Telmisartan and Hydrochlorothiazide Tablets USP – Spec & STP

The specification and Analytical Testing Procedure (ATP) / Standard Testing Procedure (STP) for the drug product Telmisartan and Hydrochlorothiazide Tablets USP (as per USP monograph). The below procedures are most updated and revised.

Specification & STP of Telmisartan and Hydrochlorothiazide Tablets USP

Sr. No. Test Specification
1.     Description As per Manufacturer Formulation
2.     Identification
  By UV The spectrum of the solution under test in the range from 200 nm to 400 nm corresponds to that of the standard solution, as obtained in assay.
  By HPLC In assay, the retention time of the principal peaks, due to Hydrochlorothiazide and Telmisartan, in the chromatogram obtained with the test solution corresponds to the retention time of the principal peaks in the chromatogram obtained with standard solution.
3.     Average weight As per Manufacturer Formulation
4.     Uniformity of weight As per USP General Chapter <905>
5.     Dissolution : BY HPLC
  For Telmisartan Not less than 80.0 % (Q) of the labeled amount is dissolved in 30 minutes
  For Hydrochlorothiazide Not less than 80.0 % (Q) of labeled amount is dissolved in 30 minutes
6.     Impurities
  Benzothiadiazine related compound A NMT 1.0 %
Impurity related to Hydrochlorothiazide NMT 0.2 %
Impurity related to Telmisartan NMT 0.2%
Total Degraded products related to Telmisartan NMT 0.2 %
Total Degraded products related to Hydrochlorothiazide NMT 1.5 %
7.     Uniformity of Dosage Units
  First Criteria The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to L1 %.( L1 is 15.0 and L2 is 25.0.)
  Second Criteria If the acceptance value is > L1%, test the next 20 units, and calculate the acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is ≤ L1%, and no individual content of any dosage unit is less than [1- (0.01)(L2)]M nor more than [1 + (0.01)(L2)]M. (L1 is 15.0 and L2 is 25.0.)
8.     Assay: Each tablet contains:
  Telmisartan IP : 95.0 % to 105.0 % of labeled amount
Hydrochlorothiazide IP : 90.0 % to 107.5.0 % of labeled amount

Standard Testing Procedure – Telmisartan and Hydrochlorothiazide Tablets USP

1.0     Description :

2.0     Identification

    • By Ultraviolet Absorption
    • The spectrum of the solution under test corresponds to that of the Standard solution, as obtained in Assay.
    • By HPLC
    • The retention time of the two major peaks of the sample solution corresponds to that of the two major peaks in standard solution A, as obtained in the Assay.

3.0   Average Weight

    • As per Manufacturer Formulation, Carry out the test on 20 tablets as per procedure.

4.0     Uniformity of Dosage Units (By Content Uniformity)

    • Procedure  :  Chromatographic condition, Mobile Phase, Diluent & Standard solution & Standard stock solution 2 of Telmisartan RS & Hydrochlorothiazide RS : Proceed as directed in the Assay.
    • Sample solution :  Take one tablet in 50 ml volumetric flask & dissolve with diluent.  Dilute 10.0 ml in 25 ml volumetric flask & makeup volume with a 1 : 1 solution of Buffer & Solution A & shake to uniform.
    • Procedure : Separately inject 10 µl of each of standard and sample preparation and record the chromatogram. Measure the peak responses for Hydrochlorothiazide & Telmisartan & calculate the % of content uniformity :
    • Hydrochlorothiazide :

Spl. Area  × Std. Wt.× 10   ×  50     ×  25  ×  Std. Potency

Std. Area  ×  50       ×  50  ×  12.5  ×  10

    • Telmisartan :

 

Spl. Area  ×  Std. Wt. ×  10  ×  50   ×  25  ×  Std. Potency

Std. Area  ×  50 ×           50  ×  40  ×  10

5.0     Water Content

    •  Take 0.5 g. sample and carry out the test  as per procedure.

6.0     Dissolution of Telmisartan and Hydrochlorothiazide Tablets USP 

    • Telmisartan  :
    • Medium : pH 7.5 phosphate buffer (13.61g/l of Potassium dihydrogen phosphate in water.
    • Adjust with 2 M Sodium hydroxide to a pH of 7.5); 900 ml.

