Quality by Design (QbD) is a philosophy that refines the level of knowledge associated with a product that uses process understanding to deliver a product with the desired critical quality attributes. The objective of this study was to develop an integrated multivariate QbD approach to develop and quantify the constituent concentrations of pioglitazone hydrochloride (PGZ) drug in its pure and formulated forms. To facilitate studies investigating the determination of PGZ in bulk drug and its pharmaceutical formulations, a rapid UPLC method was developed and validated for the determination of PGZ accompanied by its degradation studies in different stress conditions. The method fulfilled validation criteria and was shown to be sensitive, with limits of detection (LOD) and quantitation (LOQ) of 0.01 and 0.05？μg？mL？1, respectively. The percent relative standard deviations for robustness and ruggedness were observed within the range of 0.1–1.74. The calibration graph was linear in the range of 0.05–300？μg？mL？1. The applicability of the method was shown by analysis of formulated drug samples and spiked human urine. The proposed method can be used for routine analysis in quality controlled laboratories for its bulk and formulated product and this is the first reported UPLC method for the assay of PGZ. 1. Introduction Quality by design is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management [1, 2]. The objective of the QbD initiative is to demonstrate both understanding and control of pharmaceutical processes to deliver high quality pharmaceutical products while affording opportunities for continuous improvement. QbD delivers a better understanding of method capabilities and limitations and ensures a superior chance of successful downstream method validation and transfer. It has become an important paradigm in the pharmaceutical industry since its introduction by the US Food and Drug Administration [3–7]. The QbD concept can be extended to analytical methods [8–15]. The analytical methods used for the analysis of active pharmaceutical ingredients (API) and drug products are an integral part of the QbD. Pioglitazone (PGZ), chemically known as [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride (Figure 1) is an oral antihyperglycemic [16] agent used for the action to treat diabetes. It belongs to thiazolidinediones (TZDs), also known as glitazones, which are a relatively
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