Evaluation of Chromatographic Methods for Drug Products Containing Polar and Non-Polar Molecules Using Reversed Phase, Hydrophilic Interaction, and Ion Exchange Chromatography

Abstract

In recent years the pharmaceutical industry has developed an increasing variety of complex double or triple combination drug therapies. Method development for these combination drug products is particularly challenging when the analytes have significantly different polarities, often requiring multiple chromatographic methods for each active component. An alternative to the commonly used practice of developing multiple reversed phase chromatographic methods for analyzing small molecules in combination drug products is discussed herein. Ion exchange chromatography offers many advantages to other chromatographic techniques for the analysis of combination products if one of the molecules is highly polar (log P < 0) and the other moderately polar to non-polar (log P ≥ 0). As the primary mode of retention for ion exchange chromatography is based upon the charge of the molecule, the hydrophobicity of the molecule does not play as large of a part in the retention mechanism. As long as all of the molecules being analyzed are ionizable, retention on an ion exchange column should be possible. The analysis of polar and non-polar molecules simultaneously using ion exchange chromatography is a unique process, and the approach of developing accurate and robust analytical methods for analysis of all active pharmaceutical ingredients in a combination product by a single fast ion exchange method differs from the industry standard of using reverse phase methodology first. Six well characterized pharmaceuticals with varying degrees of polarity (metformin HCl, isoniazid, sodium nitroprusside, timolol maleate, naproxen sodium, and clonidine hydrochloride) have been chromatographically evaluated using RP, HILIC, and ion exchange chromatography. In addition, a well characterized pharmaceutical product, Metaglip™ Tablets, containing the highly polar molecule metformin HCl and the moderately non-polar glipizide, has been analyzed using a cation exchange (CE) HPLC method and compared to chromatography and results generated using RP-HPLC and hydrophilic interaction (HILIC)-HPLC.