Quality-by-design driven approach in the formulation of an anti-ulcer and gastro-protective oral suspension

Abstract

Objective

This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions.

Methods

Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs’ and CPPs’ impact on identified CQAs was further assessed through a 2² full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile.

Conclusions

The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

Keywords:

• Design of experiments
• factorial design
• risk management
• design space
• control strategy
• viscosity
• sucralfate

Acknowledgements

G.H. is grateful to Laboratorio Raven for allowing her to do the formulation and analytical evaluation in their facilities. The graphical abstract was created with BioRender under the license of LANOTEC.

Disclosure statement

S.V. and Y.M. work in the Research and Development department at Laboratorio Raven S.A., a Costa Rican pharmaceutical company of generic drug products. The co-authors have no conflict of interest regarding the research presented in this article, and their involvement is based solely on their scientific expertise and objective contribution. G.H. is a master’s student in the field of the NANOMED ERASMUS MUNDUS program. L.C. current affiliation is the Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS) at Université Paris Cité.

Additional information

Funding

G.H. is funded by the Education, Audiovisual and Culture Executive Agency (EACEA) of the European Commission in the field of the Erasmus Mundus Joint Master Degree (EMJMD) in Nanomedicine for Drug Delivery (NANOMED).