TY  - CONF
AU  - Aleksić, Ivana
AU  - Ćirin-Varađan, Slobodanka
AU  - Glišić, Teodora
AU  - Petrović, Nađa
AU  - Đuriš, Jelena
AU  - Parojčić, Jelena
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5067
AB  - Direct compression, as the simplest and therefore
preferable method of tableting, is often hindered by poor
flow and compaction properties of the active
pharmaceutical ingredient (API). Tableting by direct
compression is particularly challenging when high API
loading is required. The use of co-processed excipients can
result in a robust directly compressible formulation, while
melt granulation has emerged as an environmentally
friendly co-processing method that can result in highly
functional co-processed excipients (Ćirin-Varađan et al,
2022).
The aim of the present study was to investigate the
suitability of lactose co-processed with glyceryl
palmitostearate for the preparation of a directly
compressible formulation of ibuprofen, a challenging high-
dose API. The influence of initial particle size of glyceryl
palmitostearate, ibuprofen content and compression
parameters on compaction behavior of tableting mixtures
was investigated.
PB  - Macedonian Pharmaceutical Association
PB  - Ss. Cyril and Methodius University in Skopje, Faculty of Pharmacy
C3  - Macedonian Pharmaceutical Bulletin
T1  - From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations
VL  - 69
IS  - Suppl 1
SP  - 139
EP  - 140
DO  - 10.33320/maced.pharm.bull.2023.69.03.068
ER  - 

@conference{
author = "Aleksić, Ivana and Ćirin-Varađan, Slobodanka and Glišić, Teodora and Petrović, Nađa and Đuriš, Jelena and Parojčić, Jelena",
year = "2023",
abstract = "Direct compression, as the simplest and therefore
preferable method of tableting, is often hindered by poor
flow and compaction properties of the active
pharmaceutical ingredient (API). Tableting by direct
compression is particularly challenging when high API
loading is required. The use of co-processed excipients can
result in a robust directly compressible formulation, while
melt granulation has emerged as an environmentally
friendly co-processing method that can result in highly
functional co-processed excipients (Ćirin-Varađan et al,
2022).
The aim of the present study was to investigate the
suitability of lactose co-processed with glyceryl
palmitostearate for the preparation of a directly
compressible formulation of ibuprofen, a challenging high-
dose API. The influence of initial particle size of glyceryl
palmitostearate, ibuprofen content and compression
parameters on compaction behavior of tableting mixtures
was investigated.",
publisher = "Macedonian Pharmaceutical Association, Ss. Cyril and Methodius University in Skopje, Faculty of Pharmacy",
journal = "Macedonian Pharmaceutical Bulletin",
title = "From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations",
volume = "69",
number = "Suppl 1",
pages = "139-140",
doi = "10.33320/maced.pharm.bull.2023.69.03.068"
}

Aleksić, I., Ćirin-Varađan, S., Glišić, T., Petrović, N., Đuriš, J.,& Parojčić, J.. (2023). From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations. in Macedonian Pharmaceutical Bulletin
Macedonian Pharmaceutical Association., 69(Suppl 1), 139-140.
https://doi.org/10.33320/maced.pharm.bull.2023.69.03.068

Aleksić I, Ćirin-Varađan S, Glišić T, Petrović N, Đuriš J, Parojčić J. From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations. in Macedonian Pharmaceutical Bulletin. 2023;69(Suppl 1):139-140.
doi:10.33320/maced.pharm.bull.2023.69.03.068 .

Aleksić, Ivana, Ćirin-Varađan, Slobodanka, Glišić, Teodora, Petrović, Nađa, Đuriš, Jelena, Parojčić, Jelena, "From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations" in Macedonian Pharmaceutical Bulletin, 69, no. Suppl 1 (2023):139-140,
https://doi.org/10.33320/maced.pharm.bull.2023.69.03.068 . .

