Development and Validation of a Stability-Indicating UPLC Method for the Determination of Hexoprenaline in Injectable Dosage Form Using AQbD Principles.

Jesús Alberto Afonso Urich,Dalibor Jeremic,Viktoria Marko,Raymar Andreína Lara García,Katharina Boehm,Amrit Paudel

doi:10.3390/molecules26216597

Abstract

A novel and efficient stability-indicating, reverse phase ultra-performance liquid chromatographic (UPLC®) analytical method was developed and validated for the determination of hexoprenaline in an injectable dosage form. The development of the method was performed using analytical quality by design (AQbD) principles, which are aligned with the future requirements from the regulatory agencies using AQbD principles. The method was developed by assessing the impact of ion pairing, the chromatographic column, pH and gradient elution. The development was achieved with a Waters Acquity HSS T3 (50 × 2.1 mm i.d., 1.8 µm) column at ambient temperature, using sodium dihydrogen phosphate 5 mM + octane-1-sulphonic acid sodium salt 10 mM buffer pH 3.0 (Solution A) and acetonitrile (Solution B) as mobile phases in gradient elution (t = 0 min, 5% B; t = 1 min, 5% B; t = 5 min, 50% B; t = 7 min, 5% B; t = 10 min, 5% B) at a flow rate of 0.5 mL/min and UV detection of 280 nm. The linearity was proven for hexoprenaline over a concentration range of 3.50–6.50 µg/mL (R2 = 0.9998). Forced degradation studies were performed by subjecting the samples to hydrolytic (acid and base), oxidative, and thermal stress conditions. Standard solution stability was also performed. The proposed validated method was successfully used for the quantitative analysis of bulk, stability and injectable dosage form samples of the desired drug product. Using the AQbD principles, it is possible to generate methodologies with enhanced knowledge, which can eventually lead to a reduced regulatory risk, high quality data and lower operational costs.

Highlights

Introduction published maps and institutional affilHexoprenaline sulphate is a selective β2 -adrenoreceptor agonist that is used as a bronchodilator by oral or intravenous routes and by inhalation [1], and is indicated for the use in the treatment of bronchospasm associated with obstructive airways diseases, including asthma, bronchitis and emphysema [1,2]
Using the chromatography methods as an analytical technique can fulfill the needed stability-indicating condition [13], and the UPLC was chosen as a suitable tool due to having a faster response and lower solvent consumption
The proposed analytical methodology was validated according to ICH Q2 guidelines, confirming to be linear, accurate, precise, specific and robust

Summary

Introduction

Hexoprenaline sulphate is a selective β2 -adrenoreceptor agonist that is used as a bronchodilator by oral or intravenous routes and by inhalation [1], and is indicated for the use in the treatment of bronchospasm associated with obstructive airways diseases, including asthma, bronchitis and emphysema [1,2]. Hexoprenaline has been proven to have a comparable response and tolerability to other tocolytic drugs, with no major negative effects on the short and long term neonatal outcome [9,10]. Hexoprenaline is marketed as a free base, and as a dihydrochloride or sulphate salt. The oral and injectable dosage form of hexoprenaline, even if is not widely approved in all major markets, has some approved marketing authorizations among some members states of the European Union [11]. There is no compendial analytical methodology for the characterization of the molecule, and the number of analytical methodologies iations

Methods

Results

Conclusion