Pioglitazone Hydrochloride
C19H20N2O3S·HCl 392.90
2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-, monohydrochloride, (±)-;
(±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride
[112529-15-4].
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C19H20N2O3S·HCl 392.90
2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-, monohydrochloride, (±)-;
(±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride
[112529-15-4].DEFINITION
Pioglitazone Hydrochloride contains NLT 98.0% and NMT 102.0% of C19H20N2O3S·HCl, calculated on the anhydrous basis.
IDENTIFICATION
• B. Identification Tests–General, Chloride 
191
:
Dissolve 25 mg of Pioglitazone Hydrochloride in 0.5 mL of nitric acid, and add 2 mL of dilute nitric acid. It meets the requirements of the test for Chloride.
191:
Dissolve 25 mg of Pioglitazone Hydrochloride in 0.5 mL of nitric acid, and add 2 mL of dilute nitric acid. It meets the requirements of the test for Chloride.
• C.
The retention time of the pioglitazone peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Mobile phase:
Acetonitrile, 0.1 M ammonium acetate, and glacial acetic acid (25:25:1)
Standard solution:
Prepare a 0.5 mg/mL solution of USP Pioglitazone Hydrochloride RS in methanol, and dilute with Mobile phase to obtain a solution containing 50 µg/mL of pioglitazone hydrochloride.
System suitability stock solution:
0.5 mg/mL of USP Pioglitazone Hydrochloride RS and 0.13 mg/mL of benzophenone in methanol
System suitability solution:
Dilute System suitability stock solution with Mobile phase to obtain a solution containing 50 µg/mL of pioglitazone hydrochloride and 13 µg/mL of benzophenone.
Sample solution:
Prepare a 0.5 mg/mL solution of pioglitazone hydrochloride in methanol, and dilute with Mobile phase to obtain a solution containing 50 µg/mL of pioglitazone hydrochloride.
Chromatographic system
Mode:
LC
Detector:
UV 269 nm
Column:
4.6-mm × 15-cm; 5-µm packing L1
Column temperature:
25 ± 2.5
Flow rate:
0.7 mL/min
[Note—Adjust the flow rate so that the retention time of the pioglitazone peak is about 7 min. ]
Injection size:
20 µL
System suitability
Samples:
System suitability solution and Standard solution
[Note—The approximate relative retention times for pioglitazone and benzophenone are 1.0 and 2.6, respectively. ]
Suitability requirements
Tailing factor:
NMT 1.5 for pioglitazone and benzophenone, System suitability solution
Resolution:
NLT 15 between pioglitazone and benzophenone, System suitability solution
Relative standard deviation:
NMT 2.0% for six replicate injections, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C19H20N2O3S·HCl in the portion of Pioglitazone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Pioglitazone Hydrochloride RS in the Standard solution (µg/mL) |
| CU | = | = concentration of Pioglitazone Hydrochloride in the Sample solution (µg/mL) |
Acceptance criteria:
98.0%–102.0% on the anhydrous basis
IMPURITIES
Inorganic Impurities
• Residue on Ignition 281:
NMT 0.1%
281:
NMT 0.1%
• Heavy Metals
Sodium sulfide solution:
5 g of sodium sulfide in 10 mL of water and 30 mL of glycerin
Magnesium nitrate solution:
100 mg/mL of magnesium nitrate in alcohol
Standard solution:
Place 10 mL of Magnesium nitrate solution in a platinum or porcelain crucible. Ignite the alcohol to burn. Cool, add 1 mL of sulfuric acid, heat carefully, and ignite at 550 ± 50. Cool and add 3 mL of hydrobromic acid. Proceed as directed from this point under Sample solution, adding 1.0 mL of Standard Lead Solution (see Heavy Metals 231, Special Reagents) before adding water to make 50 mL.
. Cool and add 3 mL of hydrobromic acid. Proceed as directed from this point under Sample solution, adding 1.0 mL of Standard Lead Solution (see Heavy Metals 231, Special Reagents) before adding water to make 50 mL.
