20.500.12556/RUL-190143 Uporaba diferenčne dinamične kalorimetrije za oceno kompatibilnosti zdravilnih učinkovin in polimerov pri razvoju amorfnih trdnih disperzij z iztiskanjem talin Use of differential scanning calorimetry for the drug-polymer compatibility assessment in the development of amorphous solid dispersions by hot-melt extrusion Pri načrtovanju in pripravi farmacevtskih oblik z zdravilnimi učinkovinami z nizko topnostjo predstavljajo amorfne trdne disperzije pomemben pristop za izboljšanje njihove biološke uporabnosti. Amorfna oblika zdravilne učinkovine ima v primerjavi s kristalno obliko praviloma večjo navidezno topnost in hitrejše raztapljanje. Za uspešno stabilizacijo zdravilne učinkovine v amorfnem stanju je pomembna izbira ustreznega polimernega nosilca. V naši nalogi smo kompatibilnost treh zdravilnih učinkovin, paracetamola, lidokaina in mesalazina, s sedmimi polimernimi nosilci ocenili z diferenčno dinamično kalorimetrijo. Na termogramih smo spremljali predvsem pojav enega steklastega prehoda in odsotnost talilnega vrha zdravilne učinkovine med drugim segrevanjem. Na podlagi rezultatov smo izbrali najprimernejše sisteme ob upoštevanju termične stabilnosti ter lastnosti taline polimernih nosilcev, pomembnih za iztiskanje talin. Izbrane sisteme smo nato uporabili za pripravo filamentov s paracetamolom in lidokainom, medtem ko je bilo iztiskanje formulacije z mesalazinom zaradi neustreznih procesnih pogojev prekinjeno. Pripravljene filamente smo ponovno analizirali z diferenčno dinamično kalorimetrijo, da bi preverili nastanek amorfne trdne disperzije. Pri lidokainu so dobljeni termogrami podprli nastanek homogene amorfne trdne disperzije, medtem ko amorfnega stanja pri paracetamolu in mesalazinu ni bilo mogoče nedvoumno potrditi. V nadaljnjem koraku smo izdelanim filamentom izmerili premer in preverili njihove mehanske lastnosti ter s tem ocenili njihovo uporabnost pri tehnologiji 3D tiskanja. Mehanske lastnosti filamentov smo ovrednotili z analizatorjem teksture in tritočkovnim upogibnim preizkusom, pri čemer smo določili razdaljo do loma in upogibno napetost ob lomu, iz površinske togosti pa izračunali indeks procesibilnosti. Premer filamentov s paracetamolom in lidokainom je ustrezal predvideni vrednosti, vendar so le filamenti s paracetamolom izpolnjevali vse mehanske kriterije za 3D tisk, medtem ko so bili filamenti z lidokainom zaradi nezadostne togosti, potrjene z indeksom procesibilnosti, neustrezni. Rezultati so pokazali, da je diferenčna dinamična kalorimetrija uporabno orodje za začetno oceno kompatibilnosti zdravilnih učinkovin s polimernimi nosilci, vendar je pri razvoju formulacij z metodo iztiskanja talin treba upoštevati tudi procesne lastnosti celotnega sistema, predvsem viskoznost in pretočnost taline ter odpornost proti toplotnim in mehanskim obremenitvam. Uspešna izdelava filamentov s to metodo še ne zagotavlja njihove ustreznosti za uporabo v tehnologiji 3D tiskanja, saj morajo filamenti izkazovati tudi ustrezne mehanske lastnosti. In the development and preparation of pharmaceutical dosage forms with poorly soluble active pharmaceutical ingredients, amorphous solid dispersions represent an important approach for improving their bioavailability. Compared with the crystalline form, the amorphous form generally exhibits higher apparent solubility and a faster dissolution rate. An appropriate polymeric carrier is therefore important for stabilizing the active pharmaceutical ingredient in the amorphous state. In this study, the compatibility of three active pharmaceutical ingredients, paracetamol, lidocaine, and mesalazine, with seven polymeric carriers was evaluated using differential scanning calorimetry. The thermograms were assessed for the presence of a single glass transition and the absence of a melting peak of the active pharmaceutical ingredient during the second heating cycle. Based on these results, suitable systems were selected considering the thermal stability and melt properties of the polymeric carriers relevant to hot-melt extrusion. Selected systems were then used to prepare filaments containing paracetamol and lidocaine, whereas extrusion of the mesalazine formulation was discontinued due to unsuitable processing conditions. The prepared filaments were subsequently analyzed by differential scanning calorimetry to assess the amorphous solid dispersion formation. For lidocaine, the obtained thermograms supported the formation of a homogeneous amorphous solid dispersion, whereas the amorphous state of paracetamol and mesalazine could not be unequivocally confirmed. The diameter and mechanical properties of the prepared filaments were determined to assess suitability for 3D printing. Mechanical properties were evaluated using a texture analyzer and a three-point bending test, with both the breaking distance and breaking stress determined, while the processability index was calculated from surface stiffness. The diameter of the paracetamol- and lidocaine-containing filaments was within the target range; however, only the paracetamol-containing filaments met all mechanical criteria for 3D printing, whereas the lidocaine-containing filaments were unsuitable due to insufficient stiffness, as confirmed by the processability index. The results demonstrated that differential scanning calorimetry is useful for the preliminary assessment of the compatibility of active pharmaceutical ingredients with polymeric carriers. However, formulation development using hot-melt extrusion also requires consideration of the processing properties of the entire system, particularly melt viscosity and flowability, as well as resistance to thermal and mechanical stresses. Successful filament production does not in itself ensure suitability for 3D printing, as the filaments must also exhibit appropriate mechanical properties. amorfne trdne disperzije polimerni nosilci diferenčna dinamična kalorimetrija iztiskanje talin filamenti amorphous solid dispersions polymeric carriers differential scanning calorimetry hot-melt extrusion filaments true false false [E. Špringer] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-10-23 08:45:11 2026-10-23 08:45:21 2026-11-02 10:50:09 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 615(043.2) 133502 303415043 36130.pdf 36130.pdf 1 2C238E419BD9B63A3A925E1689F08DB5 3302faf152001d1c1eab1c421db68d1f3745f4802211cb5ead60f2335381d7a9 53c0c228-cead-11f1-aea2-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=251310 36131.docx 36131.docx 1 12F0F475C24F7F9BC2FE23CAD97D4023 ef84c5d763bea45c801d54473cf854244b99347a59cbda629dce01b17150791f 53c16d03-cead-11f1-aea2-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=251311 Fakulteta za farmacijo 0 0 0