Fanous, Marina, Bitar, Malak, Gold, Sarah, Sobczuk, Adam, Hirsch, Stefan, Ogorka, Joerg and Imanidis, Georgios (2021) Immediate Release 3D-Printed Dosage Forms for Poorly Soluble Drugs: Development and Exploration of Morphology-Dissolution Relationship. International journal of pharmaceutics, 26. p. 120417. ISSN DOI: 10.1016/j.ijpharm.2021.120417

Abstract

3D-printing technologies such as Fused Deposition Modeling (FDM) bring a unique opportunity for personalized and flexible near patient production of pharmaceuticals, potentially improving safety and efficacy for some medications. However, FDM-printed tablets often exhibit tendency for slow dissolution due to polymer erosion based dissolution mechanisms. Development of Immediate Release 3D-printed dosage with poorly water-soluble model compounds is even more challenging, but required to ensure wide applicability of the technology within pharmaceutical development portfolios. In this work, morphology and process for a selected formulation were considered, using BCS class IV compound lumefantrine as a model drug. Basic butylated methacrylate copolymer (Eudragit EPO) as matrix former, as well as hydrophilic plasticizer xylitol and pore former maltodextrin were selected as a promising formulation approach to achieve fast dissolution rates. Tablets of size 9 x 5 x 4 mm, i.e. acceptable for children from 6 years old, were successfully 3D-printed. Tablets with 5% lumefantrine and corresponding placebo were printed, higher drug load as required for clinically relevant dosage strength however lead to increased brittleness incompatible with FDM printing. Residual crystallinity in manufactured tablets and filaments was explored by highly sensitive Raman mapping technique. Lumefantrine was present in the fully amorphous state in the tablets as intended. Grid-designed 3D-printed tablets with 65% infill density met rapid release criteria, while 80% and 100% showed slower dissolution. For the first time, the critical structural characteristics of 3D-printed tablets with non-continuous surface such as accessible porosity, specific surface area by weight and by volume were quantified by an automated micro-CT based methodology, and were confirmed to be responsible for the dissolution rate acceleration. Increase in accessible porosity, total surface area, specific surface area by weight and by volume and decrease in relative density appeared to be critical factors for modification of lumefantrine dissolution rate, whereas increase in closed pores volume did not contribute to accelerating dissolution rate. To conclude, Immediate Release FDM-tablets with BCS class IV compound were developed and key dissolution parameters were detected with non-destructive accurate morphological analysis.

Item Type:	Article
Date Deposited:	24 Mar 2021 00:45
Last Modified:	24 Mar 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43421