Analytical Quality by Design Based Method Development for the Analysis of Cold and Cough Formulations Using an Arc Premier™ System

Importance of the Topic

Cold and cough syrups often incorporate multiple active pharmaceutical ingredients (APIs) combined with a variety of excipients, leading to complex matrices that demand efficient, precise analytical testing for quality control and regulatory compliance. A streamlined method to separate and quantify several APIs in a single run can reduce solvent use, analysis time, and operational costs while ensuring patient safety.

Objectives and Study Overview

This study aimed to develop a single ultra-high-performance liquid chromatography (UHPLC) method, guided by Analytical Quality by Design (AQbD) principles, to separate and quantify six APIs—phenylephrine, acetaminophen, doxylamine succinate, guaifenesin, dextromethorphan, and diphenhydramine—in various cough syrup formulations. The method was evaluated on four commercial products with spiked levels of potassium sorbate to assess matrix effects and robustness.

Methodology and Instrumentation

The workflow included:

• Definition of an Analytical Target Profile (ATP) focusing on resolution, precision, and reproducibility criteria.
• Risk assessment using chromatographic principles and prior knowledge to identify critical parameters (column chemistry, gradient, temperature).
• Design of Experiments (DOE) via Fusion QbD software to explore factors and establish a Method Operable Design Region (MODR).
• Optimization of gradient composition and run time to meet ATP goals.
• Verification of method performance with reproducibility, peak purity, and LOD/LOQ evaluation.

Instrumentation Used

• Arc Premier System with Quaternary Solvent Manager and Column Manager
• CORTECS Premier T3 column (2.7 µm, 2.1×100 mm) at 45 °C
• 2998 Photodiode Array detector and ACQUITY QDa mass detector
• Empower 3 and Fusion QbD software for data acquisition and AQbD design

Key Results and Discussion

The optimized method employed an 8-minute gradient from 1% to 60% acetonitrile at 0.6 mL/min. Separation achieved resolution ≥4 for all API pairs, with RSDs of retention time and peak area below 1% and tailing factors within USP limits except marginal tailing for doxylamine succinate. LODs ranged from 0.01 to 0.05 µg/mL. Method robustness was confirmed by maintaining resolution and peak purity across four formulations spiked with up to 100% excess potassium sorbate.

Benefits and Practical Applications

• Single-run analysis of six APIs reduces analysis time and solvent consumption.
• Mass spectrometry compatibility enhances identification and quantification of low-UV-absorbing compounds.
• AQbD framework ensures method robustness, reproducibility, and regulatory compliance.
• Suitable for routine QC of multi-component cough and cold products.

Future Trends and Opportunities

Advances may include integration of artificial intelligence for automated method optimization, expansion to additional dosage forms, and coupling with process analytical technology (PAT) for real-time monitoring. Further exploration of alternative stationary phases and green solvents could enhance sustainability.

Conclusion

A robust AQbD-driven UHPLC method was successfully developed and validated for simultaneous separation of six common cough syrup APIs. The approach offers a rapid, reliable solution for comprehensive quality control, aligning with ICH Q14 and USP <1220> guidelines.

Reference

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