Sample solution:
Place 1.0 g of pioglitazone hydrochloride in a platinum or porcelain crucible. Mix with 10 mL of Magnesium nitrate solution. Ignite the alcohol to burn, and carbonize by gradual heating. Cool, add 1 mL of sulfuric acid, heat carefully, and incinerate by ignition at 550 ± 50. If carbonized substances remain, moisten with a small amount of sulfuric acid, and incinerate by ignition. Cool, dissolve the residue in 3 mL of hydrobromic acid, and evaporate on a water bath to dryness. Wet the residue with 3 drops of hydrochloric acid, add 10 mL of water and dissolve by warming. Add 1 drop of phenolphthalein TS, and add ammonia TS dropwise until a pale red color develops. Add 2 mL of 1 N acetic acid, filter if necessary, wash with 10 mL of water, transfer the filtrate and washings to a Nessler tube, and add water to make 50 mL.
. If carbonized substances remain, moisten with a small amount of sulfuric acid, and incinerate by ignition. Cool, dissolve the residue in 3 mL of hydrobromic acid, and evaporate on a water bath to dryness. Wet the residue with 3 drops of hydrochloric acid, add 10 mL of water and dissolve by warming. Add 1 drop of phenolphthalein TS, and add ammonia TS dropwise until a pale red color develops. Add 2 mL of 1 N acetic acid, filter if necessary, wash with 10 mL of water, transfer the filtrate and washings to a Nessler tube, and add water to make 50 mL.
Analysis:
Add 1 drop of Sodium sulfide solution to each of the tubes containing the Standard solution and Sample solution. Mix thoroughly and allow to stand for 5 min. Compare the colors of both solutions by viewing the tubes downward or transversely against a white background. The Sample solution has no more color than the Standard solution.
Acceptance criteria:
NMT 10 ppm
Organic Impurities
• Procedure
Mobile phase and System suitability stock solution:
Proceed as directed in the Assay.
System suitability solution:
Dilute the System suitability stock solution with Mobile phase to obtain a solution containing 25 µg/mL of pioglitazone hydrochloride and 6.5 µg/mL of benzophenone.
Sample solution:
0.2 mg/mL of pioglitazone hydrochloride dissolved in 20% of the final volume with methanol, then diluted with Mobile phase to final volume
Standard solution:
1 µg/mL of pioglitazone hydrochloride prepared by diluting the Sample solution with Mobile phase
Chromatographic system
Mode:
LC
Detector:
UV 269 nm
Column:
4.6-mm × 15-cm; 5-µm packing L1
Column temperature:
25 ± 2.5
Flow rate:
0.7 mL/min
[Note—Adjust the flow rate so that the retention time of the pioglitazone peak is about 7 min. ]
Injection size:
40 µL
Run time:
At least four times the retention time of pioglitazone
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Tailing factor:
NMT 1.5 for pioglitazone and benzophenone, System suitability solution
Resolution:
NLT 15 between pioglitazone and benzophenone, System suitability solution
Relative standard deviation:
NMT 3.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Pioglitazone Hydrochloride taken:
Result = (rU/rS) × D × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of pioglitazone from the Standard solution |
| D | = | = dilution factor used to prepare the Standard solution, 0.005 |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 0.5%
Impurity Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|
|---|---|---|---|
| Hydroxypioglitazonea | 0.7 | 0.15 | |
| Pioglitazone | 1.0 | — | |
| Didehydropioglitazoneb | 1.4 | 0.15 | |
| N-Alkylpioglitazonec | 3.0 | 0.15 | |
| Any other individual impurity | — | 0.10 | |
|
a
(±)-5-{4-[2-(5-Ethylpyridin-2-yl)ethoxy]benzyl}-5-hydroxythiazolidine-2,4-dione.
b
(Z)-5-{4-[2-(5-Ethylpyridin-2-yl)ethoxy]benzylidene}thiazolidine-2,4-dione.
c
(±)-5-{4-[2-(5-Ethylpyridin-2-yl)ethoxy]benzyl}-3-[2-(5-ethylpyridin-2-yl)ethyl]thiazolidine-2,4-dione.
|
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SPECIFIC TESTS
• Water Determination, Method Ic 921:
NMT 0.5%
921:
NMT 0.5%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers, and store at room temperature.
• USP Reference Standards 11
11
USP Pioglitazone Hydrochloride RS 
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Elena Gonikberg, Ph.D.
Principal Scientific Liaison 1-301-816-8251 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4329
Pharmacopeial Forum: Volume No. 36(1) Page 126