The Need in Orthogonal Chromatographic Methods for a Small Molecule Project in Innovative Drug Development

Vladimir Ioffe, Analytical Development, CMC, Innovative R&D, Teva Pharmaceuticals Industries, Ltd., Netanya, Israel
Roxanne Schwartz, Analytical Development, CMC, Innovative R&D, Teva Pharmaceuticals Industries, Ltd., Netanya, Israel
Maher Kaadan, Analytical Development, CMC, Innovative R&D, Teva Pharmaceuticals Industries, Ltd., Netanya, Israel
Lev Keisar, Analytical Development, CMC, Innovative R&D, Teva Pharmaceuticals Industries, Ltd., Netanya, Israel
Gregory Verba, Analytical Development, CMC, Innovative R&D, Teva Pharmaceuticals Industries, Ltd., Netanya, Israel

The aim of this talk is to work out a mindset of developer of HPLC methods and to converse the need in complementary (or alternative) “orthogonal” chromatographic procedures and diverse detection techniques for complex coverage of all the possible characteristics of a biologically active (pharmaceutical) material. To illustrate this attitude, a case study of such a mindset is provided, on an example of a comparatively simple molecule. TV-3606 is a novel molecule aimed at MS therapy as an oral drug form, having a chemical structure close to a known drug, Riluzole, for treatment of amyotrophic lateral sclerosis (ALS). An RP HPLC method has been developed for testing the drug substance, capable of analyzing the main substance, as well as to quantitatively determine synthetic impurities and degradation products, thus being a discriminative stability indicating analytical procedure. Due to water insolubility, a lipid-based formulation has been developed, which demanded to either develop a complex extraction procedure, or chose an alternative analytical technique – normal phase HPLC – where the entire drug product may be dissolved in eluent-compatible solvent. For testing the formulated drug product, which is hard gelatin capsules filled with a solution of TV-3606 in medium chain triglyceride, an alternative technique, NP HPLC method has been established. On the example of the case, the principles of HPLC method development, both for RP and NP chromatography, are discussed in terms of various retention mechanisms and their combinations in chromatographic separations. Special attention is given to available tools in development of NP HPLC methods. Since NP HPLC provides fewer possibilities in mobile phase composition for optimization of separation, a “scouting of columns” had to be applied. Understanding of the usefulness of less volatile solvents in NP HPLC was gained. One of the most important points in analytical development for pharmaceutical industry which should be taken into account in an industrial R&D – to develop reliable and robust methods, friendly to a terminal user and – as simple as possible, taking into account that they are intended to be routinely run by QC analytical laboratories at a production site (“QC-able procedures”).