TY  - JOUR
AU  - Mitrović, Jelena
AU  - Bjelošević Žiberna, Maja
AU  - Vukadinović, Aleksandar
AU  - Knutson, Daniel E.
AU  - Sharmin, Dishary
AU  - Kremenović, Aleksandar
AU  - Ahlin Grabnar, Pegi
AU  - Planinšek, Odon
AU  - Lunter, Dominique
AU  - Cook, James M
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4982
AB  - 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 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.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study
VL  - 189
DO  - 10.1016/j.ejps.2023.106557
ER  - 

@article{
author = "Mitrović, Jelena and Bjelošević Žiberna, Maja and Vukadinović, Aleksandar and Knutson, Daniel E. and Sharmin, Dishary and Kremenović, Aleksandar and Ahlin Grabnar, Pegi and Planinšek, Odon and Lunter, Dominique and Cook, James M and Savić, Miroslav and Savić, Snežana",
year = "2023",
abstract = "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 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.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study",
volume = "189",
doi = "10.1016/j.ejps.2023.106557"
}

Mitrović, J., Bjelošević Žiberna, M., Vukadinović, A., Knutson, D. E., Sharmin, D., Kremenović, A., Ahlin Grabnar, P., Planinšek, O., Lunter, D., Cook, J. M., Savić, M.,& Savić, S.. (2023). Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 189.
https://doi.org/10.1016/j.ejps.2023.106557

Mitrović J, Bjelošević Žiberna M, Vukadinović A, Knutson DE, Sharmin D, Kremenović A, Ahlin Grabnar P, Planinšek O, Lunter D, Cook JM, Savić M, Savić S. Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study. in European Journal of Pharmaceutical Sciences. 2023;189.
doi:10.1016/j.ejps.2023.106557 .

Mitrović, Jelena, Bjelošević Žiberna, Maja, Vukadinović, Aleksandar, Knutson, Daniel E., Sharmin, Dishary, Kremenović, Aleksandar, Ahlin Grabnar, Pegi, Planinšek, Odon, Lunter, Dominique, Cook, James M, Savić, Miroslav, Savić, Snežana, "Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study" in European Journal of Pharmaceutical Sciences, 189 (2023),
https://doi.org/10.1016/j.ejps.2023.106557 . .

TY  - CONF
AU  - Mitrović, Jelena
AU  - Bjelošević, Maja
AU  - Đoković, Jelena
AU  - Ahlin Grabnar, Pegi
AU  - Planinšek, Odon
AU  - Knutson, Daniel
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3744
AB  - Despite of good pharmacodynamics of DK-I-56-1, novel deuterated pyrazoloquinolinones ligand, low solubility limits its administration. Nanosuspensions can help to overcome this problem, but its small particle size usually leads to particle agglomeration in short period of time. This phenomenon can be prevented by performing lyophilization. In this study cryoprotectants selection as well as characterization (particle size measurements after redispersion, scanning electron microscopy, differential scanning calorimetry and thermogravimetric measurements) of obtained freeze dried preparations was carried out. It was observed that sucrose/mannitol ratio 1:1 and 3:2 in total concentration of 10% can preserve particle size during lyophilization. However, after stability study conducted during one month storage at 25 °C and 40 °C, particle size remained in submicron range only in one sample. Changes in particle size were also followed by changes in polymorphic form of mannitol. It can be concluded that changes of crystal forms in freeze dried preparations during storage could jeopardize their stability, and therefore should be carefully examined.
T1  - Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3744
ER  - 

@conference{
author = "Mitrović, Jelena and Bjelošević, Maja and Đoković, Jelena and Ahlin Grabnar, Pegi and Planinšek, Odon and Knutson, Daniel and Cook, James and Savić, Miroslav and Savić, Snežana",
year = "2020",
abstract = "Despite of good pharmacodynamics of DK-I-56-1, novel deuterated pyrazoloquinolinones ligand, low solubility limits its administration. Nanosuspensions can help to overcome this problem, but its small particle size usually leads to particle agglomeration in short period of time. This phenomenon can be prevented by performing lyophilization. In this study cryoprotectants selection as well as characterization (particle size measurements after redispersion, scanning electron microscopy, differential scanning calorimetry and thermogravimetric measurements) of obtained freeze dried preparations was carried out. It was observed that sucrose/mannitol ratio 1:1 and 3:2 in total concentration of 10% can preserve particle size during lyophilization. However, after stability study conducted during one month storage at 25 °C and 40 °C, particle size remained in submicron range only in one sample. Changes in particle size were also followed by changes in polymorphic form of mannitol. It can be concluded that changes of crystal forms in freeze dried preparations during storage could jeopardize their stability, and therefore should be carefully examined.",
title = "Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3744"
}

Mitrović, J., Bjelošević, M., Đoković, J., Ahlin Grabnar, P., Planinšek, O., Knutson, D., Cook, J., Savić, M.,& Savić, S.. (2020). Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study. .
https://hdl.handle.net/21.15107/rcub_farfar_3744

Mitrović J, Bjelošević M, Đoković J, Ahlin Grabnar P, Planinšek O, Knutson D, Cook J, Savić M, Savić S. Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study. 2020;.
https://hdl.handle.net/21.15107/rcub_farfar_3744 .

Mitrović, Jelena, Bjelošević, Maja, Đoković, Jelena, Ahlin Grabnar, Pegi, Planinšek, Odon, Knutson, Daniel, Cook, James, Savić, Miroslav, Savić, Snežana, "Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study" (2020),
https://hdl.handle.net/21.15107/rcub_farfar_3744 .