Drug release, Method B 
724
—
Acid Stage—
Medium:
0.1 N hydrochloric acid; 900 mL.
Apparatus 1:
10-mesh basket; 100 rpm.
Xanthydrol TS—
[NOTE—Prepare this solution daily.] To about 150 mg of xanthydrol in a 100-mL volumetric flask, add 10 mL of glacial acetic acid, and swirl to dissolve. Dilute with hydrochloric acid to volume, and mix.
Standard solution—
Quantitatively dissolve an accurately weighed quantity of
USP Dirithromycin RS in 0.1 N hydrochloric acid to obtain a solution having a known concentration of about 0.28 mg per mL.
Procedure—
After 2 hours of operation, remove each Tablet, or the major portion thereof if the Tablet is not intact, from the individual vessel, and subject each Tablet to the test in the Buffer stage. Separately add 0.50 mL of acetic anhydride to 0.50 mL of the filtered solution under test and to 0.50 mL of the Standard solution, and mix. Add 5.0 mL of glacial acetic acid, allow to stand for 5 minutes, then add 0.50 mL of Xanthydrol TS, and allow 30 minutes for color development. Determine the amount of C42H78N2O14, including the 16R- and 16S-epimers, dissolved by employing UV absorption at the wavelength of maximum absorbance at about 540 nm.
Buffer Stage—
Medium:
pH 6.8 phosphate buffer; 900 mL.
Procedure—
Proceed as directed for Acid stage beginning with “Separately add 0.50 mL of acetic anhydride”.
Tolerances—
Not less than 80% (Q) of the labeled amount of C42H78N2O14, including the 16R- and 16S-epimers, is dissolved in 45 minutes.
Dissolution 711—
Proceed as directed for
Procedure for
Method B under
Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.
Acid Stage—
Medium:
0.1 N hydrochloric acid; 900 mL.
Apparatus 1:
10-mesh basket; 100 rpm.
Xanthydrol TS—
[NOTE—Prepare this solution daily.] To about 150 mg of xanthydrol in a 100-mL volumetric flask, add 10 mL of glacial acetic acid, and swirl to dissolve. Dilute with hydrochloric acid to volume, and mix.
Standard solution—
Quantitatively dissolve an accurately weighed quantity of
USP Dirithromycin RS in 0.1 N hydrochloric acid to obtain a solution having a known concentration of about 0.28 mg per mL.
Procedure—
After 2 hours of operation, remove each Tablet, or the major portion thereof if the Tablet is not intact, from the individual vessel, and subject each Tablet to the test in the Buffer stage. Separately add 0.50 mL of acetic anhydride to 0.50 mL of the filtered solution under test and to 0.50 mL of the Standard solution, and mix. Add 5.0 mL of glacial acetic acid, allow to stand for 5 minutes, then add 0.50 mL of Xanthydrol TS, and allow 30 minutes for color development. Determine the amount of C42H78N2O14, including the 16R- and 16S-epimers, dissolved by employing UV absorption at the wavelength of maximum absorbance at about 540 nm.
Buffer Stage—
Medium:
pH 6.8 phosphate buffer; 900 mL.
Procedure—
Proceed as directed for Acid stage beginning with “Separately add 0.50 mL of acetic anhydride”.
Tolerances—
Not less than 80% (Q) of the labeled amount of C42H78N2O14, including the 16R- and 16S-epimers, is dissolved in 45 minutes.
(Official April 1, 2006)
Chromatographic purity—
Potassium phosphate buffer, Mobile phase and System suitability solution—
Proceed as directed in the
Assay under
Dirithromycin.
Phosphate buffer—
Dissolve 4.35 g of dibasic potassium phosphate in 1 L of water, adjust with phosphoric acid to a pH of 8.0, and pass through a filter having a 0.5 µm or finer porosity.
Solvent 1—
Prepare a mixture of acetonitrile and Phosphate buffer (60:40).
Solvent 2—
Prepare a mixture of acetonitrile and Phosphate buffer (98:2). [NOTE—The mixture is cloudy.]
