(T1330-08-53) Personalized Orodispersible Films Using Extrusion 3D-Printing: An Impending Shift in Pharmaceutical Manufacturing

Purpose: Orodispersible films (ODFs) are solid dosage forms that disintegrate in mouth rapidly for faster API release and convenient ingestion by geriatric and pediatric patients. ODF is a dosage form of choice for patients with dysphagia. The ease of fabrication, consumption, and transportation makes it an attractive dosage form, especially for pharmacists, as they can dispense personalized dosage forms to patients customized to their needs. Pediatric patients could be prescribed low-dose ODFs, whereas geriatric patients with multimorbidity could be provided multiple drugs loaded ODFs. When placed on tongue, ODF should be flexible and thin to disintegrate comfortably, without any inconvenience to patients, and endure the mechanical stress upon transport. Such ODFs are usually prepared with a time- and resource-intensive film casting technique. 3D printing is a layer-upon-layer fabrication technique that could directly tailor size, dose, layers, and type of medication in the ODFs. This customization is highly significant within narrow therapeutic index drugs and conditions seeking faster relief. 3D printing also provides flexibility to incorporate various actives into ODFs considering the specific medical situation of patients. In this study, we fabricated multilayered ODFs utilizing various extrusion-based technologies utilizing the same active formulation. A single table-top printer was employed to investigate the feasibility of three extrusion-based technology to fabricate ODFs for compounding setting on-demand. Pneumatic extrusion and syringe-pump mechanical extrusion required a semisolid dispersion preparation step before preparing the ODFs, whereas thermoplastic extrusion required just a single step of melt mixing to fabricate multilayered ODFs. The process reproducibility and product consistency were evaluated for all printing technologies. Various printing parameters and conditions were altered to investigate their effect on the final ODF. Sumatriptan succinate (SMT), a 5-HT receptor agonist used for migraine headaches, was utilized as the model drug for investigation.

Methods: Pneumatic extrusion and mechanical extrusion involve prior preparation of semisolid feed, which is investigated for its rheological properties, followed by printability/extrudability. The semisolid dispersion was cast on a film to screen several hydrophilic polymers, and few were optimized for the 3D-Printing techniques. For the thermoplastic extrusion, all the utilized excipients were investigated for their thermal properties using DSC to look into their compatibility with SMT. Variations in printing parameters and formulation composition were assessed for their impact on final ODF. The impact of nozzle/needle size and diameter and in-process drying of the platform was investigated. The 3D models of ODFs were designed in SolidWorks, exported as STL file, and sliced using SLICER before loading into printer. The standard ODF investigation size was 2 cm*2cm* 0.3 cm (6 cm*2cm*0.3 cm for mechanical testing). ODFs, once formed, were characterized using thickness measurement (five-point caliper testing), folding endurance, film brittleness, and disintegration test. The characterization was further followed up with morphological examination (high-resolution microscopy, SEM), thermal analysis (DSC), wettability (Contact angle), Surface pH, Disintegration time, Mechanical properties (Puncture test, tensile strength) and Dissolution studies. The content uniformity and SMT assay were performed for each batch using High-Performance Liquid Chromatography (HPLC).

Results: The overall technologies and experimental procedures involved in this project are outlined in the schematic representation, as shown in Figure 1. After screening numerous hydrophilic polymers, three were selected and found appropriate to compare all three extrusion-based technologies. The melting point and thermal profile of excipients were crucial in proceeding forward, primarily with batches involving thermoplastic extrusion. The weight uniformity of the ODFs was crucial in considering the consistency of the printing process for all three techniques. An optimized ODF formulation composition was utilized for comparison. The ODFs from pneumatic and syringe-based extrusion printheads consistently created bulk batches with little to no variation. Even though the time required for formulation development of dispersion and rheological characterization was intensive, it assured the printability and final ODF formation. The rheological characterization, wettability, and morphological observations of ODFs are represented in Figure 2. Syringe-based extrusion consistently showed high precision, whereas pneumatic extrusion showed quick fabrication of batches of ODFs briefly. Pneumatic extrusion with a needle was relatively more time-consuming than nozzle-based printing, but the latter significantly improved printing resolution. Thermoplastic-based extrusion evaded the need for initial hydrogel feed preparation but faced the challenges of uniformly mixing multiple components. The drug and excipients remain stable/consistent in fabricated ODF with thermoplastic extrusion using extensive heat. The overall mechanical testing of the ODFs with all three technologies was performed, and all final products were feasible for packaging and transport. The results from mechanical testing and thermal profiling of SMT and excipients are represented in Figure 3.

Conclusion: Pneumatic extrusion offered quick fabrication; syringe-pump extrusion demonstrated precision in extruded volume, whereas thermoplastic extrusion avoided the dispersion preparation step. All three technologies appear promising in rapid ODF prototyping, thus saving time and enabling small-scale batch preparation. The possibility of consecutive application of three technologies in a single film to create multilayered ODFs is under investigation, opening up myriad possibilities in multi-drug ODF design.

Schematic representation of Orodispersible films fabrication process

Rheological characterization of prepared semisolid dispersions and surface characterization of ODFs

Thermal/Mechanical Characterization of ODFs prepared with semisolid-based extrusion and thermoplastic extrusion technology