LC and LC-MS Evaluation of Stress Degradation Behavior of Carvedilol

Abstract

In the present study, forced and accelerated degradation studies of carvedilol (CAR) were carried out according to ICH guideline Q1A (R2). The drug was subjected to acid (1.0 N HCl), alkaline (1.0 N NaOH), and neutral hydrolytic conditions by refluxing at 90°C, as well as to oxidative (7.5% H₂O₂) decomposition, protected from light, at room temperature. Photolysis was carried out in solid state of the drug and in methanolic solution. The stress degradation samples were evaluated by LC and LC–MS. The kinetics of degradation were determined by the LC method, previously developed and validated for our group, that could separate the degradation products formed under various stress conditions.

An LC-MS/MS method was developed and validated and was found to be precise, accurate, specific, and selective. Tablets of CAR from three different batches (A,B,C) were subjected to climate chamber with 40±2°C and 75%±5 relative humidity for 6 months to evaluate the stability under accelerated conditions. The samples were assayed by LC-MS/MS and UV methods. The weight variation, hardness, disintegration time, friability, content, and dissolution test were also performed. The drug was relatively stable under acidic, neutral, and photolytic stress conditions, but showed instability under alkaline and oxidative conditions. The LC–MS m/z values of the two products obtained under oxidative conditions were 224.3 and 283.3 Daltons, respectively. The parameters of quality such as hardness, disintegration time, and dissolution were influenced by humidity and temperature for product B.

Keywords:

• Accelerated stability
• Carvedilol
• Forced degradation
• LC-MS/MS method
• Tablets

ACKNOWLEDGMENTS

The authors thank FIPE (Fundo de Incentivo à Pesquisa) and FAPERGS (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul) for the financial support.

Notes

Values of correlation coefficients, r, for three reaction orders.

^a Mean of three replicates.

^b Mean of two days.

^c RSD = Relative standard deviation.

^a Mean of three replicates.

^b Mean of two analysts.

^c RSD = Relative standard deviation.

^a Mean of three replicates.

^b RSD = Relative standard deviation.

^a Sem is the standard error of the mean.

^b The recommnended chromatographic conditions were acetonitrile:acetic acid 0.1% 80:20 (v/v) as mobile phase, Synergi Fusion C₁₈ column, column temperature of 40°C, 1 mL/min flow rate (split 1:5) and 20 µL of injection volume.

^a Mean of three determinations.

N = Newton.

Specifications: ^a Mean ± 7,5%, ^b maximum 30 minutes in water, ^c minimum 30 N, ^d maximum 1.5%, ^e variation: 85–115% and relative standard deviation ≤6%, ^f %dissolved: ≥85% in 60 minutes in buffer acetate pH 4.5.