Allanamiento

nAfcillin injection⁷⁰

Nafcillin Injection is a sterile isoosmotic solution of Nafcillin Sodium and one or more buffer substances in Water for Injection. It contains dextrose as a tonicity-adjusting agent.

It contains an amount of nafcillin sodium equivalent to not less than 90.0 percent and not more than 120.0 percent of the labeled amount of nafcillin (C₂₁H₂₂N₂O₅S). It contains no antimicrobial preservatives.

pAckAging And StorAge

Preserve in containers for injections as described under injections <1>. Maintain in the frozen state.

lAbeling

It meets the requirements for Labeling under injections

<1>. The label states that it is to be thawed just prior to use, describes conditions for proper storage of the resul-tant solution, and directs that the solution is not to be refrozen.

USp reference StAndArdS <11>

USP Endotoxin RS USP Nafcillin Sodium RS identificAtion

The retention time of the major peak for nafcillin in the chromatogram of the assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the assay.

bActeriAl endotoxinS <85>

It contains not more than 0.13 USP Endotoxin Unit per mg of nafcillin.

Sterility <71>

It meets the requirements when tested as directed for membrane filtration under test for Sterility of the Product to be Examined.

pH <791>: between 6.0 and 8.5.

Particulate matter <788>: meets the requirements for small-volume injections.

ASSAy

acetic acid solution, 0.05 m Sodium acetate, diluent, mobile phase, Standard preparation, resolution solution, and chromatographic system—Proceed as directed in the assay under nafcillin Sodium.

Assay preparation

Allow one container of Injection to thaw, and mix. Transfer an accurately measured volume of Injection, equivalent to about 40 mg of nafcillin, to a 100-mL volumetric flask, dilute with diluent to volume, and mix.

procedure

Proceed as directed for Procedure in the assay under nafcillin Sodium. Calculate the quantity, in mg, of nafcil-lin (C₂₁H₂₂N₂O₅S) in each mL of the Injection taken by the formula:

0.1(c / V)(r_u / r_s)

in which c is the concentration, in μg per mL, of nafcillin in the Standard preparation; V is the volume, in mL, of Injection taken to prepare the assay preparation; and r_u and r_s are the nafcillin peak responses obtained from the assay preparation and the Standard preparation, respectively.

nAfcillin for injection⁷¹

Nafcillin for Injection contains an amount of Nafcillin Sodium equivalent to not less than 90.0 percent and not more than 120.0 percent of the labeled amount of nafcillin (C₂₁H₂₂N₂O₅S).

pAckAging And StorAge

Preserve in containers for Sterile Solids as described under injections <1>.

USp reference StAndArdS <11>

USP Endotoxin RS USP Nafcillin Sodium RS conStitUted SolUtion

At the time of use, it meets the requirements for constituted Solutions under injections <1>.

identificAtion

The retention time of the major peak for nafcillin in the chromatogram of the assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the assay.

bActeriAl endotoxinS <85>

It contains not more than 0.13 USP Endotoxin Unit per mg of nafcillin.

Sterility <71>

It meets the requirements when tested as directed for membrane filtration under test for Sterility of the Product to be Examined.

pH <791>: between 6.0 and 8.5, in the solution constituted as directed in the labeling.

Water, method i <921>: between 3.5 percent and 5.3 percent.

Particulate matter <788>: meets the requirements for small-volume injections.

other reQUireMentS

It meets the requirements for uniformity of dosage units

<905> and Labeling under injections <1>.

ASSAy

acetic acid solution, 0.05 m Sodium acetate, diluent, mobile phase, Standard preparation, resolution solution, and chromatographic system—Proceed as directed in the assay under nafcillin Sodium.

Assay preparation 1

(where it is represented as being in a single-dose container)—Constitute Nafcillin for Injection in a volume of water, accurately measured, corresponding to the volume

of solvent specified in the labeling. Withdraw all of the with-drawable contents, using a suitable hypodermic needle and syringe, and dilute quantitatively with diluent to obtain a solution having a concentration of about 0.4 mg of nafcillin (C₂₁H₂₂N₂O₅S) per mL.

Assay preparation 2

(where the label states the quantity of nafcillin in a given volume of constituted solution)—Constitute Nafcillin for Injection in a volume of water, accurately measured, corre-sponding to the volume of solvent specified in the labeling.

