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.
Keywords: Dissolution, Method development, Low dose Digoxin tablets, QbD approach, UPLC-MS, Quality control
Graphical Abstract
3