硝苯地平专利

Nifedipine Extended-Release Tablets

?

Nifedipine Extended-Release Tablets contain not less than 90.0

percent and not more than 110.0 percent of the labeled amount of

nifedipine (C

17

H< /p>

18

N

2

O

6

).

Packaging and storage

—

Preserve in tight, light-resistant containers, and

store at controlled room temperature.

Labeling

—

The labeling indicates the

Drug Release Test

with which the

product complies.

Labeling

—

The labeling indicates the

Dissolution Test

with which the product

complies.

(Official April 1, 2006)

USP Reference standards

11

—

USP Nifedipine RS

.

USP Nifedipine

Nitrophenylpyridine Analog RS

.

USP Nifedipine Nitrosophenylpyridine Analog

RS

.

NOTE

—

Nifedipine, when exposed to daylight and certain wavelengths of

artificial light, readily converts to a nitrosophenylpyridine derivative. Exposure

to UV light leads to the formation of a nitrophenylpyridine derivative. Perform

assays and tests in the dark or under golden fluorescent or other low-actinic

light. Use low-actinic glassware.

Identification

—

A:

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.

B:

Ultraviolet Absorption

197U

—

Solutions

—

Prepare a test solution as directed for the

Assay preparation

in the

Assay,

except to dilute further with

Mobile phase

to obtain a solution having a

concentration of about 0.02 mg per mL. Prepare the Standard solution as

directed for the

Standard preparation

in the

Assay

under

Nifedipine,

except to

dilute further with

Mobile phase

to obtain a solution having a known

concentration of about 0.02 mg per mL.

Drug release

724

—

TEST 1

—

If the product complies with this test, the labeling indicates that it

meets USP

Drug Release Test 1.

Medium:

water; 50 mL.

Apparatus 7:

15 to 30 cycles per minute. Do not use the reciprocating disk, but

use a 25-cm plexiglas rod, the perimeter of the Tablets being affixed to the rod

with a water- insoluble glue. The solution containers are 25-mm test tubes, 150

to 200 mm in length, and the water bath is maintained at 37 ±

0.5

. At the end

of each specified test interval, the systems are transferred to the next row of

new test tubes containing 50 mL of fresh

Medium

.

Times:

4, 8, 12, 16, 20, and 24 hours.

Diluting solution:

a mixture of methanol and water (1:1).

Standard solutions

—

Transfer about 50 mg of

USP Nifedipine RS

, accurately

weighed, to a 100-mL volumetric flask, dissolve in 50 mL of methanol, dilute

with water to volume, and mix to obtain a Standard stock solution.

Quantitatively dilute this Standard stock solution with

Diluting solution

to obtain

solutions having suitable known concentrations.

Test solution

—

Use portions of the solution under test, passed through a

0.4-?

m filter, suitably diluted with methanol, and stepwise, if necessary, with

Diluting solution

to obtain a final mixture consisting of equal parts of methanol

and water.

Procedure

—

Determine the amount of C

17

H

18

N

2

O< /p>

6

released in the

Test solution

at each 4-hour interval by employing UV absorption at the wavelength of

maximum absorbance at about 338 nm, in 0.5-cm cells. [

NOTE

—

For the 4-hour

time period, determine the absorbance at 456 nm, and use this determination

to correct for excipient interference.]

Tolerances

—

The cumulative percentages of the labeled amount of nifedipine

(C

17

H< /p>

18

N

2

O

6

), released in vivo and dissolved at the times specified, conform to

Acceptance Table 1.

Time (hours)

4

8

12

16

20

24

*

Amount dissolved

*

between 5% and 17%

—

between 43% and 80%

—

—

not less than 80%

The amount dissolved is expressed in terms of the labeled tablet

strength rather than in terms of the labeled total contents.

TEST 2

—

If the product complies with this test, the labeling indicates that it

meets USP

Drug Release Test 2.

Buffer concentrate

—

Transfer 330.9 g of dibasic sodium phosphate and 38 g

of citric acid to a 1-L volumetric flask, add water to dissolve, add 10 mL of

phosphoric acid, dilute with water to volume, and mix.

Medium

—

Mix 125.0 mL of

Buffer concentrate

and 1 L of 10% sodium lauryl

sulfate solution, and dilute to 10 L. Adjust if necessary to a pH of 6.8; 900 mL.

Apparatus 2:

50 rpm, with sinkers (see

Figure 1

).

Fig. 1 (printed with permission of the Japanese Pharmacopoeia)

Times:

3, 6, and 12 hours.