Dilute an accurately measured volume of the constituted so-lution quantitatively with diluent to obtain a soso-lution having a concentration of about 0.4 mg of nafcillin (C₂₁H₂₂N₂O₅S) per mL.

procedure

Proceed as directed for Procedure in the assay under nafcillin Sodium. Calculate the quantity, in mg, of nafcillin

(C₂₁H₂₂N₂O₅S) in the portion of constituted Nafcillin for Injection taken by the formula:

(c / 1000)(L / d)(r_u / r_s)

In which L is the labeled quantity, in mg, of nafcillin in the portion of Nafcillin for Injection taken; d is the concentra-tion, in mg per mL, of nafcillin in assay preparation 1 or assay preparation 2, as appropriate, based on the volume of constituted Nafcillin for Injection taken and the extent of dilution; and the other terms are as defined therein.

Perform the above procedure on ten containers where it is represented as being in a single-dose container and, if necessary, on ten containers where the label states the quantity of nafcillin in a given volume of constituted solution.

Use the individual results to determine the uniformity of dosage units and the average thereof as the assay value.

cApecitAbine tAbletS⁷²

definition

Capecitabine Tablets contain NLT 93.0 percent and NMT 105.0 percent of the labeled amount of capecitabine (C₁₅H₂₂FN₃O₆).

identificAtion

• A. INFRARED ABSORPTION <197K>

Analytical wave number: 1500–1760 cm^-1

Sample: Grind 1 tablet to a fine powder with a mortar and pestle. Mix 1 mg of this sample with 300 mg of potassium bromide.

• B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the assay.

ASSAy procedUre

• Diluent: Methanol, acetonitrile, and water (7:1:12)

• Solution A: 0.1 percent mixture of glacial acetic acid in water

• Solution B: Methanol, acetonitrile, and Solution a (7:1:12)

• Solution C: Methanol, acetonitrile, and Solution a (16:1:3)

• Mobile phase: See the gradient table below.

time (min) Solution b b>(%) Solution c (%)

0 100 0

5 100 0

20 49 51

30 49 51

31 100 0

40 100 0

[NOTE—The following solutions may be sonicated as necessary.]

System suitability solution: Includes 0.6 μg/mL of USP Capecitabine RS, 0.6 μg/mL of USP Capecitabine Related Compound A RS, 0.6 μg/mL of USP Capecitabine Related Compound B RS, and 0.6 μg/mL of USP Capecitabine Related Compound C RS in diluent

Standard solution: 0.6 mg/mL of USP Capecitabine RS in diluent

Sample solution: Equivalent to 0.6 mg/mL of capecitabine, from powdered tablets (NLT 20), in diluent. [NOTE—Pass through a PVDF membrane filter of 0.45-μm pore size, and use the filtrate.]

chromatographic system

(See chromatography <621>, System Suitability.) Mode: LC

Detector: UV 250 nm

Column: 4.6-mm x 25-cm; 5-μm packing L1 Column temperature: 40°

Autosampler temperature: 5°

Flow rate: 1 mL/min Injection size: 10 μL System suitability

Samples: System suitability solution and Standard solution [NOTE—For the purpose of peak identification, the approxi-mate relative retention times are given in impurity table 1.

The relative retention times are measured with respect to capecitabine.]

Suitability requirements

Resolution: NLT 1.0 between Capecitabine Related Compound A and Capecitabine Related Compound B, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 2.0 percent, Standard solution

Analysis

Samples: Standard solution and Sample solution. Calculate the percentage of C₁₅H₂₂FN₃O₆ in the portion of tablets taken:

Result=

(

r r_u/ _s

) (

× C C_s/ _u

)

×¹⁰⁰

• r_u = peak response from the Sample solution

• r_s = peak response from the Standard solution

• C_s = concentration of USP Capecitabine R_s in the

• Standard solution (mg/mL)

• C_u = nominal concentration of capecitabine in the

• Sample solution (mg/mL)

• Acceptance criteria: 93.0 percent–105.0 percent

perforMAnce teStS

• DISSOLUTION <711>

Medium: Water; 900 mL, degassed Apparatus 2: 50 rpm

Time: 30 min

StAndArd SolUtionS

For tablets labeled to contain 150 mg: 17 mg of USP Capecitabine RS in 100 mL of medium

For tablets labeled to contain 500 mg: 28 mg of USP Capecitabine RS in 50 mL of medium

Sample solution: Pass a portion of the solution under test through a fiberglass filter of 0.45-μm pore size.

