TY  - JOUR
AU  - Medarević, Đorđe
AU  - Ibrić, Svetlana
AU  - Vardaka, Elisavet
AU  - Mitrić, Miodrag
AU  - Nikolakakis, Ioannis
AU  - Kachrimanis, Kyriakos
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8803
AB  - Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals.
T2  - Pharmaceutics
T1  - Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling
VL  - 12
IS  - 1
SP  - 53
DO  - 10.3390/pharmaceutics12010053
ER  - 

@article{
author = "Medarević, Đorđe and Ibrić, Svetlana and Vardaka, Elisavet and Mitrić, Miodrag and Nikolakakis, Ioannis and Kachrimanis, Kyriakos",
year = "2020",
abstract = "Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals.",
journal = "Pharmaceutics",
title = "Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling",
volume = "12",
number = "1",
pages = "53",
doi = "10.3390/pharmaceutics12010053"
}

Medarević, Đ., Ibrić, S., Vardaka, E., Mitrić, M., Nikolakakis, I.,& Kachrimanis, K.. (2020). Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling. in Pharmaceutics, 12(1), 53.
https://doi.org/10.3390/pharmaceutics12010053

Medarević Đ, Ibrić S, Vardaka E, Mitrić M, Nikolakakis I, Kachrimanis K. Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling. in Pharmaceutics. 2020;12(1):53.
doi:10.3390/pharmaceutics12010053 .

Medarević, Đorđe, Ibrić, Svetlana, Vardaka, Elisavet, Mitrić, Miodrag, Nikolakakis, Ioannis, Kachrimanis, Kyriakos, "Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling" in Pharmaceutics, 12, no. 1 (2020):53,
https://doi.org/10.3390/pharmaceutics12010053 . .

TY  - JOUR
AU  - Ćirić, Ana
AU  - Medarević, Đorđe 
AU  - Čalija, Bojan
AU  - Dobričić, Vladimir
AU  - Mitrić, Miodrag
AU  - Đekić, Ljiljana
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8473
AB  - This study investigated the combined influence of pH adjusting agent type (hydrochloric, acetic or lactic acid) and initial pH value (3.6, 4.6, and 5.6) on formation of biocompatible chitosan/xanthan polyelectrolyte complexes (PECs), their characteristics in solid state and influence on in vitro ibuprofen release kinetics. Conductivity measurements and rheological characterization revealed generally higher extent of ionic interactions in PEC dispersions comprising acetic acid and at pH 3.6. Acid type and pH affected significantly the yield and particle size (100–250 μm) of the dried PECs. Differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) analysis of the solid PECs confirmed exclusively physical (ionic, hydrogen bonds) interactions between chitosan and xanthan gum. PECs prepared with acetic acid at pH 4.6 and 5.6 had enhanced rehydration ability in phosphate buffer pH 7.2, and at PEC-to-drug mass ratio up to 1:2, enabled extended ibuprofen release from hard capsules during 10 h. © 2020 Elsevier B.V.
T2  - International Journal of Biological Macromolecules
T1  - Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics
VL  - 148
SP  - 942
EP  - 955
DO  - 10.1016/j.ijbiomac.2020.01.138
ER  - 

@article{
author = "Ćirić, Ana and Medarević, Đorđe  and Čalija, Bojan and Dobričić, Vladimir and Mitrić, Miodrag and Đekić, Ljiljana",
year = "2020",
abstract = "This study investigated the combined influence of pH adjusting agent type (hydrochloric, acetic or lactic acid) and initial pH value (3.6, 4.6, and 5.6) on formation of biocompatible chitosan/xanthan polyelectrolyte complexes (PECs), their characteristics in solid state and influence on in vitro ibuprofen release kinetics. Conductivity measurements and rheological characterization revealed generally higher extent of ionic interactions in PEC dispersions comprising acetic acid and at pH 3.6. Acid type and pH affected significantly the yield and particle size (100–250 μm) of the dried PECs. Differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) analysis of the solid PECs confirmed exclusively physical (ionic, hydrogen bonds) interactions between chitosan and xanthan gum. PECs prepared with acetic acid at pH 4.6 and 5.6 had enhanced rehydration ability in phosphate buffer pH 7.2, and at PEC-to-drug mass ratio up to 1:2, enabled extended ibuprofen release from hard capsules during 10 h. © 2020 Elsevier B.V.",
journal = "International Journal of Biological Macromolecules",
title = "Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics",
volume = "148",
pages = "942-955",
doi = "10.1016/j.ijbiomac.2020.01.138"
}

