Comparative study between the Full Factorial, Box–Behnken, and Central Composite Designs in the optimization of metronidazole immediate release tablet
Sriram Narukulla, Subhasri Bogadi, Vyshnavi Tallapaneni, Bharat Kumar Reddy Sanapalli, Sanju Sanju, Azmat Ali Khan, Abdul Malik, Hasi Rani Barai, Tonmoy Kumar Mondal, Veera Venkata Satyanarayana Reddy Karri, Αθανάσιος Αλεξίου, Sai Kiran S. S. Pindiprolu, Gowthamarajan Kuppusamy, Vetriselvan Subramaniyan, Md. Rabiul Islam, Marios Papadakis
Abstract
This article summarizes the fundamentals, benefits, and limitations of various models of Design of Experiments such as 2-Level Full Factorial Design, Central Composite Design, and Box-Behnken Design while establishing a comparison between these models by taking the Metronidazole immediate release tablets as a case study. • Pharmaceutical Quality by Design is a systematic approach to development that begins with predetermined objectives, product and process understanding, process control based on sound science, and quality risk management. • Pharmaceutical Quality by Design improves manufacturing quality performance to ensure a safe and effective drug supply to the consumer. • Tools like Risk Assessment, Design of Experiments, and Multi-Variate Data Analysis are required to implement Pharmaceutical Quality by Design. • While full-factorial design involves only one-way and two-way interactions, higher-order interactions are well understood in composite and Box-Behnken designs. • Box-Behnken does not study the factors at their extremities, making it less efficient than composite design. • Compared to all the study designs, the composite design was good at predicting an optimized formulation in numerical optimization. The Composite design sometimes has the risk of crossing the toxicity limit of a factor due to the α points present in the design. The purpose of this paper is to summarize the fundamentals, benefits and limitations of various models of Design of Experiments (DoE) such as 2-Level Full Factorial Design, Central Composite Design (CCD), and Box-Behnken Design (BBD) while establishing a comparison between these models by taking the Metronidazole immediate release (IR) tablets as a case study. Metronidazole IR tablets were prepared by wet granulation method. The Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) were selected based on literature review and prior knowledge about the formulation. Critical Material Attributes (CMA) (concentration of binder, super disintegrant, and glidant), and Critical Process Parameters (CPP) (compression of the tablets) were identified based on their risk to the CQA. Screening and optimization of the CMA were performed using DoE. From the Full Factorial Design, it was observed that the disintegration time and dissolution at 30 mins were significantly influenced by the selected CMAs. These significant factors were further optimized using CCD and BBD to achieve the constraints (minimum disintegration and maximum dissolution). The levels of povidone K30, crospovidone, and magnesium stearate were optimized to 10 mg, 32 mg, and 1.6 mg respectively using CCD and BBD.