Printed on: Wed Feb 08 2023, 11:46:37 PM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-9957CE88-D2A3-4EEB-97B1-BF397BF344DF_3_en-US

Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: uf7kc DOI: https://doi.org/10.31003/USPNF_M2061_03_01
1

Relative standard deviation: NMT 2.0% for zolpidem

Zolpidem Tartrate Extended-Release Analysis
Tablets Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of
DEFINITION zolpidem tartrate (C42H48N6O8) in the portion of Tablets
Zolpidem Tartrate Extended-Release Tablets contain NLT taken:
90.0% and NMT 110.0% of the labeled amount of zolpidem
tartrate (C42H48N6O8). Result = (rU/rS) × (CS/CU) × 100
IDENTIFICATION rU = peak response from the Sample solution
Change to read: rS = peak response from the Standard solution
CS = concentration of USP Zolpidem Tartrate RS in the
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Standard solution (mg/mL)
Ultraviolet-Visible Spectroscopy: 197U▲ (CN 1-May-2020) CU = nominal concentration of the Sample solution
Sample: 25 µg/mL of zolpidem tartrate in 0.01 M (mg/mL)
hydrochloric acid from a suitable quantity of powder
obtained by grinding 1 Tablet Acceptance criteria: 90.0%–110.0%
Acceptance criteria: Meet the requirements
• B. The retention time of the major peak of the Sample PERFORMANCE TESTS
solution corresponds to that of the Standard solution, as • DISSOLUTION á711ñ
obtained in the Assay. Test 1
Medium: 0.01 N hydrochloric acid; 500 mL
ASSAY Apparatus 1: 100 rpm

al
• PROCEDURE Times: 30, 90, and 240 min
Buffer: 3.3 mL of phosphoric acid in 1 L of water. Adjust with Standard solution: Solution of USP Zolpidem Tartrate RS
triethylamine to a pH of 5.5. in Medium containing (L/500) mg/mL, where L is the label
Mobile phase: Acetonitrile, methanol, and Buffer (4:5:11) claim in mg/Tablet
Standard stock solution: 0.5 mg/mL of USP Zolpidem
ci Sample solution: Pass a portion of the solution under test
Tartrate RS in a mixture of alcohol and 0.01 M through a suitable filter.
hydrochloric acid (4:1) Detector: UV 295 nm
Standard solution: 0.1 mg/mL of USP Zolpidem Tartrate RS Blank: Medium
from the Standard stock solution in Mobile phase Analysis
Sample stock solution: Finely powder NLT 8 Tablets. Samples: Standard solution and Sample solution
ffi
Transfer the powder quantitatively to a suitable volumetric Calculate the percentage of the labeled amount of
flask to obtain nominally 0.5 mg/mL of zolpidem tartrate. zolpidem tartrate (C42H48N6O8) dissolved:
Add 70% of the flask volume of a mixture of alcohol and
0.01 M hydrochloric acid (5:2), and stir on a magnetic Result = (AU/AS) × (CS/L) × V × 100
stirrer for 1 h. Dilute with alcohol to volume. Allow solid
particles to settle, and pass the supernatant through a AU = absorbance of the Sample solution
O

suitable filter (Whatman 40 or equivalent). AS = absorbance of the Standard solution

Alternatively, the Sample stock solution can be prepared as CS = concentration of the Standard solution (mg/mL)
follows. Transfer NLT 20 Tablets to a suitable volumetric L = label claim (mg/Tablet)
flask to obtain a nominal concentration of 0.5 mg/mL of V = volume of Medium, 500 mL
zolpidem tartrate. Add 10% of the flask volume of alcohol
and stir for 30 min or until the Tablets have completely Tolerances: See Table 1.
disintegrated. Add another 10% of the flask volume of
alcohol and stir for another 90 min. Add 10% of the flask Table 1
volume of 0.01 M hydrochloric acid followed by 40% of Time Amount
the flask volume of a mixture of alcohol and 0.01 M (min) Dissolved
hydrochloric acid (5:2). Continue to stir for another
30 min. Remove the stirrer bar and rinse with alcohol. 30 50%–70%
Dilute with alcohol to volume. 90 70%–85%
Sample solution: Nominally 0.1 mg/mL of zolpidem
240 NLT 90%
tartrate from filtered Sample stock solution in Mobile phase.
If the Sample stock solution is prepared using the alternative
procedure, dilute the required volume of the Sample stock The percentages of the labeled amount of zolpidem
solution with Mobile phase and centrifuge instead of filtering tartrate (C42H48N6O8) dissolved at the times specified
before use. conform to Dissolution á711ñ, Acceptance Table 2.
Chromatographic system Test 2: If the product complies with this test, the labeling
(See Chromatography á621ñ, System Suitability.) indicates that it meets USP Dissolution Test 2.
Mode: LC Medium, Apparatus, and Times: Proceed as directed in
Detector: UV 240 nm Test 1.
Column: 4.6-mm × 15-cm; 5-µm packing L1 Standard solution: Solution of USP Zolpidem Tartrate RS
Column temperature: 40° in Medium containing (L/500) mg/mL, where L is the label
Flow rate: 1 mL/min claim in mg/Tablet
Injection volume: 15 µL Sample solution: Pass a portion of the solution under test
System suitability through a suitable filter.
Sample: Standard solution Instrumental conditions
Suitability requirements Mode: UV
Tailing factor: NMT 3.0 for zolpidem Analytical wavelength: 295 nm