Ćirić, A., Medarević, Đ., Čalija, B., Dobričić, V., Mitrić, M.,& Đekić, L.. (2020). Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics. in International Journal of Biological Macromolecules, 148, 942-955.
https://doi.org/10.1016/j.ijbiomac.2020.01.138

Ćirić A, Medarević Đ, Čalija B, Dobričić V, Mitrić M, Đekić L. Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics. in International Journal of Biological Macromolecules. 2020;148:942-955.
doi:10.1016/j.ijbiomac.2020.01.138 .

Ćirić, Ana, Medarević, Đorđe , Čalija, Bojan, Dobričić, Vladimir, Mitrić, Miodrag, Đekić, Ljiljana, "Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics" in International Journal of Biological Macromolecules, 148 (2020):942-955,
https://doi.org/10.1016/j.ijbiomac.2020.01.138 . .

TY  - JOUR
AU  - Medarević, Đorđe 
AU  - Cvijić, Sandra
AU  - Dobričić, Vladimir
AU  - Mitrić, Miodrag
AU  - Đuriš, Jelena
AU  - Ibrić, Svetlana
PY  - 2018
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0928098718303919
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/7861
AB  - This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, Cmax and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability. © 2018 Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach
VL  - 124
SP  - 188
EP  - 198
DO  - 10.1016/j.ejps.2018.08.026
ER  - 

@article{
author = "Medarević, Đorđe  and Cvijić, Sandra and Dobričić, Vladimir and Mitrić, Miodrag and Đuriš, Jelena and Ibrić, Svetlana",
year = "2018",
abstract = "This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, Cmax and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability. © 2018 Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach",
volume = "124",
pages = "188-198",
doi = "10.1016/j.ejps.2018.08.026"
}

Medarević, Đ., Cvijić, S., Dobričić, V., Mitrić, M., Đuriš, J.,& Ibrić, S.. (2018). Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach. in European Journal of Pharmaceutical Sciences, 124, 188-198.
https://doi.org/10.1016/j.ejps.2018.08.026

Medarević Đ, Cvijić S, Dobričić V, Mitrić M, Đuriš J, Ibrić S. Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach. in European Journal of Pharmaceutical Sciences. 2018;124:188-198.
doi:10.1016/j.ejps.2018.08.026 .

Medarević, Đorđe , Cvijić, Sandra, Dobričić, Vladimir, Mitrić, Miodrag, Đuriš, Jelena, Ibrić, Svetlana, "Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach" in European Journal of Pharmaceutical Sciences, 124 (2018):188-198,
https://doi.org/10.1016/j.ejps.2018.08.026 . .

TY  - JOUR
AU  - Medarević, Đorđe
AU  - Đuriš, Jelena
AU  - Ibrić, Svetlana
AU  - Mitrić, Miodrag
AU  - Kachrimanis, Kyriakos
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/7655
AB  - The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.
T2  - International Journal of Pharmaceutics
T1  - Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling
VL  - 540
IS  - 1-2
SP  - 150
EP  - 161
DO  - 10.1016/j.ijpharm.2018.02.011
ER  - 

@article{
author = "Medarević, Đorđe and Đuriš, Jelena and Ibrić, Svetlana and Mitrić, Miodrag and Kachrimanis, Kyriakos",
year = "2018",
abstract = "The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.",
journal = "International Journal of Pharmaceutics",
title = "Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling",
volume = "540",
number = "1-2",
pages = "150-161",
doi = "10.1016/j.ijpharm.2018.02.011"
}

Medarević, Đ., Đuriš, J., Ibrić, S., Mitrić, M.,& Kachrimanis, K.. (2018). Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling. in International Journal of Pharmaceutics, 540(1-2), 150-161.
https://doi.org/10.1016/j.ijpharm.2018.02.011

Medarević Đ, Đuriš J, Ibrić S, Mitrić M, Kachrimanis K. Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling. in International Journal of Pharmaceutics. 2018;540(1-2):150-161.
doi:10.1016/j.ijpharm.2018.02.011 .

