Article: A research and development effort in developing the optimal formulations for new tablet drugs using design of experiments: part 2 (bioequivalence studies) Journal: International Journal of Experimental Design and Process Optimisation (IJEDPO) 2012 Vol.3 No.1 pp.68 - 90 Abstract: As an extension to the dissolution comparison studies in Part 1, this paper further examines the optimal levels of inactive ingredients of a formulation, when excipient changes occur which require crossover designs be performed to demonstrate bioequivalence between the pre-change and post-change formulations. In this paper, a standard 2 × 2 crossover study, as a special type of experimental design, is integrated into the ordinary framework. In addition to the discrete computational method for assessing bioequivalence that is suggested by the FDA, we further develop a continuous method to calculate critical quality characteristics. Incorporating the Taguchi quality loss concept and regulatory requirements, we propose an enhanced formulation optimisation model by simultaneously considering both the mean and variance of related characteristics. A numerical example is given to verify the effectiveness of our proposed approach. Additionally, the simulated results show that the continuous assessment method produces more desirable optimal formulations than the discrete one. Inderscience Publishers - linking academia, business and industry through research

Title: A research and development effort in developing the optimal formulations for new tablet drugs using design of experiments: part 2 (bioequivalence studies)

Authors: Zhe Li; Byung Rae Cho; Brian J. Melloy

Addresses: Department of Industrial Engineering, Clemson University, Clemson, SC 29634, USA. ' Department of Industrial Engineering, Clemson University, Clemson, SC 29634, USA. ' Department of Industrial Engineering, Clemson University, Clemson, SC 29634, USA

Abstract: As an extension to the dissolution comparison studies in Part 1, this paper further examines the optimal levels of inactive ingredients of a formulation, when excipient changes occur which require crossover designs be performed to demonstrate bioequivalence between the pre-change and post-change formulations. In this paper, a standard 2 × 2 crossover study, as a special type of experimental design, is integrated into the ordinary framework. In addition to the discrete computational method for assessing bioequivalence that is suggested by the FDA, we further develop a continuous method to calculate critical quality characteristics. Incorporating the Taguchi quality loss concept and regulatory requirements, we propose an enhanced formulation optimisation model by simultaneously considering both the mean and variance of related characteristics. A numerical example is given to verify the effectiveness of our proposed approach. Additionally, the simulated results show that the continuous assessment method produces more desirable optimal formulations than the discrete one.

Keywords: formulation optimisation; scale-up changes; bioequivalence; design of experiments; DOE; biopharmaceutics classification system; BCS; Taguchi methods; loss function; tablet drugs; new drugs; drug formulation; crossover designs; continuous computational methods.

DOI: 10.1504/IJEDPO.2012.045615

International Journal of Experimental Design and Process Optimisation, 2012 Vol.3 No.1, pp.68 - 90

Published online: 27 Aug 2014 *

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Title: A research and development effort in developing the optimal formulations for new tablet drugs using design of experiments: part 2 (bioequivalence studies)

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