TY  - CONF
AU  - Aleksić, Ivana
AU  - Ćirin-Varađan, Slobodanka
AU  - Glišić, Teodora
AU  - Đuriš, Mihal
AU  - Đuriš, Jelena
AU  - Parojčić, Jelena
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4735
AB  - 1. INTRODUCTION
Co-processing has emerged as a suitable
approach to meet the increasing demands for
excipients with improved tableting
performance. Apart from the most commonly
used energy-consuming co-processing methods
(e.g. spray-drying and wet granulation), melt
granulation as a solvent-free and more
environmentally friendly technique has recently
gained more attention [1].
The aim of the present study was to investigate
the influence of meltable binder particle size
and compaction parameters on dilution capacity
and compaction behaviour of lactose-based coprocessed
excipients.
2. MATERIALS AND METHODS
2.1. Materials
Paracetamol (Acros Organics, Belgium) was
used as the model drug. Lactose monohydrate
(Carlo Erba Reagents, Italy) was used as filler
and glyceryl palmitostearate (Precirol® ATO 5
Gattefossé S.A.S, France) as meltable binder.
2.2. Preparation of co-processed excipients
Co-processed excipients were prepared by in
situ melt granulation in Mycrolab fluid bed
processor (OYSTAR Hüttlin, Germany).
Precirol® particles (15%) from the 125–180 μm
(≈ 150 μm) or 600–710 μm sieve fraction (≈ 655
μm) were used for granulation of lactose (85%).
The inlet air flow rate was 30 m3/h, and product
temperature during agglomeration was 65 °C.
2.3. Particle size and shape analysis
Granule size distribution was evaluated by sieve
analysis, and median particle diameter (d50) was
calculated by linear interpolation of the
cumulative percentage frequency curve.
Granule shape was examined by 2D scanned
image (4800 dpi resolution) analysis using
ImageJ software. The aspect ratio (AR) and
circularity (C) were calculated for granule shape
evaluation.
2.3. Determination of the Carr index
The bulk and tapped (1250 taps) densities of coprocessed
excipients and their mixtures with 30,
40 or 50% paracetamol were determined using
tap density tester STAV 2003 (J. Engelsmann
AG, Germany), and Carr index was calculated.
2.4. Dynamic compaction analysis
Co-processed excipients and their mixtures with
paracetamol were compressed on a single punch
instrumented tablet press (GTP D series,
Gamlen Tableting Ltd, UK). Compacts (100
mg) were compressed under compression load
of 200 kg (≈ 70 MPa) or 500 kg (≈ 173MPa),
and compression speed of 60 or 120 mm/min. 6
mm flat faced punches were used. The obtained
force-displacement curves were used to
calculate: net work of compression (NW),
detachment stress (DS), ejection stress (ES).
Tablet crushing force was determined using
tablet hardness tester Erweka TBH 125D
(Erweka GmbH, Germany), and the values
obtained were used to calculate tensile strength
(TS). Elastic recovery (24 h after compression)
was calculated, as well.
2.4. Experimental Design
In order to investigate the influence of binder
particle size, paracetamol content and
compression speed on the abovementioned
compaction properties, compacts were
prepared, at compression load of 500 kg,
according to 23 full factorial design.
3. RESULTS AND DISCUSSION
3.1. Particle size and shape
Larger initial binder particle size led to
formation of larger and more spherical granules
(Table 1).
147
Table 1. The size and shape of the co-processed
excipients’ particles.
Binder PS (μm) d50 AR C
150 564.9 1.33 0.81
655 846.2 1.14 0.86
3.2. Flowability
The Carr index values obtained indicated
considerably better flowability of the coprocessed
excipient prepared by using larger
binder particles (P655) in comparison with the
excipient prepared with smaller binder particles
(P150). This might be ascribed to more
spherical and larger particles of P655. However,
the addition of paracetamol led to an increase in
Carr index values and less pronounced
differences between two excipients (Fig. 1).
Figure 1. The influence of paracetamol loading
on flowability of co-processed excipients.
3.3. Compaction behaviour
The results obtained revealed better mechanical
properties of P150 in comparison with P655
compacts, irrespective of the compression
pressure applied. The addition of paracetamol,
as the model API with poor compaction
properties, led to decrease in tensile strength of
the compacts prepared with both excipients, and
paracetamol content showed statistically
significant influence on TS (p < 0.0001).
Acceptable tensile strength (> 1 MPa) could be
achieved for compacts with 30% paracetamol
compressed at higher compression pressure (≈
173 MPa).
Paracetamol content, compression speed and
interaction between binder particle size and
paracetamol content were found to significantly
affect NW. The influence of binder particle size
was more pronounced at higher paracetamol
content, with lower NW observed in the case of
P655. Higher compression speed led to higher
NW.
Relatively low values of detachment and
ejection stress (< 3.5 MPa) indicate good
antiadhesive and lubricating properties of the
investigated excipients. Lower values of both
parameters were observed in the case of P655
which could be related to different
agglomeration mechanisms involved. Besides
binder particle size, compression speed and
paracetamol content were found to significantly
influence these properties.
Elastic recovery values of the investigated
samples ranged between 12 and 28%. In the
case of both excipients, higher elastic recovery
values were obtained at higher compression
pressure. ER values of the compacts prepared at
higher compression pressure were significantly
affected by compression speed and interactions
of the investigated variables.
4. CONCLUSION
The results obtained show that meltable binder
particle size affects granule size and shape, and
consequently may influence flowability and
compaction behaviour of the co-processed
excipients. Interactions between binder particle
size and compaction variables were also found
to affect compaction properties of the
investigated excipients.
PB  - Slovensko farmacevtsko društvo in Univerza v Ljubljani, Fakulteta za farmacijo
C3  - 9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow: Book of Abstracts
T1  - Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation
SP  - 146
EP  - 147
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4735
ER  - 

