Analytical Quality by Design Based Method Development for the Analysis of Cold and Cough Formulations

Importance of the topic

Cold and cough syrup formulations often contain multiple active ingredients that require separate analytical assays, leading to high solvent consumption and extended development times. Implementing a single, robust chromatographic method enhances efficiency, reduces hazardous waste, and ensures consistent quality control in pharmaceutical laboratories.

Objectives and study overview

The study applied Analytical Quality by Design (AQbD) principles to develop a unified HPLC method capable of separating and quantifying six APIs commonly found in cold and cough formulations across diverse excipient matrices. Key objectives included:

• Defining an Analytical Target Profile (ATP) for method performance criteria.
• Conducting a structured risk assessment to identify critical parameters.
• Using Design of Experiments (DOE) to optimize chromatographic conditions.
• Verifying method robustness and applicability to commercial products.

Methodology and instrumentation

A four-stage AQbD workflow was implemented: ATP definition, risk assessment, DOE, and verification. An Arc Premier UHPLC system equipped with a Quaternary Solvent Manager, Column Manager, solvent select valve, and QDa Mass Detector facilitated automated condition screening. Four 2.1×100 mm, 2.7 μm CORTECS Premier columns (C18, C18+, T3, Phenyl) were evaluated. Fusion QbD software guided DOE, while Empower software processed chromatographic data.

Main results and discussion

Risk analysis highlighted column chemistry, temperature, and gradient time as high-impact variables. DOE established a robust design space, selecting a CORTECS Premier T3 column at 45 °C with a 9-minute gradient to achieve baseline resolution (>4) and tailing factors <1.5. Verification runs confirmed predicted retention times, peak area precision (RSD <0.5%), and high peak purity. Application to four commercial syrup products spiked with potassium sorbate (0–100% levels) demonstrated consistent performance and spectral homogeneity.

Benefits and practical applications

• Single-run assay for multiple APIs reduces development time.
• Lower solvent usage and hazardous waste generation.
• Automated workflow promotes reproducibility and efficiency.
• Suitable for routine QA/QC in pharmaceutical manufacturing.

Future trends and potential applications

Advancements may include integration of machine-learning algorithms for predictive method optimization, real-time monitoring via advanced detectors, adoption of greener solvent systems, and extension of AQbD strategies to other complex dosage forms.

Conclusion

The AQbD-based HPLC method developed using Fusion QbD and Empower software delivers a robust, efficient solution for multi-component cold and cough analysis. Its verified performance aligns with regulatory expectations, streamlining quality control and minimizing resource consumption.

References

1. T. Dongala, N. K. Katari, A. K. Palakurthi, S. B. Jonnalagadda. Biomed Chromatogr. 2019;33(11):e4641.
2. F. Alkhateeb, R. Cleary, P. Rainville, M. Maziarz. Robust and Rapid Method Development for Analysis of Active Pharmaceutical Ingredients in Multi-Component Cold and Flu Medication. Waters Application Note 720006287.
3. M. Maziarz, P. Rainville. Robust and Rapid Method Development for Analysis of Active Pharmaceutical Ingredients in Multi-Component Cold and Flu Medication. Waters Application Note 720006523.