Determine the amount of nifedipine (C

17

H

18

N

2

O

6

) dissolved by employing the

following method.

Mobile phase

—

Prepare a filtered and degassed mixture of acetonitrile and

water (70:30). Make adjustments if necessary (see

System Suitability

under

Chromatography

621

).

Standard solution

—

Dissolve an accurately weighed quantity of

USP

Nifedipine RS

in methanol to obtain a solution having a known concentration of

about 1.11 mg per mL. Dilute quantitatively and stepwise with

Medium

to

obtain a solution having a known concentration of 0.1 mg per mL.

Chromatographic system

—

The liquid chromatograph is equipped with a

350-nm detector and a 4.0-mm ×

125-mm column that contains 3-?

m packing

L1. The flow rate is about 1.5 mL per minute. The column temperature is

maintained at about 40

. Chromatograph the

Standard solution,

and record the

peak responses as directed for

Procedure:

the column efficiency is not less

than 2000 theoretical plates; the tailing factor is not more than 1.5; and the

relative standard deviation for replicate injections is not more than 2.0%.

Procedure

—

Separately inject equal volumes (about 20 ?

L) of filtered portions

of the

Standard solution

and the solution under test into the chromatograph,

record the chromatograms, and measure the responses for the major peaks.

Determine the amount of nifedipine (C

17

H

18

N

2

O

6

) dissolved.

Tolerances

—

The percentages of the labeled amount of nifedipine (C

17

H

18

N

2

O

6

)

released in vivo and dissolved at the times specified conform to

Acceptance

Table 1.

Time (hours)

3

6

12

Amount dissolved

between 10% and 30%

between 40% and 65%

not less than 80%

TEST 3

—

If the product complies with this test, the labeling indicates that it

meets USP

Drug Release Test 3.

FOR TABLETS LABELED TO CONTAIN 30 MG OF NIFEDIPINE

—

Phase 1:

Medium:

0.05 M phosphate buffer, pH 7.5; 900 mL.

Apparatus 2:

100 rpm.

Time:

1 hour.

Standard solution

—

Prepare a solution in

Medium

having an accurately known

concentration of about 0.034 mg of

USP Nifedipine RS

per mL. If necessary, a

volume of methanol, not exceeding 10% of the final volume, can be used to

help solubilize nifedipine.

Procedure

—

[

NOTE

—

After the run, take the Tablet out of the dissolution vessel,

adapt a sinker to it, and transfer the Tablet with the sinker to the dissolution

vessel containing the

Medium

for

Phase 2

.] Determine the amount of

C

17

H

18

N

2

O

6

released in

Phase 1

from UV absorbances at the wavelength of

maximum absorbance at about 238 nm using filtered portions of the solution

under test, in comparison with the

Standard solution

, using the

Medium

as the

blank.

Phase 2:

Medium:

0.5% sodium lauryl sulfate in simulated gastric fluid without enzyme,

pH 1.2; 900 mL.

Apparatus 2:

100 rpm.

Times:

1, 4, 8, and 12 hours.

Standard solution

—

Prepare a solution in

Medium

having an accurately known

concentration of about 0.034 mg of

USP Nifedipine RS

per mL. If necessary, a

volume of methanol, not exceeding 10% of the final volume, can be used to

help solubilize nifedipine.

Procedure

—

Determine the amount of C

17

H

18

N

2

O< /p>

6

released in

Phase 2

from

UV absorbances at the wavelength of maximum absorbance at about 238 nm

using filtered portions of the solution under test, in comparison with the

Standard solution

, using

Medium

as the blank.

Tolerances

—

The cumulative percentages of the labeled amount of nifedipine

(C

17

H< /p>

18

N

2

O

6

), released in vivo and dissolved at the times specified, conform to

Acceptance Table 1

.

Time (hours)

1

4

8

12

*

Amount dissolved

*

not more than 30%

between 30% and 55%

not less than 60%

not less than 80%

For each dosage unit, add the amount dissolved in phosphate

buffer, pH 7.5 from

Phase 1

to the amount dissolved at each time

point in

Phase 2

.

FOR TABLETS LABELED TO CONTAIN

60

MG OF NIFEDIPINE

—

Phase 1:

Medium:

0.05 M phosphate buffer, pH 7.5; 900 mL.

Apparatus 2:

100 rpm.

Time:

25 minutes.

Standard solution

—

Prepare a solution in

Medium

having an accurately known

concentration of about 0.067 mg of

USP Nifedipine RS

per mL. If necessary, a

volume of methanol, not exceeding 10% of the final volume, can be used to

help solubilize nifedipine.

