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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.

SUBMITTER: Chun MH

PROVIDER: S-EPMC8467219 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Currently, acute upper respiratory tract infections (AURTIs) are increasingly becoming a significant health burden. Gankeshuangqing dispersible tablets (GKSQDT) which have a good effect on treating AURTIs. GKSQDT is composed of baicalin and andrographolide. However, its severe bitterness limits application of patients. Due to the addition of plentiful accessories, common masking methods are unsuitable for GKSQDT. It is thus necessary to develop a new masking method.The Previous study showed that baicalin was less bitter than andrographolide. Thus, particle coating technology was adapted to prepare composite particles that baicalin coated on the surface of andrographolide to decrease bitterness. Initially, particle size of baicalin and coating time of composite was investigated to prepare composite. Then, scanning electron microscopy, wettability, and infrared (IR) spectrogram were used to characterize the microstructure of composite. Furthermore, electronic tongue test, animal preference experiment, and human sensory test were applied to evaluate the masking effect.To produce composite, baicalin should be ground in vibromill for 6 min. Then, andrographolide fine powder was added to grind together for 6 min. Contact angle of composite was smaller than mixture, and more similar to baicalin. Other physical characterization including microstructure, wettability, and IR also suggested that andrographolide was successfully coated by baicalin superfine. Furthermore, taste-masking test indicated taste-masked tablets was less bitter than original tablets.The study indicated that particle coating technology can be used for taste masking of GKSQDT without adding other substance. Moreover, it provides a new strategy of taste masking for national medicine.A new strategy to mask bitterness without adding any other substance based on coating technology was providedThe masking effect was confirmed by electronic tongue test, animal preference experiment and human sensory test. Abbreviations used: AURTIs: Acute Upper Respiratory Tract Infections; GSQDT: Gankeshuangqing Dispersible Tablets; IR: Infrared Spectrogram; LHPC: Low-substituted Hydroxypropyl Cellulose; CAs: Contact Angles; FTIR: Fourier Transform Infrared Spectra.

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

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