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Printed on: Wed Feb 08 2023, 11:46:37 PM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-9957CE88-D2A3-4EEB-97B1-BF397BF344DF_3_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: uf7kc DOI: https://doi.org/10.31003/USPNF_M2061_03_01
2

Blank: Medium Test 4: If the product complies with this test, the labeling
Analysis indicates that it meets USP Dissolution Test 4.
Samples: Standard solution and Sample solution Medium: 0.01 N hydrochloric acid; 500 mL
Calculate the percentage of the labeled amount of Apparatus 1: 100 rpm
zolpidem tartrate (C42H48N6O8) dissolved: Times: 30, 60, and 120 min
Standard solution: Solution of USP Zolpidem Tartrate RS
Result = (AU/AS) × (CS/L) × V × 100 in Medium containing (L/500) mg/mL, where L is the label
claim in mg/Tablet
AU = absorbance of the Sample solution Sample solution: Pass a portion of the solution under test
AS = absorbance of the Standard solution through a suitable filter. Replace the volume withdrawn
CS = concentration of the Standard solution (mg/mL) with an equal volume of Medium.
L = label claim (mg/Tablet) Instrumental conditions
V = volume of Medium, 500 mL Mode: UV
Analytical wavelength: 294 nm
Tolerances: See Table 2. Blank: Medium
Analysis
Table 2 Samples: Standard solution and Sample solution
Time Amount
Calculate the percentage of the labeled amount of
(min) Dissolved zolpidem tartrate (C42H48N6O8) dissolved at each time
point (Qi):
30 55%–75%

90 70%–90% Q30 = (AU/AS) × CS × V × (1/L) × 100

al
240 NLT 85%
Q60 = [(AU/AS) × CS × V × (1/L) × 100] + [Q30 × (VS/V)]
The percentages of the labeled amount of zolpidem Q120 = [(AU/AS) × CS × V × (1/L) × 100] + [(Q30 + Q60) × (VS/
tartrate (C42H48N6O8) dissolved at the times specified V)]
conform to Dissolution á711ñ, Acceptance Table 2.
Test 3: If the product complies with this test, the labeling
indicates that it meets USP Dissolution Test 3.
Medium: 0.01 N hydrochloric acid; 500 mL
ci AU
AS
CS
= absorbance of the Sample solution
= absorbance of the Standard solution
= concentration of USP Zolpidem Tartrate RS in the
Apparatus 1: 100 rpm Standard solution (mg/mL)
Times: 30, 90, and 120 min V = volume of Medium, 500 mL
ffi
Standard solution: Solution of USP Zolpidem Tartrate RS L = label claim (mg/Tablet)
in Medium containing (L/500) mg/mL, where L is the label VS = volume of the sample withdrawn (mL)
claim in mg/Tablet
Sample solution: Pass a portion of the solution under test Tolerances: See Table 4.
through a suitable filter.
Instrumental conditions Table 4
O

Mode: UV Time Amount

Analytical wavelength: 237 nm (min) Dissolved
Blank: Medium
Analysis 30 30%–55%
Samples: Standard solution and Sample solution 60 55%–80%
Calculate the percentage of the labeled amount of
120 NLT 85%
zolpidem tartrate (C42H48N6O8) dissolved:

