Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach

Abstract

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in–line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

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“…2C. From the DSC and the FTIR studies, it can be concluded that Metformin HCl is highly compatible with other excipients used in the formulation 11,12 .…”

Fixed-Dose Combination Formulations in Solid Oral Drug Therapy: Advantages, Limitations, and Design Features

“…This is demonstrated by the work of Chun et al, 2021 in which bilayer tablets were manufactured consisting of high-dose metformin in a sustained-release layer with low-dose dapagliflozin L-proline incorporated into an immediate-release layer. The optimized bilayer tablet showed similar in vitro and in vivo profiles to the reference drug, demonstrating bioequivalence of the test product and the control drug [ 171 ]. The same concept is demonstrated by Vimovo ® (Grünenthal; naproxen, esomeprazole 500/20 mg), which has been developed as a sequential-delivery tablet system comprising an outer immediate-release esomeprazole layer with an enteric coated naproxen core [ 172 ].…”

Development and Evaluation of Cannabidiol Orodispersible Tablets Using a 23-Factorial Design

“…OFAT approach requires a large number of experiments and does not allow evaluation of the interaction that exists between the factors, which may lead to inadequate conduction of the development and optimization. To overcome these problems, design of experiment (DoE) strategies are recommended to obtain better results with few numbers of experiments [ 34 , 35 , 36 , 37 , 38 ]. For developing CBD ODTs, a two-level full factorial design with three variables was used.…”