Abstract
Arformoterol (R, R) is an enantiomer of racemic formoterol, was the first long-acting beta agonist (LABA), approved by U.S. food and Drug Administration (FDA). The Arformoterol which is used for the treatment of Chronic obstructive pulmonary disease (COPD) are inhaled bronchodilator drugs which are delivered directly to the patient’s airways through a different mechanism. The formulated drug product is kept for stability study as per ICH guideline [1] and during its stability interval analysis by HPLC (High performance liquid chromatography), an unknown peak observed at level around 0.1% which is well below the identification threshold of 0.5% but after heating it crossed the identification threshold. The approach to identify anonymous species of Arformoterol aqueous formulation was adopted as first to generate the impurity in sample, isolate, enrich and Characterize through LC-MS/MS and NMR Spectroscopy. Based on the spectral data the anonymous species was identified as an “Imine impurity”, it is secondary degradant of Amine impurity of Arformoterol formed due to reaction with leachable observed in LDPE respules.
Highlights
Arformoterol was the first long-acting beta agonist (LABA) approved by the US Food and Drug Administration (FDA) for nebulized delivery
The formulated drug product is kept for stability study as per ICH guideline [1] and during its stability interval analysis by HPLC (High performance liquid chromatography), an unknown peak observed at level around 0.1% which is well below the identification threshold of 0.5% but after heating it crossed the identification threshold
Based on the spectral data the anonymous species was identified as an “Imine impurity”, it is secondary degradant of Amine impurity of Arformoterol formed due to reaction with leachable observed in Low density polyethylene (LDPE) respules
Summary
Arformoterol was the first long-acting beta agonist (LABA) approved by the US Food and Drug Administration (FDA) for nebulized delivery. The respules are manufactured from Low density polyethylene (LDPE). Low density polyethylene is produced by the polymerization of ethylene at high pressure and temperature. The material is tough but possesses moderate tensile properties and exhibits creep It has good impact and chemical resistance. The formaldehyde is generated during manufacturing of Low Density Polyethylene (LDPE) because of multiple technologies are involved, the widely High Pressure Process (HPP) is used which involves uses of peroxide catalyst at 100 ̊C - 300 ̊C and produces low density polymer which has a low melting point. The formaldehyde can be liberated through the manufacturing procedure for LDPE (Low Density Polyethylene) in the melt of thermoplastics which comprises small admixtures of polyacetal. The formaldehyde liberated from the LDPE process reacts with Amine Impurity of Arformoterol which results Imine product in presence of aqueous formulation the final product formed in this process known as Schiff’s base [7] [8]
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