@conference{
author = "Aleksić, Ivana and Ćirin-Varađan, Slobodanka and Glišić, Teodora and Đuriš, Mihal and Đuriš, Jelena and Parojčić, Jelena",
year = "2022",
abstract = "1. INTRODUCTION
Co-processing has emerged as a suitable
approach to meet the increasing demands for
excipients with improved tableting
performance. Apart from the most commonly
used energy-consuming co-processing methods
(e.g. spray-drying and wet granulation), melt
granulation as a solvent-free and more
environmentally friendly technique has recently
gained more attention [1].
The aim of the present study was to investigate
the influence of meltable binder particle size
and compaction parameters on dilution capacity
and compaction behaviour of lactose-based coprocessed
excipients.
2. MATERIALS AND METHODS
2.1. Materials
Paracetamol (Acros Organics, Belgium) was
used as the model drug. Lactose monohydrate
(Carlo Erba Reagents, Italy) was used as filler
and glyceryl palmitostearate (Precirol® ATO 5
Gattefossé S.A.S, France) as meltable binder.
2.2. Preparation of co-processed excipients
Co-processed excipients were prepared by in
situ melt granulation in Mycrolab fluid bed
processor (OYSTAR Hüttlin, Germany).
Precirol® particles (15%) from the 125–180 μm
(≈ 150 μm) or 600–710 μm sieve fraction (≈ 655
μm) were used for granulation of lactose (85%).
The inlet air flow rate was 30 m3/h, and product
temperature during agglomeration was 65 °C.
2.3. Particle size and shape analysis
Granule size distribution was evaluated by sieve
analysis, and median particle diameter (d50) was
calculated by linear interpolation of the
cumulative percentage frequency curve.
Granule shape was examined by 2D scanned
image (4800 dpi resolution) analysis using
ImageJ software. The aspect ratio (AR) and
circularity (C) were calculated for granule shape
evaluation.
2.3. Determination of the Carr index
The bulk and tapped (1250 taps) densities of coprocessed
excipients and their mixtures with 30,
40 or 50% paracetamol were determined using
tap density tester STAV 2003 (J. Engelsmann
AG, Germany), and Carr index was calculated.
2.4. Dynamic compaction analysis
Co-processed excipients and their mixtures with
paracetamol were compressed on a single punch
instrumented tablet press (GTP D series,
Gamlen Tableting Ltd, UK). Compacts (100
mg) were compressed under compression load
of 200 kg (≈ 70 MPa) or 500 kg (≈ 173MPa),
and compression speed of 60 or 120 mm/min. 6
mm flat faced punches were used. The obtained
force-displacement curves were used to
calculate: net work of compression (NW),
detachment stress (DS), ejection stress (ES).
Tablet crushing force was determined using
tablet hardness tester Erweka TBH 125D
(Erweka GmbH, Germany), and the values
obtained were used to calculate tensile strength
(TS). Elastic recovery (24 h after compression)
was calculated, as well.
2.4. Experimental Design
In order to investigate the influence of binder
particle size, paracetamol content and
compression speed on the abovementioned
compaction properties, compacts were
prepared, at compression load of 500 kg,
according to 23 full factorial design.
3. RESULTS AND DISCUSSION
3.1. Particle size and shape
Larger initial binder particle size led to
formation of larger and more spherical granules
(Table 1).
147
Table 1. The size and shape of the co-processed
excipients’ particles.
Binder PS (μm) d50 AR C
150 564.9 1.33 0.81
655 846.2 1.14 0.86
3.2. Flowability
The Carr index values obtained indicated
considerably better flowability of the coprocessed
excipient prepared by using larger
binder particles (P655) in comparison with the
excipient prepared with smaller binder particles
(P150). This might be ascribed to more
spherical and larger particles of P655. However,
the addition of paracetamol led to an increase in
Carr index values and less pronounced
differences between two excipients (Fig. 1).
Figure 1. The influence of paracetamol loading
on flowability of co-processed excipients.
3.3. Compaction behaviour
The results obtained revealed better mechanical
properties of P150 in comparison with P655
compacts, irrespective of the compression
pressure applied. The addition of paracetamol,
as the model API with poor compaction
properties, led to decrease in tensile strength of
the compacts prepared with both excipients, and
paracetamol content showed statistically
significant influence on TS (p < 0.0001).
Acceptable tensile strength (> 1 MPa) could be
achieved for compacts with 30% paracetamol
compressed at higher compression pressure (≈
173 MPa).
Paracetamol content, compression speed and
interaction between binder particle size and
paracetamol content were found to significantly
affect NW. The influence of binder particle size
was more pronounced at higher paracetamol
content, with lower NW observed in the case of
P655. Higher compression speed led to higher
NW.
Relatively low values of detachment and
ejection stress (< 3.5 MPa) indicate good
antiadhesive and lubricating properties of the
investigated excipients. Lower values of both
parameters were observed in the case of P655
which could be related to different
agglomeration mechanisms involved. Besides
binder particle size, compression speed and
paracetamol content were found to significantly
influence these properties.
Elastic recovery values of the investigated
samples ranged between 12 and 28%. In the
case of both excipients, higher elastic recovery
values were obtained at higher compression
pressure. ER values of the compacts prepared at
higher compression pressure were significantly
affected by compression speed and interactions
of the investigated variables.
4. CONCLUSION
The results obtained show that meltable binder
particle size affects granule size and shape, and
consequently may influence flowability and
compaction behaviour of the co-processed
excipients. Interactions between binder particle
size and compaction variables were also found
to affect compaction properties of the
investigated excipients.",
publisher = "Slovensko farmacevtsko društvo in Univerza v Ljubljani, Fakulteta za farmacijo",
journal = "9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow: Book of Abstracts",
title = "Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation",
pages = "146-147",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4735"
}

Aleksić, I., Ćirin-Varađan, S., Glišić, T., Đuriš, M., Đuriš, J.,& Parojčić, J.. (2022). Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation. in 9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow: Book of Abstracts
Slovensko farmacevtsko društvo in Univerza v Ljubljani, Fakulteta za farmacijo., 146-147.
https://hdl.handle.net/21.15107/rcub_farfar_4735

Aleksić I, Ćirin-Varađan S, Glišić T, Đuriš M, Đuriš J, Parojčić J. Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation. in 9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow: Book of Abstracts. 2022;:146-147.
https://hdl.handle.net/21.15107/rcub_farfar_4735 .

Aleksić, Ivana, Ćirin-Varađan, Slobodanka, Glišić, Teodora, Đuriš, Mihal, Đuriš, Jelena, Parojčić, Jelena, "Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation" in 9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow: Book of Abstracts (2022):146-147,
https://hdl.handle.net/21.15107/rcub_farfar_4735 .

