氢氯噻嗪盐酸普萘洛尔缓释胶囊USP标准.doc

Propranolol Hydrochloride and Hydrochlorothiazide Extended-Release Capsules
» Propranolol Hydrochloride and Hydrochlorothiazide Extended-Release Capsules contain not less than 90.0 percent and not more than 110.0 percent of the labeled amounts of propranolol hydrochloride (C16H21NO2·HCl) and hydrochlorothiazide (C7H8ClN3O4S2).
Packaging and storage— Preserve in well-closed containers.
USP Reference standards 11—
USP Benzothiadiazine Related Compound A RS .
USP Hydrochlorothiazide RS.
USP Propranolol Hydrochloride RS.
Identification—
A: Transfer the contents of a number of Capsules, equivalent to about 100 mg of hydrochlorothiazide, to a 20-mesh sieve. Break up any large lumps with the aid of a spatula, and collect the powder that passes through the sieve. [NOTE—Retain the material on the screen for Identification test B.] Transfer the powder that passed through the sieve to a screw-capped, 35-mL centrifuge tube, add 5 mL of solvent hexane, and shake for 5 minutes. Centrifuge, and discard the solvent. To the residue in the centrifuge tube add 10 mL of 1 N sodium hydroxide, shake, and filter, collecting the filtrate in a separator. Wash the filter with 5 mL of water, and collect the washing in the separator. Add 50 mL of ether to the separator, shake for 2 minutes, and allow the phases to separate. Drain the aqueous layer into a beaker, adjust with 6 N hydrochloric acid to a pH of about 2, induce crystallization by scratching the inner surface of the beaker with a glass rod, and allow to stand until crystallization is complete. Collect the crystals on a filter, and dry at 105 for 30 minutes. Grind the crystals to a fine powder: the IR absorption spectrum of a mineral oil dispersion of the powder so obtained exhibits maxima only at the same wavelengths as that of a similar preparation of USP Hydrochlorothiazide RS.
B: Wash the material retained on the screen from Identification test A with a small amount of water, discarding the washings. Transfer the particles remaining on the screen to a glass mortar, add about 5 mL of water, and triturate the mixture with a glass pestle. Transfer the suspension, with the aid of about 10 mL of water, to a 35-mL screw-capped centrifuge tube, add about 1 mL of 1 N sodium hydroxide, and mix. Add about 15 mL of ether, and shake by mechanical means for 5 minutes. Centrifuge the mixture, and transfer as much of the ether layer as possible to a second centrifuge tube. Add 0.1 mL of hydrochloric acid to the ether extract, and shake. Centrifuge, and discard the ether. Add about 15 mL of ether to the residue, and shake by mechanical means for 5 minutes. Centrifuge, and discard the ether layer. Dry the residue in vacuum at 45 for 30 minutes. Grind the crystals to a fine powder: the IR absorption spectrum of a mineral oil dispersion of the powder so obtained exhibits maxima only at the same wavelengths as that of a similar preparation of USP Propranolol Hydrochloride RS.
C: The retention times of the major peaks for propanolol hydrochloride and hydrochlorothiazide in the chromatogram of the Assay preparation correspond to those exhibited in the chromatogram of the Standard preparation, as obtained in the Assay.
Dissolution 711—
pH 1.5 Buffer solution, pH 6.8 Buffer solution, Media, and Apparatus— Proceed as directed in the test for Dissolution under Propranolol Hydrochloride Extended-Release Capsules.
Analytical method— Determine the amounts of hydrochlorothiazide (C7H8ClN3O4S2) and propranolol hydrochloride (C16H21NO2·HCl) dissolved, using the following method.
Standard stock solution A— Prepare a solution of USP Propranolol Hydrochloride RS in dilute hydrochloric acid (1 in 100) having a known concentration of about 0.4 mg per mL.
Standard stock solution B— Dissolve an accurately weighed quantity of USP Hydrochlorothiazide RS in 0.25 N sodium hydroxide to obtain a solution having a concentration of about 25 mg per mL. Quantitatively dilute this solution with water to obtain a solution having a known concentration of about 0.5 mg per mL.
Standard solution— Prepare, by combining aliquots of Standard stock solutions A and B, and diluting with dilute hydrochloric acid (1 in 100), solutions bracketing the expected concentration of the samples at the various time points.
Times: 30 minutes; 1.5, 4, 8, 14, and 24 hours.
Procedure— Use an automatic analyzer consisting of a liquid sampler, a proportioning pump, two UV spectrophotometers, and a manifold consisting of the components illustrated in the diagram under Automated Methods of Analysis 16. Start the sampler and conduct determinations at a rate of 30 per hour, using a ratio of about 1:1 for the sample to wash time. Calculate the amounts of C7H8ClN3O4S2 and C16H21NO2·HCl dissolved by comparison with the Standard solution.
