Impurity assessment, development and validation of an RP-HPLC method for the determination of eleven potential impurities of eltrombopag precursor.
J Pharm Biomed Anal
; 243: 116085, 2024 Jun 15.
Article
de En
| MEDLINE
| ID: mdl-38471254
ABSTRACT
Eltrombopag is an oral non-peptide thrombopoietin receptor (TPO-R) agonist indicated for the treatment of thrombocytopenia in patients with persistent or chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) or chronic hepatitis C infection and the treatment of severe aplastic anemia. The purpose of this research was to assess the possible impurities that may carry over to eltrombopag from its precursor Eltro-1 (3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid) and to develop a specific analytical method for the determination of these impurities. Eltro-1 samples synthesized by two different synthesis routes were investigated during the evaluation and method development studies. Besides the expected process-related impurities (Eltro-1A - Eltro-1J), e.g., starting materials, intermediates, and/or compounds formed from their further reactions, an unknown impurity detected above 0.10% was identified by LC-MS, synthesized and fully characterized by NMR, MS and FTIR (Eltro-1K). Accordingly, an HPLC-RP method for the determination of eleven impurities (Eltro-1A - Eltro-1K) in Eltro-1 was developed and validated according to ICH Q2. The control limits for impurities in Eltro-1 were set at ≤ 0.15% for Eltro-1A - Eltro-1J and ≤ 1.0% for Eltro-1K based on fate, spike-purge and carryover studies and in accordance with the ICH M7 classification for impurities in drug substance. Eltro-1 and eleven impurities at the specification limit were separated from each other and the diluent peaks with sufficient resolution without interference. Separation was performed on a Waters XBridge C18 column (150 × 4.6â¯mm, 3.5 µm) at 40 °C with a 10⯵L injection volume at a detection wavelength of 220â¯nm and 15 °C sample temperature. The gradient elution is performed at a flow rate of 1.0â¯mL/min for 40â¯min with mobile phase A (0.1% orthophosphoric acid in water) and B (acetonitrile) according to the following program Time (min) / Acetonitrile (%) 0/0, 35/70, 36/0, 40/0. Test and standard solutions were prepared at a concentration of 1.0â¯mg/mL and 1.0⯵g/mL, respectively, using a mixture of mobile phase A and acetonitrile (75/25) as diluent. This is the first specific, selective, sensitive, linear, precise, accurate, and robust HPLC method for the determination of Eltro-1A - Eltro-1K in Eltro-1, which showed no significant degradation under thermal stress, photostability (UV and VIS), and standard accelerated and long-term stability conditions.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pyrazoles
/
Benzoates
/
Contamination de médicament
/
/
Hydrazines
Limites:
Humans
Langue:
En
Journal:
J Pharm Biomed Anal
Année:
2024
Type de document:
Article
Pays de publication:
Royaume-Uni