TY  - JOUR
AU  - Ćirin-Varađan, Slobodanka
AU  - Đuriš, Jelena
AU  - Mirković, Miljana
AU  - Ivanović, Marija
AU  - Parojčić, Jelena
AU  - Aleksić, Ivana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4001
AB  - The introduction of the high-speed tableting machines and the lack of excipients with good flow and compaction properties required for direct compression process have increased research interest in the development of coprocessed excipients. Melt granulation, as an environmentally friendly and cost-effective method, has recently been recognized as a promising co-processing technique. The aim of the present study was to prepare lipid-based co-processed excipients by in situ fluidized bed melt granulation and to investigated their suitability for direct compression process. Lactose monohydrate was co-processed with glyceryl dibehenate (Compritol® 888 ATO) or glyceryl palmitostearate (Precirol® ATO 5), as lipophilic meltable binders. Besides the flowability testing, dynamic compaction analysis was applied for thorough investigation into the tableting properties of developed coprocessed excipients. Solid state characterization, performed by means of XRPD and DRIFT, confirmed the absence of chemical changes of the single components of co-processed excipients. Co-processed excipients showed improved flowability in comparison with single ingredients and corresponding physical mixtures. Novel co-processed excipients were found to have better tabletability profiles than physical mixtures of the ingredients, and were able to retain acceptable tensile strength values at high content of paracetamol in tableting mixture. Tablets with high tensile strength could be obtained with less work of compression needed in comparison with the commercial lactose-based excipients. Furthermore, novel lipid-based co-processed excipients were found to be highly superior regarding the antiadhesive and lubricating properties, with no additional lubricants required.
PB  - Elsevier B.V.
T2  - Journal of Drug Delivery Science and Technology
T1  - Comparative evaluation of mechanical properties of lactose-based excipients co-processed with lipophilic glycerides as meltable binders
VL  - 67
DO  - 10.1016/j.jddst.2021.102981
ER  - 

@article{
author = "Ćirin-Varađan, Slobodanka and Đuriš, Jelena and Mirković, Miljana and Ivanović, Marija and Parojčić, Jelena and Aleksić, Ivana",
year = "2022",
abstract = "The introduction of the high-speed tableting machines and the lack of excipients with good flow and compaction properties required for direct compression process have increased research interest in the development of coprocessed excipients. Melt granulation, as an environmentally friendly and cost-effective method, has recently been recognized as a promising co-processing technique. The aim of the present study was to prepare lipid-based co-processed excipients by in situ fluidized bed melt granulation and to investigated their suitability for direct compression process. Lactose monohydrate was co-processed with glyceryl dibehenate (Compritol® 888 ATO) or glyceryl palmitostearate (Precirol® ATO 5), as lipophilic meltable binders. Besides the flowability testing, dynamic compaction analysis was applied for thorough investigation into the tableting properties of developed coprocessed excipients. Solid state characterization, performed by means of XRPD and DRIFT, confirmed the absence of chemical changes of the single components of co-processed excipients. Co-processed excipients showed improved flowability in comparison with single ingredients and corresponding physical mixtures. Novel co-processed excipients were found to have better tabletability profiles than physical mixtures of the ingredients, and were able to retain acceptable tensile strength values at high content of paracetamol in tableting mixture. Tablets with high tensile strength could be obtained with less work of compression needed in comparison with the commercial lactose-based excipients. Furthermore, novel lipid-based co-processed excipients were found to be highly superior regarding the antiadhesive and lubricating properties, with no additional lubricants required.",
publisher = "Elsevier B.V.",
journal = "Journal of Drug Delivery Science and Technology",
title = "Comparative evaluation of mechanical properties of lactose-based excipients co-processed with lipophilic glycerides as meltable binders",
volume = "67",
doi = "10.1016/j.jddst.2021.102981"
}

Ćirin-Varađan, S., Đuriš, J., Mirković, M., Ivanović, M., Parojčić, J.,& Aleksić, I.. (2022). Comparative evaluation of mechanical properties of lactose-based excipients co-processed with lipophilic glycerides as meltable binders. in Journal of Drug Delivery Science and Technology
Elsevier B.V.., 67.
https://doi.org/10.1016/j.jddst.2021.102981

Ćirin-Varađan S, Đuriš J, Mirković M, Ivanović M, Parojčić J, Aleksić I. Comparative evaluation of mechanical properties of lactose-based excipients co-processed with lipophilic glycerides as meltable binders. in Journal of Drug Delivery Science and Technology. 2022;67.
doi:10.1016/j.jddst.2021.102981 .

Ćirin-Varađan, Slobodanka, Đuriš, Jelena, Mirković, Miljana, Ivanović, Marija, Parojčić, Jelena, Aleksić, Ivana, "Comparative evaluation of mechanical properties of lactose-based excipients co-processed with lipophilic glycerides as meltable binders" in Journal of Drug Delivery Science and Technology, 67 (2022),
https://doi.org/10.1016/j.jddst.2021.102981 . .