Tolerances (hydrochlorothiazide)— Use Acceptance Table 1. Not less than 80% (Q) of the labeled amount of C7H8ClN3O4S2 is dissolved in 30 minutes.
Tolerances (propranolol hydrochloride)— The percentages of the labeled amount of C16H21NO2·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours)
Amount dissolved (%)
1.5
not more than 30%
4
between 35% and 60%
8
between 55% and 80%
14
between 70% and 95%
24
between 83% and 108%
Uniformity of dosage units 905: meet the requirements for Content Uniformity with respect to propranolol hydrochloride and to hydrochlorothiazide.
Procedure for content uniformity—
Apparatus— Use an automatic analyzer consisting of (1) a 20-channel peristaltic pump; (2) an UV spectrophotometer equipped with a 10-mm flow cell and a 293-nm detector; (3) an UV spectrophotometer equipped with a 10-mm flow cell and a 273-nm detector; (4) recording devices for each of the two aforementioned detectors; and (5) a manifold consisting of components illustrated in the pertinent diagram in the chapter Automated Methods of Analysis 16.
Standard hydrochlorothiazide stock solution— Dissolve an accurately weighed quantity of USP Hydrochlorothiazide RS in methanol to obtain a solution having a known concentration of about 5 mg per mL.
Standard propranolol hydrochloride stock solution— Dissolve an accurately weighed quantity of USP Propranolol Hydrochloride RS in methanol to obtain a solution having a known concentration of about 5J mg per mL, J being the ratio of the labeled amount, in mg, of propranolol hydrochloride to the labeled amount, in mg, of hydrochlorothiazide per Capsule.
Standard preparation— Transfer 10.0 mL of the Standard hydrochlorothiazide stock solution, 10.0 mL of the Standard propranolol hydrochloride stock solution, and 10.0 mL of methanol to a 100-mL volumetric flask, dilute with 0.12 N hydrochloric acid to volume, and mix.
Test preparations— Transfer the contents of an appropriate number of individual Capsules to separate 100-mL volumetric flasks, rinsing each empty Capsule shell with 2 mL of methanol, and adding the rinsings to the respective volumetric flasks. Add 28 mL of methanol to each flask, and mix by mechanical means for 30 minutes. Dilute the contents of each flask with 0.12 N hydrochloric acid to volume, and mix.
Procedure— With the sampler in the standby position, pump all reagents through the system until a stable baseline is achieved. Activate the sampler, and allow one cycle to pass without introducing the Standard preparation or the Test preparations, then introduce a 5-mL portion of the Standard preparation into the sampler for the next two cycles and for every sixth cycle thereafter. Disregard the first value for the Standard preparation. Add the Test preparations to the sampler at the rate of 30 per hour, using a ratio of about 1:1 for the sample to wash time, to follow the second 5-mL portion of the Standard preparation. Record the absorbance values, and calculate each peak value by the difference between peak height and baseline. Calculate the quantity, in mg, of hydrochlorothiazide (C7H8ClN3O4S2) per Capsule taken by the formula:
100C(AU / AS)
in which C is the concentration, in mg per mL, of USP Hydrochlorothiazide RS in the Standard preparation; AU is the absorbance at 273 nm of the individual Test preparation; and AS is the averaged absorbance at 273 nm of the Standard preparations. Make any necessary correction of the results obtained as follows.
1. Calculate the correction, F ¢, by the formula:
F ¢ = A / P ¢
in which A is the weight of active ingredient equivalent to 1 average dosage unit obtained by the Assay procedure; and P ¢ is the weight of active ingredient equivalent to 1 average dosage unit calculated as the mean of the dosage units tested by the Content Uniformity procedure.
2. If F ¢ is between 0.970 and 1.030, no correction is required.
3. If F ¢ is not between 0.970 and 1.030, calculate the weight of active ingredient in each dosage unit by multiplying each of the weights found using the special procedure by F ¢.
Calculate the quantity, in mg, of propranolol hydrochloride (C16H21NO2·HCl) per Capsule by the same formula, in which C is the concentration, in mg per mL, of USP Propranolol Hydrochloride RS in the Standard preparation; AU is the absorbance at 293 nm of the individual Test preparation; and AS is the averaged absorbance at 293 nm of the Standard preparations. Make any necessary correction of the results obtained as directed above.
Related compounds—
Tetrabutylammonium hydroxide solution, Buffer, Mobile phase, Standard preparation, and Chromatographic system— Prepare as directed in the Assay.
