methanol.
(1) Disperse a sufficient quantity of contents of the capsules in solution B and dilute to produce a solution containing 0.4% of w/v of Erythromycin and filter (0.45μm GF/C filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.4% w/v of erythromycin for system suitability EPCRS.
(4) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6) mm packed with end-capped polar-embedded octadecylsilyl amorphous organosilica polymer (3.5 μm) (X-Terra RP18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use a column temperature of 65°.
(e) Use a detection wavelength of 210 nm.
(f) Inject 100 μL of each solution.
MOBILE PHASE
Mobile phase A 5 volumes of a 3.5% w/v solution of dipotassium hydrogen orthophosphate previously adjusted to pH 7.0 using dilute phosphoric acid, 35 volumes of acetonitrile R1 and 60 volumes of water.
Mobile phase B 5 volumes of a 3.5% w/v solution of dipotassium hydrogen orthophosphate previously adjusted to pH 7.0 using dilute phosphoric acid, 50 volumes of acetonitrile R1 and 45 volumes of water.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-44 | 100 | 0 | isocratic |
| 44-46 | 100→0 | 0→100 | linear gradient |
| 46-61 | 0 | 100 | isocratic |
| 61-63 | 0→100 | 100→0 | linear gradient |
| 63-80 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to erythromycin A (retention time about 23 minutes) are: impurity H, about 0.3; impurity A, about 0.4; impurity B, about 0.5; erythromycin C, about 0.55; impurity M, about 0.58; impurity L, about 0.63; impurity C, about 0.9; impurity D, about 1.6; erythromycin B, about 1.75; impurity F, about 1.8 and impurity E, about 2.3.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3):
the resolution between the peaks due to impurity B and erythromycin C is at least 1.2;
the peak-to-valley ratio is at least 2.0, where Hp is the height above the baseline of the peak due to impurity C and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to erythromycin A;
the peak-to-valley ratio is at least 1.5, 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 erythromycin B.
LIMITS
Identify any peaks corresponding to impurities D, E, F and L in the chromatogram obtained with solution (1), using the chromatogram obtained with solution (3), and multiply the areas of these peaks by the corresponding correction factors: impurity D, 2.0; impurity E, 0.08; impurity F, 0.08; impurity L, 0.11.
In the chromatogram obtained with solution (1):
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) (3%);
the area of any peak corresponding to impurity A or B is not greater than 2 times the area of the principal peak in the chromatogram obtained with solution (2) (2% of each);
the area of any peak corresponding to impurity D, E, F or H is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1% of each);
the area of any peak corresponding to impurity L is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4%);
the area of any other secondary peak, other than the peaks due to erythromycin B and C is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4%);
the sum of the areas of any secondary peaks, other than the peaks due to erythromycin B and C is not greater than 7 times the area of the principal peak in the chromatogram obtained with solution (2) (7%).
Disregard any peak due to erythromycin B and erythromycin C and any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.2%).
The content of each of erythromycin B and erythromycin C, as determined under Assay, is not more than 5%.
Water
The contents of the capsules contain not more than 7.5% w/w of water, Appendix IX C, using 10% w/v of imidazole in methanol in the titration vessel.
ASSAY
Weigh the contents of 20 capsules. Mix and powder if necessary. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in solution B. Prepare the solutions immediately before use and protect from light.
Solution B 40 volumes of a 1.15% w/v solution of dipotassium hydrogen orthophosphate adjusted to pH 8.0 using dilute phosphoric acid and 60 volumes of methanol.
(1) Disperse a quantity of the contents of the capsules by shaking with solution B and dilute to produce a solution containing 0.4% w/v of Erythromycin and filter.
(2) 0.4% w/v of erythromycin BPCRS.
(3) 0.4% w/v of erythromycin for system suitability EPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Related substances may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3):
the resolution between the peaks due to impurity B and erythromycin C is at least 1.2;
the peak-to-valley ratio is at least 2.0, where Hp is the height above the baseline of the peak due to impurity C and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to erythromycin A;
the peak-to-valley ratio is at least 1.5, 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 erythromycin B.
DETERMINATION OF CONTENT
Calculate the percentage content of erythromycin A (C37H67NO13), erythromycin B (C37H67NO12) and erythromycin C (C36H65NO13) using the chromatograms obtained with solutions (1) and (2) and the declared contents of C37H67NO13, C37H67NO12 and C36H65NO13 respectively in erythromycin BPCRS.
STORAGE
Erythromycin Gastro-resistant Capsules should be protected from light.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Erythromycin.
