Quality by Design (QbD)-Driven Development of Metformin HCl Sustained-Release Tablets via Fused Deposition Modeling 3D Printing

Abstract

This study explains how we used systematic Quality by Design (QbD) approach to develop slow-release metformin HCl tablets. We did this specifically using a 3D printing method called Fused Deposition Modeling (FDM). To find the best settings for printing, we employed a Box-Behnken design. This helped us identify the ideal temperature range (between 150 and 180°C), the best layer thickness (from 0.1 to 0.3 mm), and the optimal internal density (80-100%) for the tablets. We looked closely at the physical form of the metformin inside the tablets using techniques like XRPD, DSC, and TGA. Our findings confirmed that the drug formed an amorphous dispersion, meaning it was evenly spread throughout the tablet and remained stable even when heated. The specific recipe we created, which included a particular polymer known as High PVA Formulation (HPF), allowed the drug to release steadily over time. This achieved what\'s called zero-order release kinetics, and the tablet had a high dissolution efficiency of 71.25%. It successfully delivered 90% of the drug within 12 hours. Importantly, its release pattern was very similar to a commercially available product, Glucophage® XR, with a similarity factor (f2) of 68.41. When we analyzed the release data using the Korsmeyer-Peppas model, it suggested that the main way the drug left the tablet was through simple diffusion (n= 0.426). By applying this QbD-guided FDM printing method, we were able to precisely control the tablet\'s internal structure. This demonstrates that this 3D printing technique holds promise as a practical and scalable platform for creating personalized generic medicines, especially for treating type 2 diabetes.

Introduction

The oral route is the most preferred method of drug delivery due to convenience, safety, and low cost. For chronic diseases such as type 2 diabetes, sustained-release (SR) tablets help maintain steady drug levels and reduce dosing frequency. Metformin HCl, a first-line antidiabetic drug, requires SR formulations because of its short half-life and gastrointestinal side effects. However, conventional manufacturing struggles to achieve precise drug-release control, prompting the need for advanced techniques.

This study integrates Quality by Design (QbD) with Fused Deposition Modeling (FDM) 3D printing to develop sustained-release Metformin HCl tablets with predictable and customizable release profiles. QbD is used to identify and optimize Critical Quality Attributes (CQAs) such as dissolution efficiency, similarity factor, and tablet integrity. A three-factor, three-level Box-Behnken Design (BBD) evaluates the effects of printing temperature, layer height, and infill density on drug release behavior.

Formulations were prepared using Metformin HCl, HPMC K4M (for sustained release), PVA (for printability), and triethyl citrate as a plasticizer. Filaments were produced via hot-melt extrusion and printed into tablets using an FDM 3D printer. Characterization methods—XRPD, DSC, and TGA—confirmed drug amorphization, polymer compatibility, and thermal stability during processing.

In vitro dissolution studies (simulating gastric to intestinal pH transition) showed controlled drug release influenced by internal tablet architecture. Higher infill densities and optimized layer heights produced stronger, slower-releasing tablets, while lower densities increased release rates. Data modeling using similarity factors and regression analysis helped establish a design space for robust sustained-release performance.

Conclusion

This study successfully demonstrated the development of generic sustained-release 3D-printed Metformin HCl tablets using hot-melt extrusion and fused deposition modeling. Solid-state analysis confirmed the complete amorphization of Metformin within the polymer matrix, ensuring stability during processing. Dissolution studies revealed that all formulations achieved controlled release over 12 hours, with the Original Formulation showing the highest similarity (f? = 89.07) to the reference product Glucophage XR. Release kinetics were best explained by the Higuchi model, indicating diffusion-controlled drug release, with variations in erosion contribution depending on formulation design. Overall, the results confirm that FDM 3D printing can be a reliable platform for producing robust sustained-release oral dosage forms, while formulation optimization via DoE enables precise (Yu et al., 2014) tailoring of drug release profiles.

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Copyright © 2025 Vignesh Babu Sekar, Sreemoy Kanti Das. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.