Process development in the QbD paradigm: Implementing design of experiments (DoE) in anti-solvent crystallization for production of pharmaceuticals

Abstract

Developing an understanding of critical process parameters and their impact on product quality attributes is crucial for implementing quality-by-design (QbD) in a pharmaceutical crystallization process. Use of statistical design of experiments (DoE) is widely accepted to be a more efficient experimental strategy for gaining the required process understanding than the traditional one-variable-at-a-time approach. In recent years, crystallization of active pharmaceutical ingredients (APIs) has been explored to generate crystals with desirable physical characteristics. Many problems in downstream processes can be attributed to poor particle characteristics established during the crystallization step. This paper presents the implementation of a DoE driven QbD approach for the anti-solvent crystallization of Dexlansoprazole API. Focused beam reflectance measurements were used to obtain crystal morphology data. Minitab19 statistical software was utilized for experimentation design and analysis. The empirical model thus created was statistically relevant. The model has been further used to design a control strategy to enable in-process control of the crystal size distribution during crystallization, as expected in the QbD paradigm. We expect that the proposed approach may benefit those wishing to achieve consistency in product quality during API crystallization.