Analysis: Determine the amount of C₁₅H₂₂FN₃O₆ dissolved by selecting a wavelength with appropriate sensitivity between 300 and 330 nm on portions of the Sample solution, suitably diluted with medium, if necessary, in comparison with the appropriate Standard solution, using a 1-mm quartz cell. Calculate the percentage of C₁₅H₂₂FN₃O₆ dissolved in each tablet:

Result=

(

A_u/A_s

)

×C_s×

(

V L

)

×¹⁰⁰

• A_u = absorbance of the Sample solution

• A_s = absorbance of the Standard solution

• C_s = concentration of capecitabine in the Standard solution (mg/mL)

• V = volume of medium, 900 mL

• L = Tablet label claim (mg)

Tolerances: NLT 80 percent (Q) of the labeled amount of C₁₅H₂₂FN₃O₆ is dissolved.

Uniformity of Dosage Units <905>: Meet the requirements.

iMpUritieS

orgAnic iMpUritieS

• PROCEDURE

Diluent, Solution A, Solution B, Solution C, Mobile phase, System suitability solution, Standard solution, Sample solution, and Chromatographic system:

Proceed as directed in the assay.

AnAlySiS

Samples: Standard solution and Sample solution. Calculate the percentage of each impurity in the portion of tablets taken:

Result=

(

r r_{u s}

) (

× C C_{s u}

)

×¹⁰⁰ F

• r_u = peak response for each impurity from the Sample solution

• r_s = peak response for capecitabine from the Stan-dard solution

• C_s = concentration of USP Capecitabine RS in the Standard solution (mg/mL)

• C_u = nominal concentration of capecitabine in the Sample solution (mg/mL)

• F = relative response factor for each impurity, from impurity table 1

AcceptAnce criteriA

Individual impurities: See impurity table 1 Total degradation products: NMT 2.0 percent

AdditionAl reQUireMentS

• PACKAGING AND STORAGE: Preserve in tight con-tainers. Store at controlled room temperature.

• USP REFERENCE STANDARDS <11>

USP Capecitabine RS

USP Capecitabine Related Compound A RS 5′-Deoxy-5-fluorocytidine.

C₉H₁₂FN₃O₄ 245.21 USP Capecitabine Related Compound B RS5′-Deoxy-5-fluorouridine.

C₉H₁₁FN₂O₅ 246.19 USP Capecitabine Related Compound C RS 2′,3′-0-Carbonyl-5′-deoxy-5-fluoro-N⁴

-(pentyloxycarbonyl) cytidine.

C₁₆H₂₀FN₃O₇ 385.34.

Table B-1. impurity table 1

Name Relative Retention Time Relative Response Factor Acceptance Criteria, NMT (%)

Capecitabine Related Compound A 0.18 1.05 1.0

Capecitabine Related Compound B 0.19 0.81 1.0

2’,3’-Di-O-acetyl-5,’-deoxy-5-fluorocy-tidine* 0.36 0.89 —

5’-Deoxy-5-fluoro-N4-(2-methyl-1-butyloxy-carbonyl)cytidine + 5’-Deoxy-5-fluoro-N4- (3-methyl-1-butyloxy-carbonyl)cytidine*

0.95 1.01 —

Capecitabine 1.00 1.00 —

[1-[5-Deoxy-3-O-(5-deoxy- β-D-ribofura- nosyl)-β-D-ribofura-nosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.06 1.00 —

[1-[5-Deoxy-2-0-(5-deoxy-β -D-ribofura-nosyl)-β -D-ribofura-nosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.09 1.00 —

Capecitabine Related Compound C 1.11 0.91 0.5

[1-[5-Deoxy-3-0-(5-deoxy- α-D-ribofura-nosyl)-β -D-ribofura-nosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.20 1.00 —

2’,3’-Di-O-acetyl-5’-deoxy-5-fluoro-N4-(pentyloxy-carbonyl)cytidine* 1.37 0.85 —

Individual unspecified degradation product ^— 1.00 0.1

*These impurities are process impurities and are not included in the total degradation products.

nAproxen delAyed-releASe tAbletS⁷³

Naproxen Delayed-Release Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of naproxen (C₁₄H₁₄O₃).

pAckAging And StorAge

Preserve in well-closed containers, and store at controlled room temperature.

