Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach
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This paper is aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid ma...thematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria.
Ključne reči:
Analytical Quality by Design / Box-Behnken design / gradient elution RP-HPLC method / ivabradineIzvor:
Acta Chromatographica, 2022, 34, 1, 1-11Izdavač:
- Akademiai Kiado ZRt.
Finansiranje / projekti:
DOI: 10.1556/1326.2021.00885
ISSN: 1233-2356
WoS: 000692391100001
Scopus: 2-s2.0-85118212359
Institucija/grupa
PharmacyTY - JOUR AU - Tomić, Jovana AU - Đajić, Nevena AU - Agbaba, Danica AU - Otašević, Biljana AU - Malenović, Anđelija AU - Protić, Ana PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4331 AB - This paper is aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid mathematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria. PB - Akademiai Kiado ZRt. T2 - Acta Chromatographica T1 - Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach VL - 34 IS - 1 SP - 1 EP - 11 DO - 10.1556/1326.2021.00885 ER -
@article{ author = "Tomić, Jovana and Đajić, Nevena and Agbaba, Danica and Otašević, Biljana and Malenović, Anđelija and Protić, Ana", year = "2022", abstract = "This paper is aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid mathematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria.", publisher = "Akademiai Kiado ZRt.", journal = "Acta Chromatographica", title = "Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach", volume = "34", number = "1", pages = "1-11", doi = "10.1556/1326.2021.00885" }
Tomić, J., Đajić, N., Agbaba, D., Otašević, B., Malenović, A.,& Protić, A.. (2022). Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach. in Acta Chromatographica Akademiai Kiado ZRt.., 34(1), 1-11. https://doi.org/10.1556/1326.2021.00885
Tomić J, Đajić N, Agbaba D, Otašević B, Malenović A, Protić A. Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach. in Acta Chromatographica. 2022;34(1):1-11. doi:10.1556/1326.2021.00885 .
Tomić, Jovana, Đajić, Nevena, Agbaba, Danica, Otašević, Biljana, Malenović, Anđelija, Protić, Ana, "Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach" in Acta Chromatographica, 34, no. 1 (2022):1-11, https://doi.org/10.1556/1326.2021.00885 . .