Date of Award
Doctor of Philosophy (PhD)
Cho, Byung Rae
Greenstein , Joel S.
Kurz , Mary Elizabeth
Seeking the optimal pharmaceutical formulation is considered one of the most critical research components during the drug development stage. It is also an R&D effort incorporating design of experiments and optimization techniques, prior to scaling up a manufacturing process, to determine the optimal settings of ingredients so that the desirable performance of related pharmaceutical quality characteristics (QCs) specified by the Food and Drug Administration (FDA) can be achieved. It is widely believed that process scale-up potentially results in changes in ingredients and other pharmaceutical manufacturing aspects, including site, equipment, batch size and process, with the purpose of satisfying the clinical and market demand. Nevertheless, there has not been any single comprehensive research work on how to model and optimize the pharmaceutical formulation when scale-up changes occur. Based upon the FDA guidance, the documentation tests for scale-up changes generally include dissolution comparisons and bioequivalence studies. Hence, this research proposes optimization models to ensure the equivalent performance in terms of dissolution and bioequivalence for the pre-change and post-change formulations by extending the existing knowledge of formulation optimization. First, drug professionals traditionally consider the mean of a QC only; however, the variability of the QC of interest is essential because large variability may result in unpredictable safety and efficacy issues. In order to simultaneously take into account the mean and variability of the QC, the Taguchi quality loss concept is applied to the optimization procedure. Second, the standard 2×2 crossover design, which is extensively conducted to evaluate bioequivalence, is incorporated into the ordinary experimental scheme so as to investigate the functional relationships between the characteristics relevant to bioequivalence and ingredient amounts. Third, as many associated FDA and United States Pharmacopeia regulations as possible, regarding formulation characteristics, such as disintegration, uniformity, friability, hardness, and stability, are included as constraints in the proposed optimization models to enable the QCs to satisfy all the related requirements in an efficient manner. Fourth, when dealing with multiple characteristics to be optimized, the desirability function (DF) approach is frequently incorporated into the optimization. Although the weight-based overall DF is usually treated as an objective function to be maximized, this approach has a potential shortcoming: the optimal solutions are extremely sensitive to the weights assigned and these weights are subjective in nature. Moreover, since the existing DF methods consider mean responses only, variability is not captured despite the fact that individuals may differ widely in their responses to a drug. Therefore, in order to overcome these limitations when applying the DF method to a formulation optimization problem, a priority-based goal programming scheme is proposed that incorporates modified DF approaches to account for variability.
The successful completion of this research will establish a theoretically sound foundation and statistically rigorous base for the optimal pharmaceutical formulation without loss of generality. It is believed that the results from this research will have the potential to impact a wide range of tasks in the pharmaceutical manufacturing industry.
Li, Zhe, "RESEARCH AND DEVELOPMENT EFFORT IN DEVELOPING THE OPTIMAL FORMULATIONS FOR NEW TABLET DRUGS" (2012). All Dissertations. 915.