Vpliv agresivnih pogojev sušenja na proces liofilizacije in lastnosti končnega izdelka z modelno proteinsko učinkovino : enoviti magistrski študijski program Farmacija

Ćatić, Sabrina (avtor), Ahlin Grabnar, Pegi (mentor), Brus, Boris (komentor)

Faza primarnega sušenja je stroškovno in časovno najpotratnejša faza procesa liofilizacije in lahko predstavlja do 50 % celotnega liofilizacijskega cikla. Prav zaradi tega je bil glavni namen magistrske naloge razvoj agresivnega liofilizacijskega cikla, kjer bi z ustrezno izbiro agresivnih procesnih parametrov skrajšali fazo primarnega sušenja, a vseeno dobili končen izdelek sprejemljive kakovosti. Z namenom ovrednotenja vpliva sestave formulacije na kakovost končnega izdelka in hitrost sublimacije smo v vseh liofilizacijskih ciklih liofilizirali 2 formulaciji, in sicer amorfno formulacijo s saharozo in delno kristalno formulacijo s saharozo in glicinom. Proces liofilizacije smo po vsakem liofilizacijskem ciklu ovrednotili s pomočjo procesnih grafov, medtem ko smo izbrane lastnosti izdelanih liofilizatov ovrednotili z ustreznimi analiznimi metodami. Pojav kolapsa smo ovrednotili z vizualnim pregledom, pri čemer so bili vsi liofilizati sprejemljivega videza in brez izrazitih vidnih sprememb v strukturi pogače. Sledila je rekonstitucija liofilizatov z vodo, pri čemer so se vsi liofilizati raztopili hitro, nastala raztopina pa je bila bistra in brez vidnih delcev. Na podlagi rezultatov DLS in SEC meritev, ki smo jih opravili v raztopini pred liofilizacijo in po rekonstituciji liofilizatov, smo lahko izključili pojav agregacije proteina med procesom liofilizacije in med testiranjem stabilnosti. Z metodo titracije Karl Fischer smo ugotovili še vsebnost rezidualne vode, ki je bila v vseh analiziranih vzorcih nižja od 2 % (m/m), kar je za večino liofilizatov s stališča stabilnosti sprejemljiv rezultat. Morfološke lastnosti liofilizatov smo ovrednotili z vrstično elektronsko mikroskopijo, kjer smo pri produktih agresivnih liofilizacijskih ciklov opazili sledi lomljenja in taljenja pogače, kar nakazuje na pojav mikroskopskega kolapsa. Pri vrednotenju procesa liofilizacije smo se osredotočili zlasti na fazo primarnega sušenja, ki smo jo z uporabo agresivnih pogojev sušenja skrajšali za 40-45 % v primerjavi z osnovnim konzervativnim ciklom. Trajanje celotnega procesa liofilizacije smo tako skrajšali za približno 35 %. Na ta način smo močno povečali časovno in stroškovno učinkovitost procesa liofilizacije, pri čemer pa nismo pomembno vplivali na kakovost končnega izdelka.

• Jezik: Slovenski jezik
• Ključne besede: primarno sušenje sekundarno sušenje proces liofilizacije vrednotenje liofilizatov
• Vrsta gradiva: Magistrsko delo/naloga
• Tipologija: 2.09 - Magistrsko delo
• Organizacija: FFA - Fakulteta za farmacijo
• Kraj izida: Ljubljana
• Založnik: [S. Ćatić]
• Leto izida: 2017
• Št. strani: V, 63 f.
• PID: 20.500.12556/RUL-98524
• UDK: 542.47+66.047(043.3)
• COBISS.SI-ID: 4438129
• Datum objave v RUL: 05.01.2018

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: The effect of agressive drying condition on freeze-drying process and characteristics of product containing a model proetin substance

Izvleček

The primary drying phase is the most cost-effective and time-consuming phase of the lyophilization process and can represent up to 50 % of the entire lyophilization cycle. For this reason, the main purpose of this work was the development of an aggressive lyophilization cycle, whereby the appropriate selection of aggressive process parameters would shorten the primary drying phase, but nevertheless, the final product of acceptable quality would be obtained. In order to evaluate the effect of the formulation composition on the product characteristics and the sublimation rate, in all the freeze-drying cycles, 2 formulations were lyophilized, namely an amorphous formulation with sucrose and a partially crystalline formulation with sucrose and glycine. After each cycle, the lyophilization process was evaluated using process graphs, while the selected properties of the lyophilizates were determined by appropriate analytical methods. The occurrence of collapse was evaluated by a visual examination, with all the lyophilizates showing an acceptable appearance and without significant visible changes in the structure of the cake. After reconstituting lyophilizates with water, all of them dissolved rapidly, and the resulting solution was clear and free of visible particles. Based on the results of DLS and SEC measurements performed in the solution prior to lyophilization and after the reconstitution of lyophilizates, the occurrence of protein aggregation during the lyophilization process and during stability testing could be excluded. The residual water content, as determined by the Karl-Fischer titration method, was in all analyzed samples less than 2 % (m/m), which is in terms of stability a favorable result for most lyophilizates. The morphological properties of lyophilizates were evaluated by SEM, where traces of breaking and melting of the cake were observed, indicating the occurrence of microscopic collapse in products of aggressive cycles. While evaluating the lyophilization process, we focused primarily on the primary drying phase, which was reduced by 40-45 % by using the aggressive drying conditions. Thus, the duration of the entire lyophilization process was reduced by approximately 35 % compared to the basic conservative liophilization cycle. In this way, we greatly increased the time- and cost-effectiveness of the lyophiliazation process, without significantly affecting the quality of the final product.