Clarithromycin Extended-Release Tablets

Clarithromycin Extended-Release Tablets contain not less than 90.0

percent and not more than 110.0 percent of the labeled amount of
clarithromycin (C38H69NO13).
Packaging and storage Preserve in well-closed containers, protected from
light. Store at 25 , excursions permitted between 15 and 30 .
Labeling When more than one Dissolution Test is given, the labeling states
the Dissolution Test used only if Test 1 is not used.
USP Reference standards 11
USP Clarithromycin RS .
USP Clarithromycin Related Compound A RS .
Identification The retention time of the major peak in the chromatogram of
the Assay preparation corresponds to that in the chromatogram of the Standard
preparation, as obtained in the Assay.
Dissolution 711
TEST 1
Medium: 0.3 M phosphate buffer, pH 6.0 (prepared by dissolving 816.5 g of
monobasic potassium phosphate and 48 g of sodium hydroxide in about 4 L of
water, mixing, and diluting with water to 20 L. Adjust with either concentrated
phosphoric acid or 1 N sodium hydroxide to a pH of 6.0 0.05); 900 mL.
Apparatus 2: 75 rpm.
Times: 30, 45, 60, and 120 minutes.
Determine the percentages of the labeled amount of clarithromycin (C 38H69NO13)
dissolved using the following method.
Standard solutions Prepare five solutions of USP Clarithromycin RS dissolved
in acetonitrile and diluted in Medium, with known concentrations over the range
of about 60 to 600 g per mL.
Test solution Use portions of the solution under test passed through a 35-m
polyethylene filter.
Chromatographic system Proceed as directed in the Assay.
Procedure Separately inject equal volumes (about 50 L) of the five Standard
solutions and the Test solution into the chromatograph, and measure the
responses for the major peaks. Perform a linear regression analysis to generate
a standard curve using the peak area of each Standard solution versus its
concentration. Determine the amount of clarithromycin (C 38H69NO13) dissolved at
each specified time interval, using the peak area of each Test solution and the
linear regression statistics for the Standard solutions.
Tolerances The percentages of the labeled amounts of clarithromycin
(C38H69NO13) dissolved at the times specified conform to the following Acceptance
Table.
Acceptance Table 1
Amount
Time Amount dissolved dissolved
Level (minutes) (individual limits) (average limits)
L1 30 not more than 65%
45 between 55% and 85%
60 not less than 75%
120 not less than 85%
L2 30 not more than 75% not more than
65%
45 between 45% and 95% between 55%
and 85%
60 not less than 65% not less than
75%
120 not less than 75% not less than
85%
L3 30 not more than 2 tablets release more than 75%, and no not more than
individual tablet releases more than 85% 65%
45 not more than 2 tablets are outside the range of 45% to between 55%
95%, and no individual tablet is outside the range of and 85%
35% to 105%
60 not more than 2 tablets release less than 65%, and no not less than
individual tablet releases less than 55% 75%
120 not more than 2 tablets release less than 75%, and no not less than
individual tablet releases less than 65% 85%
TEST 2 If the product complies with this test, the labeling indicates that it meets
USP Dissolution Test 2.

Medium: 0.05 M phosphate buffer, pH 6.8 containing 0.5% of sodium lauryl

sulfate; 900 mL, degassed by sonication and vacuum.
Apparatus 1: 100 rpm.
Times: 2, 12, and 24 hours.
Determine the percentages of the labeled amount of clarithromycin (C 38H69NO13)
dissolved using the following method.
0.067 M Phosphate buffer, pH 2.5 Dissolve 9.2 g of monobasic sodium
phosphate monohydrate in about 800 mL of water. Adjust with phosphoric acid to
a pH of 2.5. Dilute with water to 1000 mL.
Mobile phase Prepare a filtered and degassed mixture of methanol and 0.067
M Phosphate buffer, pH 2.5 (65:35). Make adjustments if necessary (see System
Suitability under Chromatography 621 ).
Standard solution Transfer about 56 mg of USP Clarithromycin RS, accurately
weighed, to a 100-mL volumetric flask. Add 10 mL of methanol, and sonicate to
dissolve. Dilute with Medium to volume.
Test solution Centrifuge the solution under test at 2500 rpm for 10 minutes.
Chromatographic system (see Chromatography 621 ) The liquid
chromatograph is equipped with a 210-nm detector and a 4.6-mm 15-cm
column that contains 5-m packing L1. The flow rate is about 1.0 mL per minute.
The column temperature is maintained at 50 . Chromatograph the Standard
solution, and record the peak responses as directed for Procedure: the tailing
factor is not more than 2.0; the column efficiency is not less than 2000; and the
relative standard deviation for replicate injections is not more than 2.0%.
Procedure Separately inject equal volumes (about 5 L) of the Standard
solution and the Test solution into the chromatograph, record the
chromatograms, and measure the responses for the major peaks. Determine the
amount, in percentage, of clarithromycin dissolved by the formula:

in which C is the concentration, in mg per mL, of clarithromycin in the sample at

U

each time point; r and r are the peak responses obtained from the Test
U S

solutionand the Standard solution, respectively; and C is the concentration, in

S

mg per mL, of clarithromycin in the Standard solution.

