A Quality by Design (QbD) driven gradient high performance liquid chromatography method development for the
Srijita Sen1, Om Prakash Ranjan1
1Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, Assam, India.
Abstract:
Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 μL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.
Insights
A new HPLC method analyzes nilotinib and dasatinib in liposomes for chronic myeloid leukemia (CML) treatment. This Quality by Design approach ensures accurate drug quantification in novel nanocarriers.
Area of Science:
- Analytical Chemistry
- Pharmaceutical Sciences
- Oncology
Background:
- Tyrosine kinase inhibitors (TKIs) like nilotinib and dasatinib show promise in chronic myeloid leukemia (CML) treatment, especially in combination therapy.
- Co-administration of nilotinib and dasatinib demonstrates superior anticancer efficacy and cellular uptake in preclinical and clinical studies.
- Accurate quantification of these drugs within novel drug delivery systems, such as lipid nanocarriers, is crucial for therapeutic monitoring and development.
Purpose of the Study:
- To develop and optimize a novel, simultaneous High-Performance Liquid Chromatography (HPLC) method for estimating dasatinib and nilotinib.
- To apply Quality by Design (QbD) principles, utilizing Design of Experiments (DoE), for systematic method development and validation.
- To ensure the developed HPLC method is suitable for analyzing dasatinib and nilotinib within lipid nanocarrier formulations.
Main Methods:
- Implementation of Design of Experiment (DoE) with a 4-factor, 2-level full factorial design (FFD) to investigate HPLC method parameters.
- Construction of an Ishikawa diagram to identify potential variables influencing analytical performance.
- Optimization of chromatographic conditions including mobile phase composition, flow rate, column temperature, injection volume, and detection wavelength.
Main Results:
- The QbD analysis defined an optimized design space ensuring linearity, accuracy, precision, sensitivity, and robustness of the HPLC method, meeting ICH guidelines.
- The optimal method parameters were identified: a flow rate of 1 mL/min, a gradient mobile phase of Acetonitrile and 20 mM KH2PO4 (pH 7.00), column temperature at 25°C, 20 μL injection volume, and detection at 297 nm.
- The developed HPLC method demonstrated simplicity and selectivity for the simultaneous determination of dasatinib and nilotinib in lipid nanocarriers.
Conclusions:
- A robust and validated HPLC method, optimized using QbD principles, has been successfully developed for the simultaneous quantification of dasatinib and nilotinib.
- This analytical method is suitable for evaluating the content of these important TKIs within novel lipid nanocarrier formulations.
- The established method supports the advancement of combination TKI therapy for CML, particularly within advanced drug delivery systems.
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