Medarević, Đorđe, Đuriš, Jelena, Ibrić, Svetlana, Mitrić, Miodrag, Kachrimanis, Kyriakos, "Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling" in International Journal of Pharmaceutics, 540, no. 1-2 (2018):150-161,
https://doi.org/10.1016/j.ijpharm.2018.02.011 . .

TY  - JOUR
AU  - Medarević, Đorđe 
AU  - Kachrimanis, Kyriakos
AU  - Mitrić, Miodrag
AU  - Đuriš, Jelena
AU  - Đurić, Zorica
AU  - Ibrić, Svetlana
PY  - 2016
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/915
AB  - This study investigates the potential of poloxamers as solid dispersions (SDs) carriers in improving the dissolution rate of a poorly soluble drug, carbamazepine (CBZ). Solid dispersions were prepared with poloxamer 188 (P188) and poloxamer 407 (P407) by melting method in different drug:carrier ratios (1:1, 1:2 and 1:3). Prepared samples were characterized using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (HSM), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) to investigate drug physical state within the SDs matrix, possible polymorphic transitions and drug-polymer interactions. The interactions between CBZ molecules and polymeric chains were also evaluated using molecular dynamics simulation (MDS) technique. The most thermodynamically stable polymorphic form III of CBZ was present in all SDs, regardless of the type of poloxamer and drug-to-carrier ratio. The absence of drug-polymer interactions was observed by FT-IR analysis and additionally confirmed by MDS. Formation of persistent hydrogen bond between two CBZ molecules, observed by MDS indicate high tendency of CBZ molecules to aggregate and form crystalline phase within dispersion. P188 exhibit higher efficiency in increasing CBZ dissolution rate due to its more pronounced hydrophilic properties, while increasing poloxamers concentration resulted in decreasing drug release rate, as a consequence of their thermoreversible gelation.
T2  - Pharmaceutical Development and Technology
T1  - Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions
VL  - 21
IS  - 3
SP  - 268
EP  - 276
DO  - 10.3109/10837450.2014.996899
ER  - 

@article{
author = "Medarević, Đorđe  and Kachrimanis, Kyriakos and Mitrić, Miodrag and Đuriš, Jelena and Đurić, Zorica and Ibrić, Svetlana",
year = "2016",
abstract = "This study investigates the potential of poloxamers as solid dispersions (SDs) carriers in improving the dissolution rate of a poorly soluble drug, carbamazepine (CBZ). Solid dispersions were prepared with poloxamer 188 (P188) and poloxamer 407 (P407) by melting method in different drug:carrier ratios (1:1, 1:2 and 1:3). Prepared samples were characterized using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (HSM), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) to investigate drug physical state within the SDs matrix, possible polymorphic transitions and drug-polymer interactions. The interactions between CBZ molecules and polymeric chains were also evaluated using molecular dynamics simulation (MDS) technique. The most thermodynamically stable polymorphic form III of CBZ was present in all SDs, regardless of the type of poloxamer and drug-to-carrier ratio. The absence of drug-polymer interactions was observed by FT-IR analysis and additionally confirmed by MDS. Formation of persistent hydrogen bond between two CBZ molecules, observed by MDS indicate high tendency of CBZ molecules to aggregate and form crystalline phase within dispersion. P188 exhibit higher efficiency in increasing CBZ dissolution rate due to its more pronounced hydrophilic properties, while increasing poloxamers concentration resulted in decreasing drug release rate, as a consequence of their thermoreversible gelation.",
journal = "Pharmaceutical Development and Technology",
title = "Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions",
volume = "21",
number = "3",
pages = "268-276",
doi = "10.3109/10837450.2014.996899"
}

Medarević, Đ., Kachrimanis, K., Mitrić, M., Đuriš, J., Đurić, Z.,& Ibrić, S.. (2016). Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions. in Pharmaceutical Development and Technology, 21(3), 268-276.
https://doi.org/10.3109/10837450.2014.996899

Medarević Đ, Kachrimanis K, Mitrić M, Đuriš J, Đurić Z, Ibrić S. Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions. in Pharmaceutical Development and Technology. 2016;21(3):268-276.
doi:10.3109/10837450.2014.996899 .

Medarević, Đorđe , Kachrimanis, Kyriakos, Mitrić, Miodrag, Đuriš, Jelena, Đurić, Zorica, Ibrić, Svetlana, "Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions" in Pharmaceutical Development and Technology, 21, no. 3 (2016):268-276,
https://doi.org/10.3109/10837450.2014.996899 . .