Cinacalcet hydrochloride (CNT) is a novel calcimimetic agent widely used in the treatment of hyperparathy- roidism. For the first time, the authors utilized the novel concept of analytical procedure development employing several unique scientific tools for quantification CNT from its pharmaceutical dosage form. The objective behind the present work was to establish a scientifically sound and systematic work frame that overcomes the drawbacks of the earlier reported method for estimating CNT level in samples and ensuring superior method performance throughout the analytical life-cycle. In this process, at first, the risky method variables were earmarked and were subjected to a response surface methodology, followed by Monte-Carlo simulation (MCS) based robust- ness-cum-optimization studies. The inclusion of the MCS approach assessed the method performance with no additional laboratory experimentation and established the innovative hyphenation's aptness with chemometrics tools. The control strategies were established based on analytical design space and method performance evaluation results by a simulative approach. The study revealed that methanol %, flow rate, and pH are the three critical method variables influencing analytical attributes: retention time, the number of plates, and tailing. The analytical conditions include a C18 column (150mm × 4.6mm, 5μm) with an isocratic mobile phase (80:20, % v/v) of methanol and 0.01M KH2PO4 buffer (pH maintained at 3.5 using orthophosphoric acid) flowing at 1.1ml/min. Diode array detection was performed at 282 nm. Method validation was befitting to federal needs as linearity (0.5-160 μg/ml), accuracy (>99%), and precision below 1% of relative standard deviation are indicative of method suitability for the purpose. In a nutshell, the present method describes a typical analytical workflow with the significant advantage of obtaining more excellent scientific information with less systematized experimentation. It was found suitable for routine quality control of CNT in drug substance and drug product.
