Title:UPLC-MS-based Method Development, Validation, and Optimization of
Dissolution Using Quality by Design Approach for Low Dose Digoxin: A
Novel Strategy
Volume: 18
Issue: 9
Author(s): Hemanth Vikram P.R., Narasimha M. Beeraka, Pramod Kumar*, Hitesh B. Patel*B.M. Gurupadayya
Affiliation:
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Ministry of
Chemicals and Fertilizers, Govt. of India, SilaKatamur (Halugurisuk), Assam-781 101, India
- Caplinpoint Laboratories Ltd, Chennai, Analytical Research and Development, Ticel Bio Park,
Phase-II, Taramani 600113, Chennai, India
Keywords:
Dissolution, method development, low dose digoxin tablets, QbD approach, UPLC-MS, quality control.
Abstract:
Background: Digoxin, a cardiac glycoside, is one of the most significant drugs of
choice for treating congestive heart failure. As digoxin is a BCS class IV drug, dissolution is a
critical quality attribute during its solid dosage formulation.
Methods: This study aims to quantify the drug release during dissolution for low dosage digoxin
of 0.0625 mg tablets with a targeted drug release of more than 80% at 60 minutes. We used a
highly sensitive, fast, and versatile UPLC-MS technique for this work. UPLC-MS method was
operated by positive ionization mode with ACQUITY UPLC C18 (2.1 mm x 100 mm, 1.8 μm)
column and at a flow rate of 0.3 ml/minute. Subsequently, this method was developed and validated
for parameters like linearity, precision, accuracy, ruggedness, the limit of detection (LOD),
and the limit of quantification (LOQ) as per the ICH guidelines.
Results: LOD was found to be 2.1 ng/ml. Collision energy for digoxin was observed as 35 eV
for QDa mass detector along with 803.5 m/z precursor ion and 651 m/z daughter ion. An optimal
custom experimental design was employed to optimize the final dissolution conditions. The
critical dissolution factors for optimization were pH of dissolution media, dissolution media
volume, and rpm (rotations per minute). The % drug release (DR) was selected as a critical
quality attribute with the desired response of drug release > 80% at 60 minutes. Outcomes of
the design were further evaluated by statistical tools, including ANOVA. The final optimized
dissolution method consisted of 500 mL of pH 7.4 buffer with a USP apparatus of I (Basket)
rotating at 120 rpm.
Conclusion: We optimized the dissolution conditions using QbD and developed a sensitive
UPLC-MS method for quantifying digoxin that can be efficiently used in routine quality control
purposes in dissolution testing and quantifying low-dose digoxin tablets.
