Optimizacija procesov in formulacij pri 3D tiskanju tablet

Kreft, Klemen (author), Dreu, Rok (mentor)

Farmacevtska skupnost je zaradi potreb po bolj personaliziranem zdravljenju primorana razvijati nove načine za pripravo zdravil. 3D tiskanje je ena izmed potencialnih tehnologij, ki omogoča izdelavo trdnih farmacevtskih oblik s prilagojenim odmerkom. Kljub odobritvi prvega 3D tiskanega zdravila s strani FDA je področje še v fazi intenzivnih raziskav. V sklopu doktorske disertacije smo se osredotočili na dve tehnologiji 3D tiskanja: tehnologijo ciljnega nalaganja in praškovno brizgalno tehnologijo. Pri tehnologiji ciljnega nalaganja 3D tiskalnik pri povišani temperaturi pretvori vstopni material - filament (1.75 mm debela polimerna nit) v končno farmacevtsko obliko. V prvi fazi smo določili ključne parametre tiskanja, ki vplivajo na kritična atributa kakovosti, tj. čas razpadnosti tablete in enakomernost mase tablet. Izdelava filamentov s tehnologijo iztiskanja talin obsega segrevanje materiala s potencialnim razpadom učinkovine. V izogib razpadu učinkovine smo razvili preparativno metodo diferenčne dinamične kalorimetrije, ki uspešno napove celokupne nečistote modelne učinkovine v filamentu. Predstavljena metodologija omogoča hitro rešetanje sestav filamentov z vidika neustrezne termične stabilnosti učinkovine. Ko filament izdelamo, mora za prehod tiskalne glave izkazovati ustrezne mehanske lasnosti. V nasprotnem primeru se filament zagozdi v podajalnem mehanizmu. Določili smo preprost mehanski test togosti, ki opredeli filament glede na uspešnost tiskanja. Rezultate smo podprli z napovednim statističnim modelom. Poleg tega smo na podlagi meritev mehanskih in reoloških lastnosti filamentov uspešno napovedali ponovljivost nekaterih kritičnih atributov natisnjenih tablet. Napovedni modeli omogočajo hitro rešetanje filamentov, ki bi se zagozdili v podajalnem mehanizmu ali bi prispevali k veliki variabilnosti lastnosti tablet. Praškovno brizgalna tehnologija omogoča povezovanje praškaste zmesi in vezivne tekočine pri sobnih pogojih v orodisperzibilno trdno farmacevtsko obliko. Natisnjene tablete so zaradi slabih mehanskih lastnosti nagnjene k poškodbam pri rokovanju. V doktorski disertaciji smo na modelni formulaciji določili parametre tiskanja, ki izboljšajo mehanske lastnosti tablet. Po drugi strani pa je bil vpliv sestave vezivne tekočine na mehanske lastnosti tablet zanemarljiv.

• Language: Slovenian
• Keywords: 3D tiskanje, personalizirana zdravila, tehnologija ciljnega nalaganja, praškovno brizgalna tehnologija, bolniku prilagojen odmerek, razvoj formulacij in procesa.
• Work type: Doctoral dissertation
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-152453
• Publication date in RUL: 26.11.2023

Secondary language

• Language: English
• Title: Optimization of process and formulations in 3D tablet printing

Abstract

Pharmaceutical community is developing new approaches for a more personalized treatment. 3D printing is one of the technologies that enables the production of solid dosage forms with a tailored dose, if needed. In the doctoral dissertation, we focused on two 3D printing technologies: fused deposition modelling and binder jetting. In fused deposition modelling, the 3D printer converts the incoming material - filament (1.75 mm thick drug loaded polymer thread) into the dosage form at an elevated temperature. Firstly, we identified the printing parameters that affect the critical quality attributes of tablet disintegration time and tablet mass uniformity. Manufacturing of filaments via hot-melt extrusion technology involves elevated temperatures with potential drug degradation. We developed a preparative method employing differential scanning calorimetry, which is able to simulate the occurrence of the total impurities of the model drug in the filament after extrusion. The presented methodology enables quick screening of potential filament compositions to ensure sufficient thermal stability of the drug substance during processing. Once the filament is prepared, it should have adequate mechanical properties to effortlessly pass through the printhead. Otherwise, the filament will break or jam the feeding mechanism. We have identified a simple mechanical surface stiffness test that through predictive statistical model assesses filament feedability. In addition, we successfully predicted the reproducibility of certain critical attributes of printed tablets based on the mechanical and rheological properties of the filaments. In binder jetting, the deposited powder blend is bound by the binding liquid into an orodispersible solid dosage form. Printed tablets may be susceptible to damage during handling due to poor mechanical properties. In the doctoral dissertation, we identified the printing parameters that improve the mechanical properties of printed tablets based on model formulation. Contrary, the influence of the binding liquid composition on the mechanical properties was negligible.

• Keywords: 3D printing, personalized medicine, fused deposition modelling, binder jetting, patient-tailored dose, formulation and process development