MODERNIZATION OF USP MONOGRAPHS FOR NAPHAZOLINE HYDROCHLORIDE AND PHENIRAMINE MALEATE OPHTHALMIC AND NASAL SOLUTIONS

Importance of the Topic

The modernization of USP monographs for naphazoline hydrochloride and pheniramine maleate ophthalmic and nasal solutions addresses evolving regulatory expectations and analytical challenges. Up-to-date compendial methods ensure accurate quality control, improved safety margins, and reliable detection of impurities in commonly used allergy‐relief formulations.

Objectives and Study Overview

This study aimed to update three USP monographs—naphazoline HCl nasal solution, naphazoline HCl ophthalmic solution, and the combined pheniramine maleate/naphazoline HCl ophthalmic solution—by developing a unified liquid chromatography (LC) method. Key goals included simultaneous assay of active pharmaceutical ingredients (APIs) and their related substances, enhanced specificity, and compliance with modern safety standards.

Methodology and Instrumentation

A reversed‐phase LC method was optimized through systematic screening of columns, mobile phases, pH levels, gradient profiles, and additives. Sample preparations involved dilution of standard and commercial formulations in a 90:10 water/acetonitrile diluent.

Used Instrumentation

• LC System: ACQUITY Arc with photodiode array (PDA) detector and ACQUITY QDa mass detector
• Column: XSelect CSH C18, 4.6×150 mm, 5 µm; 40 °C
• Mobile Phase A: 0.05% triethylamine & 0.05% phosphoric acid in water
• Mobile Phase B: 0.05% phosphoric acid in acetonitrile; flow rate 2.0 mL/min
• Detection: PDA at 280 nm; MS ESI+ and ESI–, 100–250 Da

Key Results and Discussion

• Chromatographic Resolution: Achieved baseline separation of APIs and related substances with USP resolution ≥2.2.
• Peak Tailing: Inclusion of triethylamine reduced pheniramine tailing from 2.2 to 1.5.
• Linearity and Sensitivity: Calibration curves (80–120%) yielded R2 >0.999; signal‐to‐noise ratios ≥30 at 0.1% impurity level.
• System Suitability: Five replicate injections showed <1% RSD in retention times and peak areas.
• Recovery: API recoveries in commercial eye and nasal products ranged between 90–110% per USP limits.
• Spectral Purity: UV and MS peak purity tools confirmed homogeneity of pheniramine and naphazoline peaks.

Benefits and Practical Applications

The single LC method simplifies quality‐control workflows by combining assay and related substance testing for multiple monographs. Integration of mass detection accelerates analyte identification and peak confirmation, enhancing laboratory efficiency in pharmaceutical analysis.

Future Trends and Potential Applications

• Adoption of high‐resolution MS for comprehensive impurity profiling.
• Method transfer to automated and online QC platforms for real‐time monitoring.
• Extension to new formulations and preservative systems in ophthalmic and nasal products.
• Implementation of chemometric tools for rapid method development and robustness testing.

Conclusion

A robust, single LC method was developed to modernize three USP monographs for naphazoline HCl and pheniramine maleate solutions. The approach delivers reliable separation, accurate quantification, and spectral confirmation of APIs and impurities, meeting current regulatory and quality demands.

References

1. USP Monograph, Naphazoline Hydrochloride Nasal Solution, USP40-NF35, The United States Pharmacopeia Convention, official December 2017
2. USP Monograph, Naphazoline Hydrochloride Ophthalmic Solution, USP40-NF35, The United States Pharmacopeia Convention, official December 2017
3. USP Monograph, Naphazoline Hydrochloride and Pheniramine Maleate Ophthalmic Solution, USP40-NF35, The United States Pharmacopeia Convention, official December 2017