Apparatus 2        :             Paddle

Rpm                      :               75

Time                     :             30 minutes.

    • Hydrochlorothiazide  :   

Medium                :         0.1 N hydrochloric acid; 900 ml

Apparatus            :         Basket

Rpm                       :         100

Time                     :         30 minutes.

    • Analysis : Determine the amounts of Telmisartan and Hydrochlorothiazide dissolved by the following method.
    • Solution A  :  5.0 g/l of Ammonium di-hydrogen phosphate in water.  Adjust with Phosphoric acid to a pH of 3.0.
    • Solution B  :  Acetonitrile.
    • Standard Stock Solution  :  Appropriate amounts of USP Telmisartan RS and USP Hydrochlorothiazide RS in methanol .
    • Telmisartan  RS :  44mg  →   100 ml.
    • Hydrochlorothiazide RS :  28 mg →   100 ml
    • Telmisartan Standard Solution : Dilute the Standard stock solution with Telmisartan Medium to obtain a solution having a known concentration of Telmisartan similar to that expected in the Sample solution.

 Dilution : 10 ml of Standard stock solution → 100 ml

    • Hydrochlorothiazide Standard Solution : Dilute the Standard stock solution with Hydrochlorothiazide Medium to obtain a solution having a known concentration of hydrochlorothiazide similar to that expected in the Sample solution.

Dilution : 5 ml of Standard stock solution  →  100 ml

    • Sample Solution :  Pass a portion of the solution through a suitable filter of 0.45-µm pore size, discard the first few ml.

    • Chromatographic System :

    • Model                :         LC
    • Detector            :         UV 270 nm for Hydrochlorothiazide and 298 nm for Telmisartan
    • Column             :         3.0 mm × 6 cm; 5 µm packing L7
    • Column temp.  :         40°
    • Flow rate           :         0.6 ml/min from 0-5.0 min and 1.0 ml/min. from 5.01– 6.20 minutes.  The flow rate goes back to 0.6 ml from 6.21 – 9.70,
    • Injection size         :         4 µl
    • Mobile phase         :         See the gradient table below :
          Tim (min) Solution A (%) Solution B (%)
0 85 15
1.50 85 15
1.51 60 40
5.00 60 40
5.01 20 80
6.20 20 80
6.21 85 15
9.70 85 15

    • System Suitability  :

    • Samples : Telmisartan standard solution or Hydrochlorothiazide standard solution.

[Note:- The relative retention times for hydrochlorothiazide and Telmisartan are 0.33 and 1.0 respectively].

    • Suitability Requirements  :
    • Tailing Factor : Not more than 2.5 for both Hydrochlorothiazide and Telmisartan.
    • Relative Standard Deviation : Not more than 2.0%.
    • Calculate the percentage of Telmisartan or hydrochlorothiazide dissolved :

Result          =       (ru/rs)  ×  (Cs/L)  ×  V  ×  100

ru       =  peak response of Telmisartan or Hydrochlorothiazide in the  sample solution.

rs       =  peak response of Telmisartan in the Telmisartan standard solution or Hydrochlorothiazide standard solution.

Cs      =        Concentration of Telmisartan in the Telmisartan standard solution or Hydrochlorothiazide in the Hydrochlorothiazide standard

solution (mg/ml).

L       =        Tablet label claim for Telmisartan or Hydrochlorothiazide (mg)

V      =        volume of Medium, 900 ml

    • Tolerances : Not less than 80.0% (Q) of the labeled amount of Telmisartan and hydrochlorothiazide is dissolved.

7.0     Organic Impurities

Diluent, Buffer, Solution A, Mobile Phase, Standard Stock Solution 1, Standard solution A, Sample Solution, and Chromatographic Systems :  Proceed as directed in the Assay.