Use the solution under test as obtained in the buffer stage of the dissolution test.

Standard solution

Use the Standard solution prepared as directed in the buffer stage of the dissolution test.

B: 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, delayed-release dosage forms, method b <711>

Acid StAge

acid stage medium: 0.1 N hydrochloric acid; 1000 mL.

apparatus 2: 50 rpm.

time: 2 hours.

procedure

Determine the amount of C₁₄H₁₄O₃ dissolved by employing UV absorption at the wavelength of maximum absorbance at about 332 nm on filtered portions of the solution under test, suitably diluted with acid stage medium, if necessary, in comparison with a Standard solution having a known concen-tration of USP Naproxen RS in the same acid stage medium.

tolerances

Not more than 10 percent (Q) of the labeled amount of C₁₄H₁₄O₃ is dissolved in 2 hours.

bUffer StAge

buffer stage medium: 0.2 M phosphate buffer, pH 6.8; 1000 mL.

apparatus 2: 50 rpm.

time: 45 minutes.

procedure

Determine the amount of C₁₄H₁₄O₃ dissolved by employing UV absorption at the wavelength of maximum absorbance at about 332 nm on filtered portions of the solution under test, suitably diluted with buffer stage medium, if necessary, in comparison with a Standard solution having a known concen-tration of USP Naproxen RS in the same buffer stage medium.

tolerances

Not less than 80 percent (Q) of the labeled amount of C₁₄H₁₄O₃ is dissolved in 45 minutes.

Uniformity of dosage units <905>: meet the requirements.

procedUre for content UniforMity Mobile phase, diluent A, diluent b, and chromatographic system

Proceed as directed in the assay.

Standard solution

Transfer about 12.5 mg of USP Naproxen RS, accurately weighed, to a 50-mL volumetric flask, dilute with diluent a to volume, and mix well. Transfer 10 mL of this solution to a 25-mL volumetric flask, dilute with diluent b to volume, and mix.

test solution

Transfer 1 tablet to a 200-mL volumetric flask, and add about 140 mL of diluent b. Shake by mechanical means for 15 minutes, sonicate for 15 minutes, dilute with diluent b to volume, and mix. Pass a portion of this solution through a filter having a porosity of 0.45 μm, pipet 2.0 mL of the filtrate for a 500-mg tablet and 2.5 mL for a 375-mg tablet into a 50-mL volumetric flask, dilute with mobile phase to volume, and mix.

ASSAy Mobile phase

Prepare a filtered and degassed mixture of 1 percent acetic acid solution and acetonitrile (11 : 9).

diluent A

Use acetonitrile and water (9 : 1).

diluent b

Use acetonitrile and water (1 : 1).

Standard stock preparation

Transfer about 12.5 mg of USP Naproxen RS, accurately weighed, to a 25-mL volumetric flask. Dissolve in and dilute with diluent a to volume, and mix.

Standard preparation

Accurately transfer 10.0 mL of the Standard stock prepara-tion into a 50-mL volumetric flask, and dilute with mobile phase to volume, and mix.

Assay preparation

Weigh and powder 20 tablets. Accurately weigh an amount of the powder, equivalent to about 250 mg of naproxen, into a 100-mL volumetric flask, and add about 70 mL of diluent b. Shake by mechanical means for 15 minutes, sonicate for 15 minutes, dilute with diluent b to volume, and mix. Pass this solution through a filter having a porosity of 0.45 μm, transfer 2.0 mL of the filtrate into a 50-mL volumetric flask, dilute with mobile phase to volume, and mix.

chromatographic system (see chromatography <621>—

The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 25-cm column that contains 5-μm packing L1. The flow rate is about 1.0 mL per minute.

Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor of the naproxen peak is not more than 1.5, and the relative standard deviation for replicate injections of the Standard preparation is not more than 2.0 percent.

procedure

Separately inject equal volumes (about 50 μL) of the Standard preparation and the assay preparation into the chromatograph, record the chromatograms, and measure the responses for the naproxen peak. Calculate the Table B-1. impurity table 1

Name Relative Retention Time Relative Response Factor Acceptance Criteria, NMT (%)

Capecitabine Related Compound A 0.18 1.05 1.0

Capecitabine Related Compound B 0.19 0.81 1.0

2’,3’-Di-O-acetyl-5,’-deoxy-5-fluorocy-tidine* 0.36 0.89 —

Capecitabine Related Compound C 1.11 0.91 0.5

[1-[5-Deoxy-3-0-(5-deoxy- α-D-ribofura-nosyl)-β -D-ribofura-nosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.20 1.00 —

2’,3’-Di-O-acetyl-5’-deoxy-5-fluoro-N4-(pentyloxy-carbonyl)cytidine* 1.37 0.85 —

Individual unspecified degradation product ^— 1.00 0.1

*These impurities are process impurities and are not included in the total degradation products.

the peak responses obtained from the assay preparation and the Standard preparation, respectively.