Procedure

—

[

NOTE

—

After the run, take the Tablet out of the dissolution vessel,

adapt a sinker to it, and transfer the Tablet with the sinker to the dissolution

vessel containing the

Medium

for

Phase 2.

] Determine the amount of

C

17

H

18

N

2

O

6

released in

Phase 1

from UV absorbances at the wavelength of

maximum absorbance at about 238 nm using filtered portions of the solution

under test, in comparison with the

Standard solution

, using the

Medium

as the

blank.

Phase 2:

Medium:

0.5% sodium lauryl sulfate in simulated gastric fluid without enzyme,

pH 1.2; 900 mL.

Apparatus 2:

100 rpm.

Times:

1, 4, 8, and 12 hours.

Standard solution

—

Prepare a solution in

Medium

having an accurately known

concentration of about 0.067 mg of

USP Nifedipine RS

per mL. If necessary, a

volume of methanol, not exceeding 10% of the final volume, can be used to

help solubilize nifedipine.

Procedure

—

Determine the amount of C

17

H

18

N

2

O< /p>

6

released in

Phase 2

from

UV absorbances at the wavelength of maximum absorbance at about 238 nm

using filtered portions of the solution under test, in comparison with the

Standard solution

, using

Medium

as the blank.

Tolerances

—

The cumulative percentages of the labeled amount of nifedipine

(C

17

H< /p>

18

N

2

O

6

), released in vivo and dissolved at the times specified, conform to

Acceptance Table 1.

Time (hours)

1

4

8

12

*

Amount dissolved

*

not more than 30%

between 40% and 70%

not less than 70%

not less than 80%

For each dosage unit, add the amount dissolved in phosphate

buffer, pH 7.5 from

Phase 1

to the amount dissolved at each time

point in

Phase 2

.

TEST 4

—

If the product complies with this test, the labeling indicates that the

product meets USP

Drug Release Test 4.

Medium:

0.5% sodium lauryl sulfate in simulated gastric fluid without enzyme,

pH 1.2; 900 mL.

Apparatus 2:

100 rpm.

Times:

1, 4, and 12 hours.

Standard solution

—

Prepare a solution in

Medium

having an accurately known

concentration of about 0.067 mg of

USP Nifedipine RS

per mL for Tablets

labeled to contain 60 mg, and of about 0.034 mg of

USP Nifedipine RS

per mL

for Tablets labeled to contain 30 mg. If necessary, a volume of methanol, not

exceeding 10% of the final volume, can be used to help solubilize nifedipine.

Procedure

—

Determine the amount of C

17

H

18

N

2

O< /p>

6

released from UV

absorbances at the wavelength of maximum absorbance at about 238 nm

using filtered portions of the solution under test, in comparison with the

Standard solution

, using the

Medium

as the blank.

Tolerances

—

The cumulative percentages of the labeled amount of nifedipine

(C

17

H< /p>

18

N

2

O

6

), released at the times specified, conform to

Acceptance Table 1.

FOR TABLETS LABELED TO CONTAIN 30 MG OF NIFEDIPINE

Time (hours)

Amount dissolved

1

4

12

between 12% and 35%

between 44% and 67%

not less than 80%

FOR TABLETS LABELED TO CONTAIN 60 MG OF NIFEDIPINE

Time (hours)

Amount dissolved

1

4

12

Dissolution

711

—

TEST 1

—

If the product complies with this test, the labeling indicates that it

between 10% and 30%

between 40% and 63%

not less than 80%

meets USP

Dissolution Test 1.

Medium:

water; 50 mL.

Apparatus 7

(see

Drug Release

724

):

15 to 30 cycles per minute. Do not

use the reciprocating disk, but use a 25-cm plexiglas rod, the perimeter of the

Tablets being affixed to the rod with a water-insoluble glue. The solution

containers are 25-mm test tubes, 150 to 200 mm in length, and the water bath

is maintained at 37 ±

0.5

. At the end of each specified test interval, the

systems are transferred to the next row of new test tubes containing 50 mL of

fresh

Medium

.

Times:

4, 8, 12, 16, 20, and 24 hours.

Diluting solution:

a mixture of methanol and water (1:1).

Standard solutions

—

Transfer about 50 mg of

USP Nifedipine RS

, accurately

weighed, to a 100-mL volumetric flask, dissolve in 50 mL of methanol, dilute

with water to volume, and mix to obtain a Standard stock solution.