Action and use
Non-benzodiazepine hypnotic.
DEFINITION
Zolpidem Tablets contain Zolpidem Tartrate. They are coated.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of zolpidem tartrate, C42H48N6O8
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Shake a quantity of the powdered tablets containing 30 mg of Zolpidem Tartrate with 5 mL of water, centrifuge and filter the supernatant liquid through a 0.45-μm nylon filter. To the filtrate add 0.1 mL of diethylamine and dilute to 10 mL with methanol.
(2) Dissolve 15 mg of zolpidem tartate BPCRS in 2.5 mL of methanol, add 0.05 mL of diethylamine and dilute to 5 mL with methanol.
(3) Dilute 1 volume of solution (2) to 2 volumes with a 0.3% w/v solution of flunitrazepam BPCRS in dichloromethane.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase described below.
(c) Apply 5 μL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
MOBILE PHASE
10 volumes of diethylamine, 45 volumes of cyclohexane and 45 volumes of ethyl acetate.
SYSTEM SUITABILITY
The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2).
B. In the Assay, the principal peak in the chromatogram obtained with solution (1) has the same retention time as the principal peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of 37°, as the dissolution medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium and filter. Use the filtered medium, diluted with the dissolution medium, if necessary, to produce a solution expected to contain 0.00055% w/v of Zolpidem Tartrate.
(2) 0.00055% w/v of zolpidem tartate BPCRS in the medium.
(3) 0.005% w/v each of zolpidem tartrate BPCRS and zolpidem impurity A BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 3.9 mm) packed with octadecylsilyl silica gel for chromatography (4 μm) (Novapack C18 column is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
18 volumes of acetonitrile, 23 volumes of methanol and 59 volumes of a solution containing 0.56% w/v of orthophosphoric acid adjusted to pH 5.5 with triethylamine.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and zolpidem is at least 2.0.
DETERMINATION OF CONTENT
Calculate the total content of zolpidem tartrate, C42H48N6O8, in the medium from the chromatograms obtained and using the declared content of C42H48N6O8 in zolpidem tartate BPCRS.
LIMITS
The amount of Zolpidem Tartrate released is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the powdered tablets containing 10 mg of Zolpidem Tartrate with 80 mL of mobile phase A, mix with the aid of ultrasound, add sufficient mobile phase A to produce 100 mL and filter through a 0.45-μm nylon filter.
(2) Dilute 1 volume of solution (1) to 50 volumes with mobile phase A. Dilute 1 volume of this solution to 10 volumes with mobile phase A.
(3) 0.005% w/v each of zolpidem tartrate BPCRS and zolpidem impurity A BPCRS in mobile phase A.
(4) Dilute 1 volume of solution (2) to 2 volumes with mobile phase A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 3.9 mm) packed with octadecylsilyl silica gel for chromatography (4 μm) (Novapack C18 column is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A 18 volumes of acetonitrile, 23 volumes of methanol and 59 volumes of a solution containing 0.56% w/v of phosphoric acid adjusted to pH 5.5 with triethylamine.
Mobile phase B acetonitrile.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-20 | 100 | 0 | isocratic |
| 20-40 | 100→50 | 0→50 | linear gradient |
| 40-45 | 50 | 50 | isocratic |
| 45-45 | 50→100 | 50→0 | linear gradient |
| 46-60 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions the retention times relative to zolpidem (retention time about 10.5 minutes) are: tartaric acid, about 0.16 and impurity A, about 0.8.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and zolpidem is at least 2.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the area of any secondary peaks is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%).
Disregard any peak: with an area less than the area of the principal peak obtained with solution (4) (0.1%); due to tartaric acid.
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in the mobile phase.
(1) Add 80 mL of the mobile phase to a quantity of the powdered tablets containing 10 mg of Zolpidem Tartrate and mix with the aid of ultrasound. Add sufficient mobile phase to produce 100 mL and filter through a 0.45-μm nylon filter. Dilute 1 volume of the filtrate to 10 volumes.
(2) 0.001% w/v of zolpidem tartrate BPCRS.
(3) 0.005% w/v each of zolpidem tartrate BPCRS and zolpidem impurity A BPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic procedure described under Dissolution may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and zolpidem is at least 2.0.
DETERMINATION OF CONTENT
Calculate the content of C42H48N6O8 in the tablets using the declared content of C42H48N6O8 in zolpidem tartrate BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed in the monograph for Zolpidem Tartrate.