Result = (AU/AS) × (CS/L) × V × 100 The percentages of the labeled amount of zolpidem
tartrate (C42H48N6O8) dissolved at the times specified
AU = absorbance of the Sample solution conform to Dissolution á711ñ, Acceptance Table 2.
AS = absorbance of the Standard solution Test 5: If the product complies with this test, the labeling
CS = concentration of the Standard solution (mg/mL) indicates that it meets USP Dissolution Test 5.
L = label claim (mg/Tablet) Medium: pH 6.8 phosphate buffer (Dissolve 6.8 g of
V = volume of Medium, 500 mL monobasic potassium phosphate and 0.8 g of sodium
hydroxide in 1 L of water. Adjust with phosphoric acid or
Tolerances: See Table 3. 1 N sodium hydroxide to a pH of 6.8.); 900 mL
Apparatus 1: 50 rpm
Table 3 Times: 60, 180, and 360 min
Time Amount Buffer: Dissolve 5.6 g of phosphoric acid in 1 L of water.
(min) Dissolved Adjust with triethylamine to a pH of 5.5.
Mobile phase: Methanol, acetonitrile, and Buffer
30 25%–45%
(28:22:50)
90 65%–85% Standard stock solution: 0.5 mg/mL of USP Zolpidem
Tartrate RS in methanol
120 NLT 80%
Standard solution: (L/900) mg/mL of USP Zolpidem
Tartrate RS from Standard stock solution in Medium, where
The percentages of the labeled amount of zolpidem L is the label claim in mg/Tablet
tartrate (C42H48N6O8) dissolved at the times specified Sample solution: Pass a portion of the solution under test
conform to Dissolution á711ñ, Acceptance Table 2. through a suitable filter.

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Printed on: Wed Feb 08 2023, 11:46:37 PM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-9957CE88-D2A3-4EEB-97B1-BF397BF344DF_3_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: uf7kc DOI: https://doi.org/10.31003/USPNF_M2061_03_01
3

Chromatographic system AS = absorbance of the Standard solution

(See Chromatography á621ñ, System Suitability.) CS = concentration of the Standard solution (mg/mL)
Mode: LC
Detector: UV 254 nm Calculate the percentage of the labeled amount (Qi) of
Column: 4.6-mm × 7.5-cm; 3.5-µm packing L1 zolpidem tartrate (C42H48N6O8) dissolved at each time
Column temperature: 40° point (i):
Flow rate: 1 mL/min
Injection volume: 25 µL Result1 = C1 × V × (1/L) × 100
Run time: NLT 2.5 times the retention time of zolpidem
System suitability Result2 = [(C2 × V) + (C1 × VS)] × (1/L) × 100
Sample: Standard solution
Suitability requirements Result3 = {(C3 × V) + [(C2 + C1) × VS]} × (1/L) × 100
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0% Ci = concentration of zolpidem tartrate in the portion
Analysis of sample withdrawn at time point i (mg/mL)
Samples: Standard solution and Sample solution V = volume of Medium, 500 mL
Calculate the percentage of the labeled amount of L = label claim (mg/Tablet)
zolpidem tartrate (C42H48N6O8) dissolved: VS = volume of the Sample solution withdrawn from
the Medium (mL)
Result = (rU/rS) × (CS/L) × V × 100
Tolerances: See Table 6.
rU = peak response of the Sample solution

al
rS = peak response of the Standard solution Table 6
CS = concentration of the Standard solution (mg/mL) Time Point Time Amount
L = label claim (mg/Tablet) (i) (min) Dissolved
V = volume of Medium, 900 mL 1 15 45%–65%

Tolerances: See Table 5. 2 60 63%–83%

Time
Table 5
Amount
ci 3 120 NLT 80%

(min) Dissolved The percentages of the labeled amount of zolpidem

tartrate (C42H48N6O8) dissolved at the times specified
ffi
60 55%–75% conform to Dissolution á711ñ, Acceptance Table 2.
180 NLT 75% Test 7: If the product complies with this test, the labeling
indicates that it meets USP Dissolution Test 7.
360 NLT 85% Medium: 0.01 N hydrochloric acid; 500 mL
Apparatus 1: 100 rpm
The percentages of the labeled amount of zolpidem Times: 30, 90, and 240 min
O