Standard solution— Transfer about 25 mg of USP Benzothiadiazine Related Compound A RS, accurately weighed, to a 200-mL volumetric flask, add 30 mL of methanol, and swirl to dissolve. Dilute with Buffer to volume, and mix. Dilute an accurately measured volume of this solution quantitatively, and stepwise if necessary, with Mobile phase to obtain a solution having a known concentration of about 0.5 µg per mL.
Test solution— Use the Assay preparation prepared as directed in the Assay.
Procedure— Proceed as directed for Procedure in the Assay, except to inject equal volumes (about 50 µL) of the Standard solution and the Test solution. Calculate the percentage of benzothiadiazine related compound A in the Capsules taken by the formula:
1000(C/NL)(rU / rS)
in which C is the concentration, in µg per mL, of USP Benzothiadiazine Related Compound A RS in the Standard solution; N is the number of Capsules taken to prepare the Test solution; L is the labeled amount, in mg, of hydrochlorothiazide in each Capsule taken; and rU and rS are the peak responses of benzothiadiazine related compound A obtained from the Test solution and the Standard solution, respectively: not more than 1.0% is present.
Assay—
Tetrabutylammonium hydroxide solution— Use a suitable aqueous or methanolic solution having a known concentration of tetrabutylammonium hydroxide.
Buffer— Dissolve 31.25 g of monobasic potassium phosphate in 500 mL of water in a 1000-mL volumetric flask. Add 18.75 mL of phosphoric acid, mix, and add a volume of Tetrabutylammonium hydroxide solution equivalent to about 13 g of tetrabutylammonium hydroxide. Dilute with water to volume, and mix. Dilute 100 mL of this solution with water to obtain 1000 mL of solution, adjusting, if necessary, with phosphoric acid or 10 N potassium hydroxide to a pH of 2.4 ± 0.1.
Mobile phase— Prepare a suitable mixture of Buffer and methanol (850:150). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard hydrochlorothiazide stock solution— Transfer about 25 mg of USP Hydrochlorothiazide RS, accurately weighed, to a 100-mL volumetric flask, add 15 mL of methanol, and sonicate for 5 minutes, adding ice to the bath, if necessary, to maintain the temperature at not more than 20. Dilute with Buffer to volume, and mix. Use this solution within 3 days.
Standard propranolol hydrochloride stock solution— Dissolve an accurately weighed quantity of USP Propranolol Hydrochloride RS in Mobile phase to obtain a solution having a known concentration of about 0.25J mg per mL, J being the ratio of the labeled quantity, in mg, of propranolol hydrochloride to the labeled quantity, in mg, of hydrochlorothiazide per Capsule.
Standard preparation— Transfer 5.0 mL of Standard hydrochlorothiazide stock solution and 5.0 mL of Standard propranolol hydrochloride stock solution to a 25-mL volumetric flask, dilute with Mobile phase to volume, and mix. This solution contains about 50 µg of hydrochlorothiazide and 50J µg of propranolol hydrochloride per mL. Use this solution within 3 days.
Assay preparation— Carefully open an accurately counted number of Capsules, equivalent to about 500 mg of hydrochlorothiazide, and transfer the contents and the Capsule shells to a 500-mL volumetric flask. Add 5.0 mL of water to the flask, and allow to stand for 5 minutes. Dilute with methanol to volume, mix, and sonicate for 10 minutes, adding ice to the bath, if necessary, to maintain the temperature at not more than 20. Remove the flask from the bath, and shake it occasionally for 1 hour. Centrifuge a portion of the contents of the flask, if necessary, to obtain a clear solution. Transfer 5.0 mL of the clear solution to a 100-mL volumetric flask, add 10.0 mL of methanol, dilute with Buffer to volume, and mix.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4-mm × 15-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency determined from the propranolol peak is not less than 2500 theoretical plates when calculated by the formula:
5.545(t/Wh / 2)2
the tailing factor for the hydrochlorothiazide and propranolol peaks 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 50 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. The retention time for propranolol is between 12 and 25 minutes; and the relative retention times are about 0.25 for benzothiadiazine related compound A, 0.4 for hydrochlorothiazide, and 1.0 for propranolol. Calculate the quantities, in mg, of hydrochlorothiazide (C7H8ClN3O4S2) and propranolol hydrochloride (C16H21NO2·HCl) in each Capsule taken by the same formula:
10(C/N)(rU / rS)
in which C is the concentration, in µg per mL, of USP Propranolol Hydrochloride RS or USP Hydrochlorothiazide RS in the Standard preparation; N is the number of Capsules taken to prepare the Assay preparation; and rU and rS are the peak responses of the corresponding analyte obtained from the Assay preparation and the Standard preparation, respectively.
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