TY  - CONF
AU  - Lazić, Irina
AU  - Kučević, Sabina
AU  - Ćirin-Varađan, Slobodanka
AU  - Aleksić, Ivana
AU  - Đuriš, Jelena
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4569
AB  - Formulation of modified-release ibuprofen tablets presents a challenge due to its high
dose, limited compressibility and compactibility. The potential for preparing ibuprofen
modified release matrix tablets, by direct compression procedure using co-processed
excipients (1, 2), was evaluated. Co-processed excipients of hydrophilic and lipid properties
were used. Commercially available co-processed excipient based on
hydroxypropylmethylcellulose and lactose (RetaLac ®), as well as co-processed excipient
made in-house, using lipid matrix forming agent based on glyceryl palmitostearate
(Precirol® ) and lactose were used. The influence of co-processed excipient type, ibuprofen
ammount in tablets (25% and 50%) and the compression load (100 and 500 kg) on the
mechanical properties of the hydrophilic or lipid matrix tablets was evaluated. Also,
ibuprofen release rate was investigated in a rotating paddle apparatus with medium change
(0.1M HCl and phosphate buffer pH 6.8). The tensile strength of formulations was in the
range of 0.5-2 MPa. The compression load and the co-processed excipient type showed a
significant effect on tensile strength. Ibuprofen was released in a sustained manner from all
formulations, with the amount released after 8 hours varying from 35 to 80%, depending on
the matrix forming material type. The release of ibuprofen from lipid matrix tablets was
slower compared to hydrophilic tablets, with neither the compression load nor the ibuprofen
content showing a significant effect. Zero-order kinetics was achieved from both types of
matrix tablets. Based on the obtained results, it can be concluded that co-processed
excipients enable direct compression of ibuprofen modified release hydrophilic and lipid
matrix tablets.
AB  - Formulacija tableta sa modifikovanim oslobađanjem ibuprofena predstavlja izazov
zbog visoke doze lekovite supstance ograničene kompresibilnosti i kompaktibilnosti. U ovom
radu procenjena je mogućnost izrade matriks tableta sa modifikovanim oslobađanjem
ibuprofena postupkom direktne kompresije uz primenu koprocesovanih ekscipijenasa (1, 2).
Upotrebljeni su koprocesovani ekscipijensi hidrofilnih i lipidnih karakteristika. Korišćeni su
komercijalno dostupan koprocesovani ekscipijens na bazi hidroksipropilmetilceluloze i
laktoze (RetaLac® ), kao i koprocesovani ekscipijens izrađen u laboratorijskim uslovima, kao
lipidno matriks formirajuće sredstvo na bazi glicerilpalmitostearata (Precirol ®) i laktoze.
Praćen je uticaj vrste koprocesovanog ekscipijensa, udela ibuprofena u tabletama (25%,
odnosno 50%) i opterećenja pri kompresiji (100, odnosno 500 kg) na mehaničke
karakteristike izrađenih hidrofilnih, odnosno lipidnih matriks tableta. Takođe, ispitivana je
brzina oslobađanja ibuprofena iz pripremljenih matriks tableta u aparaturi sa rotirajućim
lopaticama uz izmenu medijuma (0,1M HCl i fosfatni pufer pH 6,8). Zatezna čvrstoća
ispitivanih formulacija je bila u opsegu ~ 0.5-2 MPa. Opterećenje pri kompresiji i tip
koprocesovanog ekscipijensa su pokazali značajan uticaj na zateznu čvrstoću. Ibuprofen se iz
svih formulacija oslobađao usporeno, pri čemu je količina oslobođena nakon 8 sati
ispitivanja varirala od 35 do 80%, u zavisnosti od prirode matriks formirajućeg materijala.
Oslobađanje ibuprofena iz lipidnih matriks tableta je bilo sporije u poređenju sa hidrofilnim
tabletama, pri čemu ni opterećenje pri kompresiji ni udeo ibuprofena nisu pokazali značajan
uticaj. Iz oba tipa matriks tableta postignuto je oslobađanje ibuprofena kinetikom nultog
reda. Na osnovu dobijenih rezultata može se zaključiti da koprocesovani ekscipijensi
omogućavaju izradu hidrofilnih i lipidnih matriks tableta sa modifikovanim oslobađanjem
ibuprofena postupkom direktne kompresije.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Formulation of ibuprofen-modified release hydrophilic and lipid matrix tablets using co-processed excipients
T1  - Formulacija hidrofilnih i lipidnih matriks tableta sa modifikovanim oslobađanjem ibuprofena primenom koprocesovanih ekscipijenasa
VL  - 72
IS  - 4 suplement
SP  - S3400
EP  - S401
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4569
ER  - 