AcetAMinophen extended-releASe tAbletS⁷⁴

Acetaminophen Extended-Release Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of acetaminophen (C₈H₉NO₂).

pAckAging And StorAge Preserve in tight containers.

lAbeling

Where the tablets are gelatin-coated, the label so states.

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 Acetaminophen RS Identification

A: infrared absorption <197K>—Use a portion of powdered tablets.

B: 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: simulated gastric fluid TS (without enzyme); 900 mL.

apparatus 2: 50 rpm.

times: 15 minutes, 1 hour, and 3 hours.

procedure

Determine the amount of C₈H₉NO₂ dissolved from UV ab-sorbances at 280 nm, using a filtered portion of the solution under test in comparison with a Standard solution having a known concentration of USP Acetaminophen RS in the same medium.

tolerances

The percentages of the labeled amount of C₈H₉NO₂ dis-solved at the times specified conform to acceptance table.

Time Amount dissolved

15 minutes between 45% and 65%

1 hour between 60% and 85%

3 hours not less than 85%

for gelAtin-coAted tAbletS Medium, Apparatus, and procedure Proceed as directed above.

times: 30 minutes, 90 minutes, and 4 hours.

tolerances

The percentage of the labeled amount of C₈H₉NO₂ dissolved at the times specified conform to acceptance table.

Time Amount dissolved

30 minutes between 40% and 60%

90 minutes between 55% and 85%

4 hours not less than 80%

teSt 2

If the product complies with this test, the labeling indicates that it meets USP dissolution test 2.

Medium, Apparatus, and procedure Proceed as directed for test 1.

tolerances

The percentages of the labeled amount of C₈H₉NO₂ dis-solved at the times specified conform to acceptance table.

Time Amount dissolved

15 minutes between 40% and 60%

1 hour between 55% and 75%

3 hours not less than 80%

Uniformity of dosage units <905>: meet the requirements.

ASSAy mobile phase

Prepare a mixture of water and phosphoric acid (9 : 1).

Combine 1 mL of this solution with a mixture of water and methanol (700 : 300). Filter and degas. Make adjustments if necessary. See System Suitability under chromatography

<621>.

Standard preparation

Dissolve an accurately weighed quantity of USP Acetaminophen RS in methanol, and dilute quantitatively, and stepwise if necessary, with mobile phase to obtain a solution having a known concentration of about 0.65 mg per mL.

Assay preparation

Transfer 10 tablets into a 250-mL volumetric flask contain-ing 50 mL of water and a magnetic stir bar. Stir at least 30 minutes or until the coating has dissolved. Add 150 mL of methanol, and stir for 45 minutes. Tablet cores should be disintegrated at least 15 minutes prior to ending the stirring.

Remove the magnetic stir bar and rinse into the flask with methanol. Dilute with methanol to volume, mix well, and centrifuge. Transfer 5 mL of the clear supernatant to a 200-mL volumetric flask, dilute with mobile phase to volume, and mix well.

chromatographic system (see chromatography <621>—

The liquid chromatograph is equipped with a 295-nm detector and a 3.9-mm x 15-cm column that contains packing L1. The flow rate is about 2.0 mL per minute.

Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor is not more than 3.0, and the relative standard deviation for replicate injections is not more than 2.0 percent.

procedure

Separately inject equal volumes (about 20 μL) of the Standard preparation and the assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of acetaminophen (C₈H₉NO₂) in each tablet taken by the formula:

1000C r r

(

_{u s}

)

In which c is the concentration, in mg per mL, of USP Acetaminophen RS in the Standard preparation; and r_u and r_s are the acetaminophen peak responses obtained from the assay preparation and the Standard preparation, respectively.

29

Chapter 3

In document MANUAL de CAPACITACIÓN (página 83-88)