title: Investigating Pharmaceutical 3D Printing: From Process Assessment to Product Characteristics
Creators: name: Pflieger, Thomas Rainer
Publisher: name: Universität Tübingen
Year: 2024
Subjects: subject: 3D-Druck , Arzneiform , Individualisierte Medizin , Granulat , Rheologie , Freisetzung , Polymere , Pharmazeutische Technologie

description: In recent years, pharmaceutical 3D printing (3DP) has emerged as a revolutionary technology with profound importance for personalized drug manufacturing. By employing additive manufacturing principles, this innovative technology enables the production of pharmaceutical oral dosage forms with tailored properties, such as release kinetics, and shapes previously unattainable by conventional methods. Unlike the conventional “one size fits all” approach, the convergence of pharmaceuticals to patient needs holds potential for enhancing drug efficacy, patient compliance, and therefore therapeutic outcomes. As the field continues to advance, pharmaceutical 3DP offers unprecedented opportunities for innovation in the pharmaceutical industry, but also raises new research questions. The main goal of this thesis was to explore the use of 3DP as a pharmaceutical tool for personalized therapy. This involved a thorough assessment, covering everything from analyzing the fundamental scientific processes to examining the characteristics of the final products. One objective included employing small amplitude shear oscillatory (SAOS) rheology to investigate pharmaceutical granules of two polymers, establishing correlations between polymer viscosity and printability for a novel 3DP setup. The novelty lies in the technical design of the printhead, as granules-fed single screw extrusion was used to produce tablets. The findings highlight the critical importance of the printing temperature for successful printability of a formulation, constrained by process parameters and API decomposition. Material characterization through differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA) helped to understand at which temperatures and formulation compositions thermal stability and component miscibility is given. Uniformity of mass and dosage were tested and conformed to European Pharmacopoeia (Ph. Eur.) standards. Also, the sustained release properties of 3D printed tablets containing theophylline (TPH), a drug with a narrow therapeutic window (NTW), were precisely explored. Through a Taguchi orthogonal array design of experiments (DOE), tablet design parameters were optimized for process stability and tailored dosages in terms of statistical effect sizes, signal-to-noise ratios (S/N) and factor level related standard deviations (SDs). Release profiles were analyzed with various mathematical models, establishing a predictable relationship between printed doses and sustained drug release kinetics. In-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling confirmed the tablets' efficacy for a selected patient group. Additionally, the potential of 3DP for combination therapy, printing bi-layered tablets with the drugs TPH and prednisolone (PSL), was investigated. This study aimed to understand the interaction between separate distinctive tablet compartments on individual drug dissolution release profiles. Employing a full factorial statistical experimental design, various doses were produced and analyzed for their drug release profiles. The results indicated that the addition of a second compartment did not significantly influence TPH's sustained release, while PSL's immediate release was influenced but still reached the required release rates. The bi-layered tablets showed high release curve similarity to mono-tablets, confirming the feasibility of dose individualization in combination therapies without altering proportional drug release. Overall, this thesis helps to take another step towards precise dosages, targeted release profiles, and effective combination therapies through pharmaceutical 3DP.