@conference{
author = "Lazić, Irina and Kučević, Sabina and Ćirin-Varađan, Slobodanka and Aleksić, Ivana and Đuriš, Jelena",
year = "2022",
abstract = "Formulation of modified-release ibuprofen tablets presents a challenge due to its high
dose, limited compressibility and compactibility. The potential for preparing ibuprofen
modified release matrix tablets, by direct compression procedure using co-processed
excipients (1, 2), was evaluated. Co-processed excipients of hydrophilic and lipid properties
were used. Commercially available co-processed excipient based on
hydroxypropylmethylcellulose and lactose (RetaLac ®), as well as co-processed excipient
made in-house, using lipid matrix forming agent based on glyceryl palmitostearate
(Precirol® ) and lactose were used. The influence of co-processed excipient type, ibuprofen
ammount in tablets (25% and 50%) and the compression load (100 and 500 kg) on the
mechanical properties of the hydrophilic or lipid matrix tablets was evaluated. Also,
ibuprofen release rate was investigated in a rotating paddle apparatus with medium change
(0.1M HCl and phosphate buffer pH 6.8). The tensile strength of formulations was in the
range of 0.5-2 MPa. The compression load and the co-processed excipient type showed a
significant effect on tensile strength. Ibuprofen was released in a sustained manner from all
formulations, with the amount released after 8 hours varying from 35 to 80%, depending on
the matrix forming material type. The release of ibuprofen from lipid matrix tablets was
slower compared to hydrophilic tablets, with neither the compression load nor the ibuprofen
content showing a significant effect. Zero-order kinetics was achieved from both types of
matrix tablets. Based on the obtained results, it can be concluded that co-processed
excipients enable direct compression of ibuprofen modified release hydrophilic and lipid
matrix tablets., Formulacija tableta sa modifikovanim oslobađanjem ibuprofena predstavlja izazov
zbog visoke doze lekovite supstance ograničene kompresibilnosti i kompaktibilnosti. U ovom
radu procenjena je mogućnost izrade matriks tableta sa modifikovanim oslobađanjem
ibuprofena postupkom direktne kompresije uz primenu koprocesovanih ekscipijenasa (1, 2).
Upotrebljeni su koprocesovani ekscipijensi hidrofilnih i lipidnih karakteristika. Korišćeni su
komercijalno dostupan koprocesovani ekscipijens na bazi hidroksipropilmetilceluloze i
laktoze (RetaLac® ), kao i koprocesovani ekscipijens izrađen u laboratorijskim uslovima, kao
lipidno matriks formirajuće sredstvo na bazi glicerilpalmitostearata (Precirol ®) i laktoze.
Praćen je uticaj vrste koprocesovanog ekscipijensa, udela ibuprofena u tabletama (25%,
odnosno 50%) i opterećenja pri kompresiji (100, odnosno 500 kg) na mehaničke
karakteristike izrađenih hidrofilnih, odnosno lipidnih matriks tableta. Takođe, ispitivana je
brzina oslobađanja ibuprofena iz pripremljenih matriks tableta u aparaturi sa rotirajućim
lopaticama uz izmenu medijuma (0,1M HCl i fosfatni pufer pH 6,8). Zatezna čvrstoća
ispitivanih formulacija je bila u opsegu ~ 0.5-2 MPa. Opterećenje pri kompresiji i tip
koprocesovanog ekscipijensa su pokazali značajan uticaj na zateznu čvrstoću. Ibuprofen se iz
svih formulacija oslobađao usporeno, pri čemu je količina oslobođena nakon 8 sati
ispitivanja varirala od 35 do 80%, u zavisnosti od prirode matriks formirajućeg materijala.
Oslobađanje ibuprofena iz lipidnih matriks tableta je bilo sporije u poređenju sa hidrofilnim
tabletama, pri čemu ni opterećenje pri kompresiji ni udeo ibuprofena nisu pokazali značajan
uticaj. Iz oba tipa matriks tableta postignuto je oslobađanje ibuprofena kinetikom nultog
reda. Na osnovu dobijenih rezultata može se zaključiti da koprocesovani ekscipijensi
omogućavaju izradu hidrofilnih i lipidnih matriks tableta sa modifikovanim oslobađanjem
ibuprofena postupkom direktne kompresije.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Formulation of ibuprofen-modified release hydrophilic and lipid matrix tablets using co-processed excipients, Formulacija hidrofilnih i lipidnih matriks tableta sa modifikovanim oslobađanjem ibuprofena primenom koprocesovanih ekscipijenasa",
volume = "72",
number = "4 suplement",
pages = "S3400-S401",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4569"
}

Lazić, I., Kučević, S., Ćirin-Varađan, S., Aleksić, I.,& Đuriš, J.. (2022). Formulation of ibuprofen-modified release hydrophilic and lipid matrix tablets using co-processed excipients. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S3400-S401.
https://hdl.handle.net/21.15107/rcub_farfar_4569

Lazić I, Kučević S, Ćirin-Varađan S, Aleksić I, Đuriš J. Formulation of ibuprofen-modified release hydrophilic and lipid matrix tablets using co-processed excipients. in Arhiv za farmaciju. 2022;72(4 suplement):S3400-S401.
https://hdl.handle.net/21.15107/rcub_farfar_4569 .

Lazić, Irina, Kučević, Sabina, Ćirin-Varađan, Slobodanka, Aleksić, Ivana, Đuriš, Jelena, "Formulation of ibuprofen-modified release hydrophilic and lipid matrix tablets using co-processed excipients" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S3400-S401,
https://hdl.handle.net/21.15107/rcub_farfar_4569 .

