Development and Validation of a Stability‐Indicating High‐Performance Liquid Chromatography Method Coupled With a Diode Array Detector for Quantifying Haloperidol in Oral Solution Using the Analytical Quality‐by‐Design Approach

Abstract

This study developed a stability‐indicating HPLC‐DAD method for quantifying haloperidol in oral solution using analytical quality‐by‐design principles. Haloperidol stability was tested under acidic, alkaline, oxidative, and photolytic stress conditions. The analytical quality‐by‐design approach began by defining the analytical target profile and identifying critical material attributes and critical method parameters via risk analysis. Factorial and Box–Behnken designs, conducted in Design Expert 13, were used to select critical method parameters and determine the method operable design region. The oral solution degraded significantly under acidic and alkaline conditions. Continuous critical method parameters such as mobile phase flow rate, gradient slope, column temperature, and pH were optimized. A quadratic Box–Behnken design with critical method attributes was applied and validated, resulting in robust regression models with significant p‐values (> 0.05), absence of lack‐of‐fit (p‐values < 0.05), and R2‐adjusted > 0.85. The method proved selective, accurate, and precise within the method operable design range. Normal operating conditions (NOCs) were established using a Waters Symmetry C18 column with a 100‐mM formate buffer (pH 3.8) and acetonitrile, with a gradient profile and detection at 246 nm. The operational region included flow rates between 1.2 and 1.35 mL/min (NOC = 1.3 mL/min), temperatures of 8°C–20°C (NOC = 15°C), and mobile phase pH variations from 3.3 to 4.3 (NOC = 3.8). The analytical quality‐by‐design–based method was robust and effective for stability monitoring, reducing subjectivity while maximizing reliability.