(342e) A Reduced-Order Mechanistic Tablet Coating Model to Capture Downstream Drug-Release Variability.

The drug release process of pharmaceutical tablets is divided into three phases: the lag phase, the zero-order phase, and the decaying phase. In the case of coated tablets, the underlying mechanism of release can be governed by osmotic pumping or diffusion, depending on the permeability of the coating layer. Although mechanistic models to predict drug release profiles of film coated tablets have been proposed, the expected variability in release profiles for a batch of coated tablets is an open question ^[1]. Furthermore, understanding the impact of tablet coating on the expected variability in release profiles is important for better process control on the coating process, especially at different operating scales. A model-driven tablet coating approach will aid in achieving a tightly controlled drug release profile for the entire batch, especially in the case of controlled-release tablets. In order to develop a quality by design (QbD) approach for tablet coating and dissolution, it is necessary to examine the variability of both processes.

First, we adopt a reduced-order mechanistic model to describe the quality of the tablet coating process in terms of dimensionless numbers ^[2]. Second, we measure the drug release profile of a randomly selected sample set of the coated tablets. We then statistically investigate the correlation between the process parameters, the coating dimensionless numbers, and the measured variability in the drug-release profile of the batch. From the results, we examine whether inter-tablet coating variability (i.e., the nonuniform coating layer thickness across tablets) indicates downstream dissolution variability. In this context, inter-tablet variability is represented by the coefficient of variation (CoV) of coating mass between tablets produced in a single batch, for which approximate closed form equations can be found in the literature ^[3]. Finally, the CoV is incorporated into the mechanistic tablet dissolution model to predict the drug release profile. The overarching goal of the proposed work is to maintain the quality of tablet coating and the drug release profile of the batch simultaneously during scale-up.

References:

1. Kaunisto, Erik, et al. "Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems." International journal of pharmaceutics1 (2011): 54-77.
2. am Ende, Mary Tanya, and Alfred Berchielli. "A thermodynamic model for organic and aqueous tablet film coating." Pharmaceutical development and technology1 (2005): 47-58.
3. Kalbag, Arjun, and Carl Wassgren. "Inter-tablet coating variability: tablet residence time variability." Chemical Engineering Science11 (2009): 2705-2717.

Author Disclosure: All authors are Sanofi employees and may hold shares and/or stock options in the company.