UPLC-MS-based Method Development, Validation, and Optimization of Dissolution Using Quality by Design Approach for Low Dose Digoxin: A Novel Strategy

Abstract

Background: Digoxin, a cardiac glycoside is the one of the most significant drugs of choice for the congestive heart failure treatment. As Digoxin is a BCS class IV drug, the dissolution is a critical quality attribute for its tablet formulation. Methods: Current work aims to quantify the dissolution drug release for low dosage digoxin of 0.0625mg tablets with targeted drug release of more than 80% at 60 minutes by highly sensitive, fast, and versatile UPLC-MS technique. UPLC-MS method operated by positive ionization mode with ACQUITY UPLC C18 (2.1 cm x 100 mm, 1.8 µm) column and flow rate of 0.3ml/min has been developed and validated for parameters like linearity, precision, accuracy, ruggedness, limit of detection (LOD) and limit of quantification (LOQ) as per the ICH guidelines. Results: LOD was found to be 21 ng/mL. Collision energy for digoxin was observed as 35eV for QDa mass detector along with 803.5m/z precursor ion and 651m/z daughter ion. An optimal custom experimental design was employed to optimize the final dissolution conditions. The critical dissolution factors selected for optimization were pH of dissolution media, dissolution media volume, rpm (rotations per minute). The %drug release (DR) was selected as a critical quality attribute with the desired response of drug release >80% at 60minutes. Outcomes of the design were further evaluated by statistical tools including ANOVA. The final optimized dissolution method consists of 500mL of pH 7.4 buffer with a USP apparatus of I (Basket) rotating at 120 rpm. Conclusion: In this current work, we have optimized the dissolution conditions by QbD, and developed a sensitive UPLC-MS method for quantification of digoxin, that can be used in routine quality control purposes efficiently in dissolution testing and quantification of batches of low dose digoxin tablets.