    •  Placebo Preparation : Take about 2.5 g Telmisartan placebo sample + Take about 2.0g hydrochlorothiazide placebo sample in 250 ml of volumetric flask and add 12.5 ml of 0.1 M sodium hydroxide mix and sonicate, makeup the volume.
    • Dilute 1.0 ml of this solution to 5.0 ml with a solution prepared by diluting equal volume s of mobile phase A and mobile phase B.
    • Standard Solution B : a 0.5-µg/ml solution for tablet strengths of 40 mg/12.5 mg.
    • Take Benzothiadiazine related compound A. as per assay Standard Stock Solution 2 _____(10 ml) ________ (50 ml) mobile phase A & B.
    • Standard Stock Solution 3 : 1.6 mg/ml of USP Telmisartan RS and 0.5 mg/ml of USP Hydrochlorothiazide RS in Diluent for Tablet strengths of 40 mg/12.5 mg
    • Take solution as per assay for 1.6 mg/ml of USP Telmisartan RS and 0.5 mg/ml of USP Hydrochlorothiazide RS (Benzothiadiazide) Standard Stock Solution 2  Telmisartan & Hydrochlorothiazide in assay.
    • Sensitivity Solution:  Dilute 10 ml of Standard stock solution 3 with Diluent to 100 ml. Combine 1.0 ml of this solution with 2.0 ml of Standard stock solution 1 and dilute with Diluent to 100 ml.  Dilute 1 mL of this solution to 5 ml with a (1 : 1) equal volumes of mobile phase A and mobile phase B.

    • System Suitability  :

    • Samples  :  Standard solution A and Sensitivity solution.
    • Suitability Requirements  :
    • Resolution : Not less than 2.0 between Hydrochlorothiazide and Benzothiadiazide related compound A, Standard solution A.
    • Relative Standard Deviation : Not more than 2.0% for both the Telmisartan and Hydrochlorothiazide peaks, Standard solution A.
    • Signal–to-noise Ratio : Not less than 3.0 for the Telmisartan, hydrochlorothiazide and Benzothiadiazine related compound A peaks from the Sensitivity solution.

    • Analysis  :

    • Samples  : Standard solution A, Standard solution B, and Sample solution.
    • Calculate the percentage of Benzothiadiazide related compound A in the portion of tablet taken :

Result          =        (ru/rs)  ×  (Cs/Cu)  ×  100

    •  ru     =   peak response of Benzothiadiazide related compound A from the sample solution.
    • rs       =  peak response of Benzothiadiazide related compound A from standard solution B
    • Cs      =  concentration of USP Benzothiadiazide related compound A RS from standard solution B (mg/ml)
    • Cu      =        concentration of Hydrochlorothiazide in the sample solution(mg/ml)

Calculate the percentage of each unspecified degradation impurity related to Hydrochlorothiazide in the portion of tablets taken :

Result =       (ru/rs)  ×  (Cs/Cu)  ×  100

    • ru       =        peak response of each unspecified degradation impurity at 270 nm from the sample solution.
    • rs       =        peak response of Hydrochlorothiazide from standard solution A
    • Cs       =        concentration of USP Hydrochlorothiazide RS in standard solution A (mg/ml)
    • Cu      =        concentration of Hydrochlorothiazide in the sample solution (mg/ml)

Calculate the percentage of each unspecified degradation impurity related to Telmisartan in the portion of tablets taken :

Result          =       (ru/rs)  ×  (Cs/Cu)  ×  100

    • ru       =        peak response of each unspecified degradation impurity at 298 nm from the sample solution.
    • rs       =        peak response of Telmisartan from standard solution A
    • Cs       =        concentration of USP Telmisartan RS in standard solution A (mg/ml)
    • Cu      =        concentration of Telmisartan in the sample solution (mg/ml)

  • Acceptance Criteria  :

    • Individual Impurities: Not more than 1.0% of Benzothiadiazine related compound A and Not more than 0.2% of each individual unspecified degradation impurity related to Hydrochlorothiazide or Telmisartan.
    • Total Impurities  :  Not more than 0.2% of the sum of all degradation products related to Telmisartan and Not more than 1.5% of the sum of all Hydrochlorothiazide degradation products.