tartrate (C42H48N6O8) dissolved at the times specified Standard stock solution: 0.5 mg/mL of USP Zolpidem
conform to Dissolution á711ñ, Acceptance Table 2. Tartrate RS in methanol. Sonication may be used to aid
Test 6: If the product complies with this test, the labeling complete dissolution.
indicates that it meets USP Dissolution Test 6. Standard solution: 0.0125 mg/mL of USP Zolpidem
Medium: 0.01 N hydrochloric acid; 500 mL Tartrate RS from Standard stock solution in Medium
Apparatus 1: 100 rpm Sample solution: Pass a portion of the solution under test
Times: 15, 60, and 120 min through a suitable filter of 0.45-µm pore size. Discarding
Diluent: Methanol and water (50:50) the first 2 mL of filtrate.
Standard stock solution: 0.25 mg/mL of USP Zolpidem Instrumental conditions
Tartrate RS in Diluent. Sonication may be used to aid Mode: UV
complete dissolution. Analytical wavelength: 237 nm
Standard solution: (L/500) mg/mL of USP Zolpidem Cell: 5.0 mm
Tartrate RS from Standard stock solution in Medium, where Blank: Medium
L is the label claim in mg/Tablet Analysis
Sample solution: Pass a portion of the solution under test Samples: Standard solution, Sample solution, and Blank
through a suitable filter of 0.45-µm pore size. Replace the Correct the instrument by using the Blank.
volume withdrawn with an equal volume of Medium. Calculate the concentration (Ci) of zolpidem tartrate
Instrumental conditions (C42H48N6O8) dissolved at each time point (i):
Mode: UV
Analytical wavelength: 295 nm Ci = (AU/AS) × CS
Blank: Medium
Analysis AU = absorbance of the Sample solution
Samples: Standard solution and Sample solution AS = absorbance of the Standard solution
Calculate the concentration of zolpidem tartrate CS = concentration of the Standard solution (mg/mL)
(C42H48N6O8) in the sample withdrawn at each time
point (i): Calculate the percentage of the labeled amount of
zolpidem tartrate (C42H48N6O8) dissolved at each time
Ci = (AU/AS) × CS point (i):
AU = absorbance of the Sample solution Result1 = C1 × V × (1/L) × 100

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Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: uf7kc DOI: https://doi.org/10.31003/USPNF_M2061_03_01
4

Result2 = {[C2 × (V − VS)] + (C1 × VS)} × (1/L) × 100 Analysis

Sample: Sample solution
Result3 = ({C3 × [V − (2 × VS)]} + [(C2 + C1) × VS]) × (1/L) × Calculate the percentage of each impurity in the portion of
100 Tablets taken:

Ci = concentration of zolpidem tartrate in the portion Result = (rU/rT) × (1/F) × 100

of sample withdrawn at the specified time point
i (mg/mL) rU = peak response for each impurity from the
V = volume of Medium, 500 mL Sample solution
L = label claim (mg/Tablet) rT = sum of all the peak responses from the Sample
VS = volume of the Sample solution withdrawn at each solution
time point (mL) F = relative response factor of the corresponding
impurity (see Table 8)
Tolerances: See Table 7.
Acceptance criteria: See Table 8.
Table 7
Time Point Time Amount
Table 8
(i) (min) Dissolved Relative Relative Acceptance
Retention Response Criteria,
1 30 70%–90% Name Time Factor NMT (%)
2 90 NLT 75% Zolpidem acida 0.3 1.2 0.20
3 240 NLT 80% Zolpidem related com-

al
pound Ab 0.9 1.0 0.20
The percentages of the labeled amount of zolpidem Zolpidem 1.0 — —
tartrate (C42H48N6O8) dissolved at the times specified
Any unspecified degra-
conform to Dissolution á711ñ, Acceptance Table 2. dation —
• UNIFORMITY OF DOSAGE UNITS á905ñ: Meet the product 1.0 0.20
requirements
IMPURITIES
• ORGANIC IMPURITIES
ci Total impurities — —

a 2-(6-Methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid.
0.5

b N,N-Dimethyl-2-(7-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide.
Buffer, Mobile phase, Standard stock solution, Sample
solution, and Chromatographic system: Proceed as
ffi
directed in the Assay. ADDITIONAL REQUIREMENTS
System suitability solution: Dissolve a suitable amount of • PACKAGING AND STORAGE: Preserve in well-closed
USP Zolpidem Related Compound A RS in the Standard containers, and store at controlled room temperature.
stock solution to obtain a solution containing 1 µg/mL of • LABELING: When more than one Dissolution test is given, the
zolpidem related compound A. Dilute 1 mL of the resulting labeling states the Dissolution test used only if Test 1 is
solution with Mobile phase to 5 mL. not used.
O

System suitability • USP REFERENCE STANDARDS á11ñ

Sample: System suitability solution USP Zolpidem Related Compound A RS
Suitability requirements N,N-Dimethyl-2-(7-methyl-2-p-tolylimidazo[1,2-a]
Resolution: NLT 1.5 between zolpidem related pyridin-3-yl)acetamide.
compound A and zolpidem C19H21N3O 307.39
Tailing factor: NMT 3.0 for the zolpidem peak USP Zolpidem Tartrate RS
Relative standard deviation: NMT 2.0% for the
zolpidem peak

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