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A vital problem that limits the use of drug nanocrystals in pharmaceutics is their physical instability. Freeze-drying is known to be an excellent technique to improve long-term stability of colloidal systems. But still, except of empirical principles, there is little known about the mutual dependency of formulation and process design as well as particle properties when freeze-drying drug nanocrystals. Nanocrystals represent a type of solid nanoparticles, which became popular during the last years as they improve bioavailability. Furthermore they are used in parenteral formulations for sustained release and can also be used to bypass first-pass metabolism. The purpose of the present study was to investigate the influence of different formulations and process conditions on freeze-dried paliperidone palmitate nanocrystals. As a preliminary study, freeze-thawing was performed in order to screen for the most appropriate cryoprotectant and investigate the influence of buffer (citrate, histidine, Na−phosphate, K−phosphate). It is based on the principle that an excipient, which protects drug nanocrystals during the freezing step, is likely to be an effective cryoprotectant. Measurements of particle size and number showed that, the type of buffer has a negligible effect on steric stabilization. Samples with cryoprotectants showed type-dependent cryoprotection. Sucrose successfully prevented particles against aggregation in contrast to mannitol. On the basis of the previous results, freeze-drying was performed to investigate the impact of ice crystal formation applying conservative ramp freezing, annealing or controlled nucleation. Six different drug nanocrystals formulations containing three different sucrose concentrations and poloxamer 407 or polysorbate 20 as steric stabilizers, were lyophilized. Drug nanocrystal stability was monitored using a comprehensive set of analytical techniques. The properties of the freeze-dried cake, namely the residual moisture content and the specific surface area, were analysed as well. The freezing regime showed no significant influence on drug nanocrystal stability. In contrast, the combined effect of steric stabilizer and cryoprotectant significantly contribute to drug nanocrystal stability. Storage under ccelerated stress conditions led to cake collapse in all formulations after two weeks, most possibly due to high residual moisture contents. Izziv, s katerim se sooča farmacija pri uporabi nanokristalov, je njihova fizikalna nestabilnost. Znano je, da je liofilizacija odlična tehnika za izboljšanje dolgoročne stabilnosti koloidnih sistemov. Kljub temu je slabo raziskana medsebojna odvisnost sestave formulacij, procesnih pogojev in lastnosti liofiliziranih nanokristalov. Nanokristali predstavljajo vrsto trdnih nanodelcev, ki so pri slabo topnih učinkovinah postali priljubljeni predvsem v zadnjih letih, saj izboljšujejo njihovo biološko uporabnost. Najpogosteje se uporabljajo pri parenteralni obliki aplikacije za podaljšano sproščanje zdravila in izogibanje metabolizmu prvega prehoda. Namen magistrske naloge je raziskati vpliv različnih formulacij in procesnih pogojev na fizikalne lastnosti liofiliziranih nanokristalov paliperidon palmitata. Predhodna študija je obsegala cikle zamrzovanja/odmrzovanja, s katero je bil raziskan vpliv različnih pufrov (citrat, histidin, Na−fosfat, K−fostat) in izbran najprimernejši krioprotektant, ki je uspešno zaščitil nanokristale med procesom zamrzovanja. Rezultati velikosti in števila delcev kažejo, da ima vrsta pufra zanemarljiv učinek na sterično stabilizacijo. Nasprotno je stabilizacija nanokristalov odvisna od vrste krioprotektanta. V primerjavi z manitolom je saharoza uspešno preprečila aglomeracijo delcev. Na podlagi prejšnjih rezultatov je sledila liofilizacija nanokristalov paliperidon palmitata, s katerim je bil raziskan vpliv nastajanja ledenih kristalov z uporabo konzervativnega zamrzovanja, temperiranja ali nadzorovane nukleacije. Liofiliziranih je bilo šest različnih formulacij nanokristalov v kombinaciji treh razičnih koncentracij saharoze in poloksamera 407 ali polisorbata 20 kot sterična stabilizatorja. Stabilnost nanokristalov je bila raziskana z uporabo obsežnega analitičnega postopka. Poleg tega so bile analizirane tudi lastnosti liofilizata, in sicer preostala vsebnost vlage in specifična površina. Rezultati so pokazali, da režim zamrznitve nima pomembnega vpliva na stabilnost nanokristalov. Nasprotno je kombinacija steričnega stabilizatorja in krioprotektanta bistveno prispevala k stabilnosti liofiliziranih nanokristalov. Pri shranjevanju liofiliziranih produktov pri pospešenih stresnih pogojih je po dveh tednih prišlo do kolapsa liofilizata pri vseh formulacijah, najverjetneje zaradi visoke vsebnosti preostale vlage po liofilizaciji. |