Calculate the amount, in percentage, of clarithromycin dissolved with volume
correction:
in which C is the concentration, in mg per mL, of clarithromycin in the Test
n

solution at each time point; 900 is the volume, in mL, of Medium; V is the
U

volume, in mL, of sample withdrawn at each time point; n is the number of time
points [NOTEThe summation of the amount of clarithromycin removed at
previous sampling time points is applicable only where n>1.]; 100 is the
conversion factor to percentage; and LC is the Tablet label claim, in mg.
Tolerances The percentages of the labeled amounts of clarithromycin
(C38H69NO13) dissolved at the times specified conform to Acceptance Table 2.

Time (hours) Amount dissolved

2 not more than 20%
12 between 45% and 70%
24 not less than 80%

TEST 3If the product complies with this test, the labeling indicates that it meets
USP Dissolution Test 3.

Medium: acetate buffer, pH 4.75 (prepared by dissolving 3.59 g of sodium

acetate trihydrate and 11.0 mL of 2 N acetic acid in 1000 mL of water, and
adjusting with 2 N acetic acid to a pH of 4.75); 1000 mL.
Apparatus 1: 10 mesh; 50 rpm.
Times: 1, 2, 4, 8, and 12 hours.

Determine the percentages of the labeled amount of clarithromycin (C 38H69NO13)

dissolved by employing the following method.
0.067 M Phosphate buffer Dissolve 9.12 g of monobasic potassium phosphate
in 1000 mL of water, and mix.
Mobile phase Prepare a filtered and degassed mixture of methanol and 0.067
M Phosphate buffer (65:35), mix, and adjust with phosphoric acid to a pH of 4.0.
Make adjustments if necessary (see System Suitability under Chromatography
621 ).
Standard stock solution Dissolve quantitatively an accurately weighed quantity
of USP Clarithromycin RS in methanol, shaking and sonicating if necessary to
ensure dissolution, to obtain a stock solution having a known concentration of
about 625 g of clarithromycin per mL, taking into account the stated potency, in
g per mg, of USP Clarithromycin RS.
Standard solution Transfer 10.0 mL of the Standard stock solution to a 50-mL
volumetric flask, dilute with Mobile phase to volume, and mix. This solution
contains about 125 g of clarithromycin per mL.
System suitability solution Dissolve quantitatively an accurately weighed
quantity of USP Clarithromycin Related Compound A RS in methanol to obtain a
solution containing about 625 g of clarithromycin related compound A per mL.
Transfer 10 mL of this solution and 10 mL of the Standard stock solution to a 50-
mL volumetric flask, dilute with Mobile phase to volume, and mix.
Test solution Withdraw 10-mL of the solution under test. Transfer 3 mL to a 25-
mL volumetric flask, and dilute with Mobile phase to volume. Pass portions of this
dilution through a 0.45-m filter. Replace 10 mL of Medium in each vessel.
Chromatographic system (see Chromatography 621 ) The liquid
chromatograph is equipped with a 210-nm detector and a 4.6-mm 15-cm
column that contains 5-m packing L1. The flow rate is about 1.0 mL per minute.
The column temperature is maintained at 50 . Chromatograph the System
suitability solution, and record the peak responses as directed for Procedure: the
relative retention times are about 0.75 for clarithromycin and 1.0 for
clarithromycin related compound A; and the resolution, R, between clarithromycin
and clarithromycin related compound A is not less than 2.0. Chromatograph
the Standard solution, and record the responses as directed for Procedure: the
column efficiency, determined from the clarithromycin peak, is not less than 750
theoretical plates; the tailing factor is not less than 0.9 and not more than 2; and
the relative standard deviation for replicate injections is not more than 2.0%.
Procedure Separately inject equal volumes (about 50 L) of the Standard
solution and the Test solution into the chromatograph, record the
chromatograms, and measure the responses for the major peaks. Determine the
amount, in percentage, of clarithromycin (C 38H69NO13) dissolved by the formula:

in which C is the concentration, in mg per mL, of clarithromycin in the sample at

U

each time point; r and r are the peak responses obtained from the Test
U S

solutionand the Standard solution, respectively; C is the concentration, in mg per

S

mL, of clarithromycin in the Standard solution; 100 is the conversion factor to

percentage; and LC is the Tablet label claim, in mg.
Calculate the amount, in percentage, of clarithromycin dissolved with volume
correction at time points n 2:
in which C is the concentration, in mg per mL, of clarithromycin in the Test
n