Standard solution—
Quantitatively dissolve an accurately weighed quantity of
USP Dirithromycin RS in
Solvent 1 to obtain a solution having a known concentration of about 0.2 mg per mL.
[NOTE—Inject the
Standard solution into the chromatograph immediately after preparation.
]
Test solution—
Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 745 mg of dirithromycin, to a 50-mL volumetric flask, dissolve in and dilute with Solvent 2 to volume, and mix. Centrifuge a portion of this solution, transfer 6.0 mL of the clear supernatant to a 10-mL volumetric flask, dilute with Phosphate buffer to volume, and mix. [NOTE—Inject the Test solution into the chromatograph immediately after preparation.]
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 205-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1 and is maintained at a constant temperature of about 40
. The flow rate is about 2 mL per minute. Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.7 for 9-(
S)-erythromycylamine, 1.0 for dirithromycin (16
R-epimer), and 1.12 for dirithromycin 16
S-epimer; the resolution,
R, between the dirithromycin (16
R-epimer) and dirithromycin 16
S-epimer is not less than 2.0, and between dirithromycin (16
R-epimer) and 9-(
S)-erythromycylamine is not less than 5.0; and the tailing factor for the dirithromycin (16
R-epimer) peak is not more than 2.0.
Procedure—
Separately inject equal volumes (about 20 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms for a period of time that is not less than three times the retention time of dirithromycin (16
R-epimer), and measure the peak areas. Calculate the percentage of each impurity found in the portion of Tablets taken by the formula:
50,000(C / 6W)(L / T)(ri / rS),
in which
C is the concentration, in mg per mL, of
USP Dirithromycin RS in the
Standard solution; W is the quantity, in mg, of Tablet powder taken to prepare the
Test solution; L is the labeled amount, in mg, of dirithromycin in each Tablet;
T is the average weight, in mg, of each Tablet;
ri is the peak response for each impurity obtained from the
Test solution; and
rS is the peak response of dirithromycin (16
R-epimer) obtained from the
Standard solution: not more than 1.5% of 9-(
S)-erythromycylamine is found; and not more than 5.0% of total impurities is found.
[NOTE—Do not regard dirithromycin 16
S-epimer as an impurity.
]
Assay—
Potassium phosphate buffer, Mobile phase, System suitability solution, and Solvent—
Proceed as directed in the
Assay under
Dirithromycin.
Standard preparation—
Quantitatively dissolve an accurately weighed quantity of
USP Dirithromycin RS in
Solvent to obtain a solution having a known concentration of about 2.5 mg per mL.
Assay preparation—
Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 250 mg of dirithromycin, to a 100-mL volumetric flask, dissolve in and dilute with Solvent to volume, and mix. Centrifuge a portion of this solution, and use the clear supernatant as the Assay preparation.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 205-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1 and is maintained at a constant temperature of about 40
. The flow rate is about 2 mL per minute. Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.7 for 9-(
S)-erythromycylamine, 1.0 for dirithromycin (16
R-epimer), and 1.12 for dirithromycin 16
S-epimer; the resolution,
R, between the dirithromycin (16
R-epimer) and dirithromycin 16
S-epimer is not less than 2.0, and between dirithromycin (16
R-epimer) and 9-(
S)-erythromycylamine is not less than 5.0; the tailing factor for the dirithromycin (16
R-epimer) peak is not more than 2.0; and the relative standard deviation determined from the dirithromycin (16
R-epimer) peak for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 10 µL) of the
Standard preparation and the
Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantity, in mg, of dirithromycin (C
42H
78N
2O
14), which includes the 16
R- and 16
S-epimers, in the portion of Tablets taken by the formula:
40C(rU + rE) / rS,
in which
C is the concentration, in mg per mL, of
USP Dirithromycin RS in the
Standard preparation; rU and
rE are the peak responses for dirithromycin (16
R-epimer) and dirithromycin 16
S-epimer, respectively, obtained from the
Assay preparation; and
rS is the peak response of dirithromycin (16
R-epimer) obtained from the
Standard preparation.
