title: Formulation Development for 3D Printing of Immediate Release Cabozantinib Tablets with Personalized Dosage
Creators: name: Lenhart, Jonas
Publisher: name: Universität Tübingen
Year: 2025

description: 3D printing as an additive manufacturing technique has proven valuable in many fields. Primarily, the ability to produce prototypes quickly and the flexible production options make this technology desirable. Due to strict regulatory requirements, pharmaceutical production is not very flexible when using new technologies. However, work has also been ongoing for many years on the possibilities and challenges of additive manufacturing for producing pharmaceuticals and medical devices. The first market approvals have already been achieved. There are, however, several different technologies in the field of 3D printing. The following thesis deals with the fused filament fabrication (FFF) process. In this process, objects are printed by melting a mixture of polymer and other excipients, layering them, and allowing them to cool and solidify. There are two ways to move the material to a position where it can be molten. The first is mainly used in hobby printing and small-scale production and consists of producing so-called filaments employing melt extrusion. This filament can be seen as a thread of constant thickness, which is then pushed through the heated nozzle of a 3D printer by a conveyor element. The other option is to convey pellets or powder of the polymer directly to the nozzle using a screw or piston to melt it under pressure and shear to produce the melt required for printing. This approach is relatively new in commercial 3D printing. In the present work, such direct extrusion is used. Possible fields of application for 3D printing in the pharmaceutical sector are primarily preparations that require close patient-specific dosing since the process is much slower and more expensive than tablet pressing and, therefore, not attractive for the broad mass of drugs. This study aimed to develop a formulation for the immediate release of the active ingredient cabozantinib (CAB). It is used in cancer therapy, and its dosage is regularly adjusted to the individual patient due to its side effect profile. Available prescription drugs offer only a limited possibility for individual dosing, as is known from the production of injectable cancer therapeutics. Doses of 20-140 mg are desired depending on the type of cancer, while only 20 mg increments are possible, and several tablets must be taken due to the combination of different strengths. To produce 3D-printed tablets containing cabozantinib, the active ingredient must be incorporated at some point. In the case of filament printing, the active ingredient can be incorporated directly into the filament during production or subsequently introduced using a solvent-based process. Using ibuprofen and different solvents, the second of the two methods was tested on commercial PVA filament and rejected as too disadvantageous. The next step was to focus on extrusion and direct printing from the powder. For the first steps of formulation development, loperamide (LOP) was selected as a model drug based on the solubility parameters of cabozantinib. Manipulating the dosage via a change of the infill and adding further excipients to improve the dissolution rate were tested. The findings of these trials were transferred to the ongoing formulation development containing CAB. The poor solubility of CAB is why an attempt was made here to process it in the form of a solid amorphous dispersion. The release and apparent solubility can be improved for many substances in such a way. Additionally, to achieve higher solubility, the dissolution rate had to be improved to reach the goal of immediate release. Mixing sorbitol with the polymers was done for two reasons. First, its highly water-soluble nature leads to the expectation of an improved dissolution rate for the mixture. Second, miscibility with the polymers and the plasticizing effects lead to a reduced extrusion and printing temperature, which is necessary to avoid thermal degradation of CAB. In addition to sorbitol, the class of disintegrants croscarmellose sodium (CCS) and sodium starch glycolate (SSG) were used to accelerate release. Finally, formulations were developed with an immediate release of CAB. An approach for designing individual dosages from a powder mixture of constant drug concentration was developed using these formulations. It uses the drug concentration, desired dose, and experimentally determined density of the printed mixture to calculate the computer-aided design (CAD) parameters for a capsule-shaped tablet. With this approach, printing 20-140 mg dosages in 10 mg increments could be realized in individual tablets. To gain further insight into the printing behavior, the melt rheology of many formulations was tested using a small-amplitude oscillatory shear rheology testing setup. The results indicate the need for relatively low viscosity for successful printing. State-of-the-art methods such as DSC, STA, XRD, and Raman microspectroscopy were used to characterize excipients and the final tablets.