TY  - CONF
AU  - Ćirin-Varađan, Slobodanka
AU  - Đuriš, Jelena
AU  - Ibrić, Svetlana
AU  - Parojčić, Jelena
AU  - Aleksić, Ivana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4671
AB  - The lack of directly compressible excipients and the introduction of the high-speed
manufacturing machines have further increased the interest in the development of co-processed
excipients. In the present study, in situ fluidized bed melt granulation (FBMG) as an environmental
friendly and cost-effective method, was applied to co-process the most common filler, lactose
monohydrate, with lipid excipients glyceryl dibehenate (Compritol ® 888 ATO) or glyceryl
palmitostearate (Precirol ® ATO 5) known for their antiadhesive, lubricant and flowing aid properties
(1, 2). The goal of this study was to develop the lipid-based co-processed excipients and to investigate
their flowability and tableting properties using a solvent-free and eco-friendly, FBMG method.
The flow properties of the tested samples (the single-component excipients, their physical
mixtures, lactose (85% (w/w)) co-processed with Precirol® or Compritol ® (15% (w/w)), and
commercially available lactose-based co-processed excipients (Retalac ® and Ludipress®) were
evaluated by Carr index and Hausner ratio. Dynamic compaction analysis of the investigated excipients
was performed on a single punch instrumented tablet press (GTP D series, Gamlen Tableting Ltd, UK).
Comparable or even better flowability of co-processed excipients obtained via in situ FBMG, in
comparison to commercial co-processed excipients indicate their suitability for direct compression. Co-
processed excipients with Precirol ® and Compritol ®, as well as the corresponding physical mixtures,
showed two to almost three times lower values of total work of compression than those obtained for
commercial lactose-based excipients. Furthermore, co-processed excipients prepared with lipid
excipients showed up to 50-fold lower detachment work and up to 20-fold lower ejection work than
those obtained for Retalac ® and Ludipress®. Superior antiadhesive and lubricating properties of the
excipients prepared by in situ FBMG can be attributed to the properties of lipid excipients. Both
commercially available and the investigated co-processed excipients, prepared with lipid excipients,
showed relatively high tensile strength values (>1.7 MPa).
The results presented in this study indicate that in situ fluidized bed melt granulation can be
used as suitable co-processing technique, as a time and energy less consuming method in comparison
with commonly applied techniques such as spray drying and wet granulation. According to the results
obtained, by co-processing lactose with selected lipid excipients excellent flowability, as well as
improved tableting properties can be achieved. Novel co-processed excipients were even found to be
highly superior regarding their antiadhesive and lubricating properties in comparison to commercial
lactose-based co-processed excipients.
AB  - Nedostatak direktno kompresibilnih ekscipijenasa i uvođenje proizvodne opreme velike brzine
rada dodatno su povećali interesovanje za razvoj koprocesovanih ekscipijenasa. U ovoj studiji, in situ
granulacija topljenjem u uređaju tipa fluidizirajućeg sistema (eng. fluidized bed melt granulation,
FBMG), kao ekološki prihvatljiva i ekonomična metoda, primenjena je za koprocesovanje najčešće
korišćenog sredstva za dopunjavanje, laktoze, monohidrata, sa lipidnim ekscipijensima,
glicerildibehenatom (Compritol® 888 ATO) ili glicerilpalmitostearatom (Precirol® ATO 5), koji su
poznati po svojim antiadhezivnim, lubrikatnim i protočnim osobinama (1, 2). Cilj ovog ispitivanja je bio
razvoj novih koprocesovanih ekscipijenasa na bazi lipida primenom ekološki prihvatljive metode, koja
ne zahteva upotrebu rastvarača, i ispitivanje njihove protočnosti i tabletabilnosti.
Protočne karakteristike ispitivanih uzoraka (pojedinačni ekscipijensi, njihove fizičke smeše,
laktoza ((85% (m/m)) koprocesovana sa Precirol ®-om ili Compritol®-om (15% (m/m)), i komercijalno
dostupni koprocesovani ekscipijensi na bazi laktoze (Retalac ® i Ludipress® )) procenjene su na osnovu
vrednosti Carr-ovog indeksa i Hausner‐ovog odnosa. Laboratorijski simulator kompakcije (GTP D serija,
Gamlen Tableting Ltd, UK) korišćen je za dinamičku analizu kompakcije.
Uporedive ili čak bolje protočne karakteristike koprocesovanih ekscipijensa dobijenih metodom
in situ FBMG, u poređenju sa komercijalno dostupnim koprocesovanim ekscipijensima, ukazuju na
njihovu podobnost za direktnu kompresiju. Koprocesovani ekscipijensi sa Precirol®-om i Compritol ®-
om, kao i odgovarajuće fizičke smeše, pokazale su dva do skoro tri puta niže vrednosti ukupnog rada
kompresije od komercijalno dostupnih ekscipijenasa na bazi laktoze. Dodatno, koprocesovani
ekscipijensi na bazi lipida pokazali su do 50 puta manji rad odvajanja i do 20 puta manji rad izbacivanja
od Retalac ®-a i Ludipress® -a. Superiorna antiadhezivna i lubrikatna svojstva koprocesovanih
ekscipijenasa pripremljenih in situ FBMG mogu se pripisati lipidnim ekscipijensima. Komercijalno
dostupni kao i ispitivani koprocesovani ekscipijensi, na bazi lipidnih ekscipijenasa, pokazali su
relativno visoke vrednosti zatezne čvrstine (> 1,7 MPa).
Predstavljeni rezultati ukazuju na to da se granulacija topljenjem u uređaju tipa fluidizirajućeg
sistema može koristiti kao pogodna metoda za koprocesovanje, koja zahteva manji utrošak energije i
vremena u poređenju sa uobičajenim tehnikama, poput sušenja raspršivanjem ili vlažne granulacije.
Dobijeni rezultati pokazuju da se koprocesovanjem laktoze sa odabranim lipidnim ekscipijensima može
postići odlična protočnost, kao i poboljšana tabletabilnost. Novi koprocesovani ekscipijensi su čak
pokazali superiornije karakteristike u pogledu svojih antiadhezivnih i lubrikatnih karakteristika u
poređenju sa komercijalno dostupnim koprocesovanim ekscipijensima na bazi laktoze.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Application of solventless granulation method for developent of novel co‐processed excipeints
T1  - Primena metode granulacije bez upotrebe rastvarača u razvoju novih koprocesovanih ekscipijenasa
VL  - 71
IS  - 5 suplement
SP  - S80
EP  - S81
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4671
ER  - 

