Objective: To establish an HPLC method for determination of related substances and purity in pregabalin API. Methods: The analytical column was an Inertsil ODS-3 (150 mm×4.0 mm, 3 μm), the mobile phase A was buffer (7.05 g ammonium dihydrogen phosphate and 1.45 g diammonium hydrogen phosphate dissolved in 1 000 mL water)-methanol-acetonitrile(900∶80∶20) and the mobile phase B was acetonitrile, the whole carried out by gradient elution at a flow rate of 0.8 mL·min-1, the detection wavelength was set at 210 nm, the column temperature was 30 ℃ and the injection volume was 50 μL. Results: Pregabalin was separated completely from the impurities and degradation products (the resolution>2.0). The test solution was stable for at least 48 h. The LOQs of other impurities (verification was performed by using pregabalin), lactam, 4-alkene pregabalin, 5-alkene pregabalin, trimer, 3-isobutylglutaric acid (PGB-3), 3-isobutyl glutaric acid monoamide (PGB-5), R-phenethylamine, 4-isobutyl-2,6-piperidinedione (PGB-5B), monoamide phenylethylamine (PGB-5C) and phenylethylamine adipate (PGB-5D) were 0.05%, 0.01%, 0.01%, 0.03%, 0.01%, 0.05%, 0.03%, 0.01%, 0.01%, 0.01% and 0.01%. The linear correlation coefficients of other impurities (verification was performed by using pregabalin), lactam, 4-alkene pregabalin, 5-alkene pregabalin, trimer, PGB-3 and PGB-5 were all more than 0.99. The linear ranges were LOQ-150% of impurities’ specification, respectively. The average recoveries (n=9) of lactam, 4-alkene pregabalin, 5-alkene pregabalin, trimer, PGB-3 and PGB-5 were 100.6%(RSD=0.56%), 100.2%(RSD=0.38%), 100.5%(RSD=0.46%), 101.1%(RSD=1.1%), 100.0%(RSD=0.63%), 100.0%(RSD=0.54%). The repeatability and intermediate precision completely met the requirements. The impurities contents in three batches of pregabalin API 6 months accelerate and 60 months long-term stability test completely met the requirements, respectively. Conclusion: This method is simple, rapid, sensitive and specific to be used for the determination of related substances and purity in phenethylamine process pregabalin API.
JIN Yun
,
YIN Juan
,
ZHANG Xian-hua
,
ZHANG Tian
,
WANG You-gui
,
ZHAO Long-shan
. Determination of purity and ten process impurities in pregabalin API by HPLC[J]. Chinese Journal of Pharmaceutical Analysis, 2024
, 44(10)
: 1780
-1788
.
DOI: 10.16155/j.0254-1793.2023-0831
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