solution at each time point; 900 is the volume, in mL, of Medium; V is the
U

volume, in mL, of sample withdrawn at each time point; n is the time point (at 2
hours, n = 2), summation of the concentration of the Test solution from the first to
the (n 1)th time point (only applicable for n 2); 100 is the conversion factor to
percentage; and LC is the Tablet label claim, in mg.
Tolerances The percentages of the labeled amount of clarithromycin
(C38H69NO13) dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 not more than 15%
2 between 10% and 30%
4 between 35% and 55%
8 not less than 80%
12 not less than 90%
TEST 4 If the product complies with this test, the labeling indicates that it meets
USP Dissolution Test 4.
Medium: phosphate buffer, pH 6.0 (prepared by dissolving 68.0 g of potassium
dihydrogen phosphate and 1.8 g of sodium hydroxide in 10 L of water, and
adjusting with dilute sodium hydroxide or phosphoric acid to a pH of 6.0 0.1);
900 mL.
Apparatus 2: 50 rpm.
Times: 2, 4, 8, and 12 hours.
Determine the percentages of the labeled amount of clarithromycin (C 38H69NO13)
dissolved by employing the following method.
Buffer solution Dissolve 6.8 g of potassium dihydrogen phosphate in 1 L of
water. Adjust with dilute sodium hydroxide or phosphoric acid to a pH of 4.5
0.1.
Mobile phase Prepare a filtered and degassed mixture of methanol and Buffer
solution (64:36). Make adjustments if necessary (see System
Suitability underChromatography 621 ).
Standard solution Transfer about 20 mg of USP Clarithromycin RS, accurately
weighed, to a 50-mL volumetric flask. Add about 30 mL of Medium, and sonicate
until dissolved, about 10 minutes. Add 2 mL of methanol, and dilute
with Medium to volume.
Test solution Use the solution under test passed through a 0.45-m suitable
filter.
Chromatographic system (see Chromatography 621 ) The liquid
chromatograph is equipped with a 203-nm detector and a 4.0-mm 12.5-cm
column that contains 5-m packing L7. The flow rate is about 1.0 mL per minute.
The column temperature is maintained at 30 . Chromatograph the Standard
solution, and record the peak responses as directed for Procedure: the tailing
factor is not more than 2.0, and the relative standard deviation for replicate
injections is not more than 2.0%.
Procedure Separately inject equal volumes (about 20 L) of the Standard
solution and the Test solution into the chromatograph, record the
chromatograms, and measure the responses for the major peaks. Determine the
amount, in percentage, of clarithromycin dissolved by the formula:

in which C is the concentration, in mg per mL, of clarithromycin in the Test

U

solution at each time point; r and r are the peak responses obtained from
U S

the Test solution and the Standard solution, respectively; and C is the
S

concentration, in mg per mL, of clarithromycin in the Standard solution.

Calculate the amount, in percentage, of clarithromycin dissolved at each time
point by the formula:

in which C is the concentration, in mg per mL, of clarithromycin in the Test

n

solution at each time point; 900 is the volume, in mL, of Medium; V is the
S
volume, in mL, of the sample taken at each time point; and LC is the Tablet label
claim, in mg.
Tolerances The percentages of the labeled amount of clarithromycin
(C38H69NO13) dissolved at the times specified conform to Acceptance Table 2.

Time (hours) Amount dissolved

2 not more than 25%
4 between 20% and 40%
8 between 45% and 75%
12 not less than 80%
Loss on drying 731 Dry a portion of powdered Tablets in vacuum at a
pressure not exceeding 5 mm of mercury at 110 for 3 hours: it loses not more
than 5.0% of its weight.
Uniformity of dosage units 905 : meet the requirements.
Assay
Mobile phase, Resolution solution, and Chromatographic system Proceed as
directed in the Assay under Clarithromycin Tablets.
Standard preparation Prepare as directed for Standard preparation in
the Assay under Clarithromycin Tablets.
Assay preparation Finely powder an accurately counted number of Tablets,
equivalent to about 2000 mg of clarithromycin. With the aid of methanol
quantitatively transfer the powder to a 500-mL volumetric flask, add about 350
mL of methanol, and shake by mechanical means for 30 minutes. Dilute with
methanol to volume, and mix. Sonicate for 30 minutes. Cool to room
temperature, and allow to stand for at least 16 hours. Mix, and allow any
insoluble matter to settle. Transfer 3.0 mL of the supernatant to a 100-mL
volumetric flask, dilute with Mobile phase to volume, and mix. Pass a portion of
this solution through a filter having a 0.5-m or finer porosity, and use the filtrate
as the Assay preparation.
Procedure Proceed as directed for Procedure in
the Assay under Clarithromycin Tablets. Calculate the quantity, in mg, of
clarithromycin (C38H69NO13) in each Extended-Release Tablet taken by the
formula:
(50/3)(C/N)(r / r )
U S

in which N is the number of Tablets taken, and the other terms are as defined
therein.
Auxiliary Information Please check for your question in the FAQs before
contacting USP.
Topic/Question Contact Expert Committee
Monograph Ahalya Wise, M.S. (MDANT05) Monograph
Scientist Development-Antibiotics
1-301-816-8161
Reference Lili Wang, Technical Services
Standards Scientist
1-301-816-8129
RSTech@usp.org
711 Margareth R.C. Marques, (BPC05) Biopharmaceutics05
Ph.D.
Senior Scientist
1-301-816-8106
USP32NF27 Page 1959
Pharmacopeial Forum: Volume No. 32(3) Page 775
Chromatographic Column
CLARITHROMYCIN EXTENDED-RELEASE TABLETS
Chromatographic columns text is not derived from, and not part of, USP 32 or NF
27.