Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1) : process parameters and lyoprotectant selection through the stability study

Mitrović, Jelena R. (author), Bjelošević Žiberna, Maja (author), Ahlin Grabnar, Pegi (author), Planinšek, Odon (author), Savić, Snežana D. (author)

Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7-methoxy-2-(4-methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10°C or -45°C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10°C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 μm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.

• Language: English
• Keywords: pyrazoloquinolinone, nanocrystals, freeze-drying, sucrose, trehalose, mannitol
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 12 str.
• Numbering: Vol. 189, art. 106557
• PID: 20.500.12556/RUL-148364
• UDC: 66.017-022.513.2:620.3
• ISSN on article: 0928-0987
• DOI: 10.1016/j.ejps.2023.106557
• COBISS.SI-ID: 161164291
• Publication date in RUL: 18.08.2023

Record is a part of a journal

• Title: European Journal of Pharmaceutical Sciences
• Shortened title: Eur. j. pharm. sci.
• Publisher: Elsevier
• ISSN: 0928-0987
• COBISS.SI-ID: 17553413

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: pirazolokinolinon, nanokristali, liofilizacija, saharoza, trehaloza, manitol, farmacevtske oblike, nanomateriali