Development of mechanistic models to identify critical formulation and process variables of pastes for 3D printing of modified release tablets

Ahmed Zidan; Alaadin Alayoubi; Sarah Asfari; James Coburn; Bahaa Ghammraoui; Sabir Aqueel; Celia N Cruz; Muhammad Ashraf

doi:10.1016/j.ijpharm.2018.11.044

Development of mechanistic models to identify critical formulation and process variables of pastes for 3D printing of modified release tablets

Int J Pharm. 2019 Jan 30:555:109-123. doi: 10.1016/j.ijpharm.2018.11.044. Epub 2018 Nov 16.

Authors

Ahmed Zidan¹, Alaadin Alayoubi², Sarah Asfari³, James Coburn⁴, Bahaa Ghammraoui⁴, Sabir Aqueel², Celia N Cruz², Muhammad Ashraf²

Affiliations

¹ Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA. Electronic address: Ahmed.Zidan@fda.hhs.gov.
² Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA.
³ Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA; Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, FDA, MD, USA.
⁴ Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, FDA, MD, USA.

PMID: 30453019
DOI: 10.1016/j.ijpharm.2018.11.044

Abstract

The future of pharmaceutical manufacturing may be significantly transformed by 3-dimensional (3D) printing. As an emerging technology, the indicators of quality for materials and processes used in 3D printing have not been fully established. The objective of this study was to identify the critical material attributes of semisolid paste formulations filled into cartridges for 3D printing of personalized medicine. Nineteen semisolid formulations were prepared per a fractional factorial design with three replicates of the center point. The variables investigated included percent loading of API and various soluble and insoluble excipients. Pastes were characterized for viscoelastic characteristics during the 3D printing process including creep recovery, cross-modulus and extrudability models. Packing efficiency of pastes into 3D printing cartridges was also evaluated by X-ray tomography. Changes in composition of 3D printing pastes resulted in significant variations in their viscoelastic parameters, namely their elastic deformation, flow and relaxation behaviors. The percent of soluble excipients incorporated was the most significant factor affecting the creep behavior of pastes. Cross-over stresses were assessed to indicate the minimum pressure needed for the pastes to initiate flow. Increasing solid and swellable contents of the pastes from 7% to 63% w/w increased significantly (p < 0.05) the cross-over stress from 0.93 × 10^-3 Pa to 9.47 × 10^-3 Pa. Increasing soluble ingredients of paste from 30% to 80% w/w was found to increase flow of the paste from 0.41 × 10^-3 to 3.85 × 10^-3 %/s. X-ray tomography images revealed inclusion of air bubbles during packing of pastes into cartridges. These bubbles may affect the relaxation behavior of the pastes; hence bubbles should be eliminated. This study unveiled the critical material attributes that could be controlled for consistent 3D printing by microextrusion.

Keywords: 3D printing; 3D printing pastes; Additive manufacturing; Micro-extrusion; Modified release tablets; Personalized medicine.

Published by Elsevier B.V.

MeSH terms

Chemistry, Pharmaceutical / methods
Delayed-Action Preparations
Drug Liberation
Excipients / chemistry*
Models, Theoretical*
Pharmaceutical Preparations / administration & dosage
Pharmaceutical Preparations / chemistry
Printing, Three-Dimensional*
Solubility
Tablets
Technology, Pharmaceutical / methods*

Substances

Delayed-Action Preparations
Excipients
Pharmaceutical Preparations
Tablets