20.500.12556/RUL-169211 Vpliv vrste polimera in procesnih parametrov na lastnosti trdnih disperzij nifedipina, izdelanih z iztiskanjem talin The influence of polymer type and process parameters on the properties of nifedipine solid dispersions produced by hot-melt extrusion Izboljšanje biološke uporabnosti slabo vodotopnih učinkovin je eden izmed poglavitnih izzivov sodobne farmacije. To lahko dosežemo na več načinov, med drugim tudi s pretvorbo učinkovine iz kristalne v amorfno obliko oz. tvorbo amorfne trdne disperzije. Gre za enofazni sistem, sestavljen iz molekul slabo vodotopne zdravilne učinkovine, razpršene ali raztopljene v enem ali več polimernih nosilcev. Tvorba amorfnih trdnih disperzij je pomembna predvsem iz vidika topnosti in večje biološke uporabnosti, saj med raztapljanjem omogočajo začasno višjo koncentracijo zdravilne učinkovine. Ena izmed najučinkovitejših tehnologij za pripravo trdne disperzije je iztiskanje talin. Cilj magistrske naloge je bil z variiranjem procesnih parametrov iztiskanja talin pripraviti popolnoma amorfno trdno disperzijo z visokim deležem nifedipina (49,5 %) in Soluplusom® ali Kollidonom® VA64 kot polimernim nosilcem. V programu Umetrics MODDE® smo pripravil štiri eksperimentalne načrte in rezultate statistično obdelali. Raziskali smo kako variiranje procesnih parametrov vpliva na odstotek kristala, vsebnost in hitrost sproščanja učinkovine v pripravljeni amorfni trdni disperziji. Ugotovili smo, da pri konstantni temperaturi cevi in hitrosti obratov vijakov ekstruderja ni zaznati pomembnega vpliva hitrosti doziranja materiala na delež rezidualnega kristala. Pri višjih temperaturah procesa (v režimu mešanja) preostali parametri iztiskanja nimajo vpliva na učinkovitost tvorbe amorfne trdne disperzije. Pri nižjih temperaturah procesa (v režimu topnosti) smo se tališču učinkovine približali z dovajanjem mehanske energije. Ta je odvisna tako od temperature cevi (preko navora) kot tudi od hitrosti obratov vijakov in hitrosti dovajanja materiala v ekstruder. Dokazali smo, da z variiranjem procesnih parametrov lahko uspešno pridobimo enofazni in dobro mešljiv sistem, pri čemer se amorfni nifedipin uspešno razprši v polimernem nosilcu, ter ni zaznati rezidualne kristalinične učinkovine. Statistični modeli so pokazali, da imata višja temperatura ekstruzijske cevi in višji obrati vijakov negativen vpliv na delež rezidualnega kristala. Po drugi strani variiranje procesnih parametrov ni vplivalo na vsebnost učinkovine. Ta je ostala stabilna pri vseh kombinacijah procesnih parametrov. Izbrana metoda sproščanja se je izkazala kot manj primerna za preučevanje hitrosti in odstotka sproščene učinkovine, zato rezultatov te metode ni bilo mogoče povezati s stopnjo kristaliničnosti. Izkazalo se je, da je učinkovina bolj topna v Kollidonu® VA64, saj je bil delež rezidualnega kristala nižji v primerjavi z vzorci izdelanimi pri enakih parametrih iztiskanja ob uporabi Soluplusa® kot polimernega nosilca. Improvement of the bioavailability of poorly water-soluble active ingredients is one of the main challenges in modern pharmacy. This can be achieved with different approaches, one being by converting the active ingredient from its crystalline to amorphous form, thus forming an amorphous solid dispersion. This is a single-phase system composed of molecules of poorly water-soluble active ingredients dispersed or dissolved in one or more polymeric carriers. The formation of amorphous solid dispersions is particularly important in terms of solubility and improved bioavailability, as they enable temporarily increased concentration of the active ingredient during dissolution. One of the most effective technologies for the preparation of solid dispersions is hot-melt extrusion. The aim of this master's thesis was to prepare a completely amorphous solid dispersion with a high percentage of nifedipine (49.5%) and Soluplus® or Kollidon® VA64 as the polymeric carrier, by varying the process parameters. In the Umetrics MODDE® program we prepared four experimental designs and presented the results through statistical models. We investigated how the variation of process parameters affects residual crystallinity, content, and release rate of the active ingredient in the prepared amorphous solid dispersion. The results showed that with constant barrel temperature and screw speed, no significant effect of material feed rate on the percentage of residual crystal was observed. At higher process temperatures (in the miscibility regime) remaining extrusion parameters had no effect on the ability to form an amorphous solid dispersion. At lower process temperatures (in the solubility regime) we approached the melting point of the active ingredient by applying mechanical energy, which depended on both the barrel temperature (via torque) and screw speed as well as the material feed rate. We proved that by varying the process parameters, we can successfully obtain a single-phase and well-miscible system, in which amorphous nifedipine is effectively dispersed in the polymeric carrier, with no detectable residual crystal. Statistical models showed that higher barrel temperatures and screw speeds reduced the percentage of residual crystal. On the other hand, varying process parameters did not affect the active ingredient content which remained stable across all combinations of process parameters. The chosen release method was not suitable for studying the release rate and percentage of released active ingredient. Consequently the results could not be linked to the residual crystallinity. It was found that the active substance was more soluble in Kollidon® VA64, as the residual crystal content was lower compared to samples made with Soluplus® as the polymeric carrier under the same extrusion parameters. amorfna trdna disperzija iztiskanec tehnologija iztiskanja talin stopnja kristaliničnosti eksperimentalni načrt amorphous solid dispersion extrudate hot melt extrusion residual crystallinity design of experiments true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2025-05-18 07:45:06 2025-05-18 07:45:18 2025-05-19 03:59:57 0000-00-00 00:00:00 2025 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 114755 26975.pdf 26975.pdf 1 591368DBDB8FB27C08E992AC4027829F d0ffd876697458269e4442a96386ec98ffdd8c8d80ced1d8a698a91087dab65a 0a50a04d-33aa-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=210443 Fakulteta za farmacijo 0 0 0