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 TM 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.

Abstract. The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.