8.0     Assay of  Telmisartan and Hydrochlorothiazide Tablet USP

    • Diluent  :  0.005 M Methanolic solution of Sodium hydroxide.
    • Mobile phase A  :  2.0 g/l of Ammonium dihydrogen phosphate.  Adjust with Phosphoric acid to a pH of 3.0.
    • Mobile phase B  :  Methanol and acetonitrile  (1 : 1).
    • Mobile Phase  :  See the gradient table below :
Time (min.) Buffer (%) Solution A
0 85 15
3.50 85 15
3.51 45 55
7.70 45 55
7.71 20 80
12.0 20 80
12.1 85 15
15.5 85 15
    •  Standard Stock Solution 1 : 0.025 mg/mL of USP Benzothiadiazide Related Compound A RS in Diluent.

(Dilution : 2.5 mg   →    100 ml                               (Standard Stock Solution 1)

    • Standard Stock Solution 2 : 1.6 mg/mL of USP Telmisartan RS, 0.5 mg/mL of USP Hydrochlorothiazide RS, and 2.5 µg/mL of USP Benzothiadiazide Related Compound A RS (from Standard stock solution 1) in Diluent.

(Dilution for  :  Telmisartan RS :  80 mg  →   50ml   Standard Stock Solution 2

             Hydrochlorothiazide RS : 25 mg  →   50ml   Standard Stock Solution 2

    • Benzothiadiazide Related compound A RS :

5 ml of standard stock solution 1 → 50 ml Standard Stock Solution 2

    • Standard Solution A : Dilute Standard stock solution 2 with a 1 : 1 solution of Buffer and Solution A to prepare 0.32 mg/mL of Telmisartan, 0.1 mg/mL of Hydrochlorothiazide, and 0.5 µg/mL of Benzothiadiazide related compound A

(Dilution : Dilute each 10ml Standard Stock Solution 2 of Hydrochlorothiazide RS, Benzothiadiazide related compound A & 10ml of Telmisartan RS in 50 ml volumetric flask, mix & make up the volume 50ml with a 1 : 1 solution of Buffer & Solution A).

    • Sample Stock Solution :

    • Transfer Not less than 10 tablets into a suitable volumetric flask, add 0.1 N Sodium hydroxide solution (5% of the total volume of the flask), and shake until the Tablets have completely disintegrated.
    • Add methanol (80% of the total volume of the flask).  Sonicate for 10 minutes and stir vigorously for 30 minutes.
    • Allow to cool to room temperature, dilute with methanol to volume, and mix.
    • The concentration of the Sample stock solution is about 1.6 mg/mL of Telmisartan. [Note:–  The hydrochlorothiazide concentration may vary depending on the ratio of Telmisartan to Hydrochlorothiazide in the Tablet].
    • Centrifuge a portion of the solution at 4000 rpm.  [Note:- To prevent heat from degrading the sample, do not extend the sonication time and also maintain the bath temperature at NMT 22° by adding ice].

Dilution : 10 Tablets    →     250 ml.

    • Sample Solution : Dilute 1 mL of the Sample stock solution to 5 mL in a (1 : 1) equal volume s of mobile phase A and mobile phase B.

    • Chromatographic System :

    • Mode                     :         LC,
    • Detector                :         UV 270 nm for hydrochlorothiazide and 298 nm for Telmisartan,
    • Column                 :         4.0 mm × 12.5 cm; 5 µm packing L7,
    • Column temp.      :         40°
    • Flow rate               :         1.2 ml/minute.
    • Injection size        :         10 µl
    • System Suitability  :
    • Resolution  :  Not less than 2.0 between Hydrochlorothiazide and Benzothiadiazide related compound A.
    • Relative Standard Deviation  :  Not more than 2.0% for both the Telmisartan and Hydrochlorothiazide peaks.

Calculate the percentage of the labeled amount of Telmisartan (C33H30N4O2) and Hydrochlorothiazide (C7H8CIN3O4S2) in the portion of tablets taken :

Result    =    (ru/rs)  ×  (Cs/Cu)  ×  100

 

ru = peak response of Telmisartan or Hydrochlorothiazide from the Sample solution.
rs = peak response of Telmisartan or Hydrochlorothiazide from standard solution A
Cs = concentration of USP Telmisartan RS or the Hydrochlorothiazide peak in Standard solution A (mg/ml)
Cu = nominal concentration of Telmisartan or Hydrochlorothiazide in the sample solution (mg/ml).
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