A quality by design approach to impurity method development for atomoxetine hydrochloride (LY139603).

The development of an ion-pairing HPLC method and associated system suitability parameters for the analysis of atomoxetine hydrochloride (LY139603 HCl) using a quality by design approach is described. Potential method conditions were evaluated for their ability to meet design requirements and statistically designed experiments were used to optimize conditions and demonstrate method robustness for the separation of atomoxetine and impurities. The separation of two early eluting impurities, phenyl methylaminopropanol (PMAP (+/-)3-methylamino-1-phenylpropanol) and mandelic acid is correlated to the separation of other impurities that elute near the main sample component and the resolution of this peak pair is used as a system suitability test without the need for impurity reference standards.

A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials.

Establishing appropriate impurity specifications for active pharmaceutical ingredient (API) starting materials is an important component of the commercialization and registration of an API. Multiple sources and routes of manufacture of starting materials and the capability of the API synthetic process for tolerating impurities introduced with starting materials must be understood. A strategy for purity method development and use test evaluation of starting materials to aid in establishing quality requirements is described.

Determination of the enantiomer and positional isomer impurities in atomoxetine hydrochloride with liquid chromatography using polysaccharide chiral stationary phases.

A normal-phase isocratic chiral liquid chromatographic method has been developed and validated for atomoxetine hydrochloride. In addition to the S-enantiomer of atomoxetine, the conditions separate both para and meta positional isomers and the phenyl des-methyl analog. Method development strategies included (a) evaluation of polysaccharide-based chiral stationary phases with nonaqueous mobile phases, (b) the use of an octyl stationary phase with a sulfated-beta-cyclodextrin mobile phase additive, and (c) capillary electrophoresis using a single isomer heptakis-6-sulfato-beta-cyclodextrin modifier.