@conference{
author = "Ćirin-Varađan, Slobodanka and Đuriš, Jelena and Ibrić, Svetlana and Parojčić, Jelena and Aleksić, Ivana",
year = "2021",
abstract = "The lack of directly compressible excipients and the introduction of the high-speed
manufacturing machines have further increased the interest in the development of co-processed
excipients. In the present study, in situ fluidized bed melt granulation (FBMG) as an environmental
friendly and cost-effective method, was applied to co-process the most common filler, lactose
monohydrate, with lipid excipients glyceryl dibehenate (Compritol ® 888 ATO) or glyceryl
palmitostearate (Precirol ® ATO 5) known for their antiadhesive, lubricant and flowing aid properties
(1, 2). The goal of this study was to develop the lipid-based co-processed excipients and to investigate
their flowability and tableting properties using a solvent-free and eco-friendly, FBMG method.
The flow properties of the tested samples (the single-component excipients, their physical
mixtures, lactose (85% (w/w)) co-processed with Precirol® or Compritol ® (15% (w/w)), and
commercially available lactose-based co-processed excipients (Retalac ® and Ludipress®) were
evaluated by Carr index and Hausner ratio. Dynamic compaction analysis of the investigated excipients
was performed on a single punch instrumented tablet press (GTP D series, Gamlen Tableting Ltd, UK).
Comparable or even better flowability of co-processed excipients obtained via in situ FBMG, in
comparison to commercial co-processed excipients indicate their suitability for direct compression. Co-
processed excipients with Precirol ® and Compritol ®, as well as the corresponding physical mixtures,
showed two to almost three times lower values of total work of compression than those obtained for
commercial lactose-based excipients. Furthermore, co-processed excipients prepared with lipid
excipients showed up to 50-fold lower detachment work and up to 20-fold lower ejection work than
those obtained for Retalac ® and Ludipress®. Superior antiadhesive and lubricating properties of the
excipients prepared by in situ FBMG can be attributed to the properties of lipid excipients. Both
commercially available and the investigated co-processed excipients, prepared with lipid excipients,
showed relatively high tensile strength values (>1.7 MPa).
The results presented in this study indicate that in situ fluidized bed melt granulation can be
used as suitable co-processing technique, as a time and energy less consuming method in comparison
with commonly applied techniques such as spray drying and wet granulation. According to the results
obtained, by co-processing lactose with selected lipid excipients excellent flowability, as well as
improved tableting properties can be achieved. Novel co-processed excipients were even found to be
highly superior regarding their antiadhesive and lubricating properties in comparison to commercial
lactose-based co-processed excipients., Nedostatak direktno kompresibilnih ekscipijenasa i uvođenje proizvodne opreme velike brzine
rada dodatno su povećali interesovanje za razvoj koprocesovanih ekscipijenasa. U ovoj studiji, in situ
granulacija topljenjem u uređaju tipa fluidizirajućeg sistema (eng. fluidized bed melt granulation,
FBMG), kao ekološki prihvatljiva i ekonomična metoda, primenjena je za koprocesovanje najčešće
korišćenog sredstva za dopunjavanje, laktoze, monohidrata, sa lipidnim ekscipijensima,
glicerildibehenatom (Compritol® 888 ATO) ili glicerilpalmitostearatom (Precirol® ATO 5), koji su
poznati po svojim antiadhezivnim, lubrikatnim i protočnim osobinama (1, 2). Cilj ovog ispitivanja je bio
razvoj novih koprocesovanih ekscipijenasa na bazi lipida primenom ekološki prihvatljive metode, koja
ne zahteva upotrebu rastvarača, i ispitivanje njihove protočnosti i tabletabilnosti.
Protočne karakteristike ispitivanih uzoraka (pojedinačni ekscipijensi, njihove fizičke smeše,
laktoza ((85% (m/m)) koprocesovana sa Precirol ®-om ili Compritol®-om (15% (m/m)), i komercijalno
dostupni koprocesovani ekscipijensi na bazi laktoze (Retalac ® i Ludipress® )) procenjene su na osnovu
vrednosti Carr-ovog indeksa i Hausner‐ovog odnosa. Laboratorijski simulator kompakcije (GTP D serija,
Gamlen Tableting Ltd, UK) korišćen je za dinamičku analizu kompakcije.
Uporedive ili čak bolje protočne karakteristike koprocesovanih ekscipijensa dobijenih metodom
in situ FBMG, u poređenju sa komercijalno dostupnim koprocesovanim ekscipijensima, ukazuju na
njihovu podobnost za direktnu kompresiju. Koprocesovani ekscipijensi sa Precirol®-om i Compritol ®-
om, kao i odgovarajuće fizičke smeše, pokazale su dva do skoro tri puta niže vrednosti ukupnog rada
kompresije od komercijalno dostupnih ekscipijenasa na bazi laktoze. Dodatno, koprocesovani
ekscipijensi na bazi lipida pokazali su do 50 puta manji rad odvajanja i do 20 puta manji rad izbacivanja
od Retalac ®-a i Ludipress® -a. Superiorna antiadhezivna i lubrikatna svojstva koprocesovanih
ekscipijenasa pripremljenih in situ FBMG mogu se pripisati lipidnim ekscipijensima. Komercijalno
dostupni kao i ispitivani koprocesovani ekscipijensi, na bazi lipidnih ekscipijenasa, pokazali su
relativno visoke vrednosti zatezne čvrstine (> 1,7 MPa).
Predstavljeni rezultati ukazuju na to da se granulacija topljenjem u uređaju tipa fluidizirajućeg
sistema može koristiti kao pogodna metoda za koprocesovanje, koja zahteva manji utrošak energije i
vremena u poređenju sa uobičajenim tehnikama, poput sušenja raspršivanjem ili vlažne granulacije.
Dobijeni rezultati pokazuju da se koprocesovanjem laktoze sa odabranim lipidnim ekscipijensima može
postići odlična protočnost, kao i poboljšana tabletabilnost. Novi koprocesovani ekscipijensi su čak
pokazali superiornije karakteristike u pogledu svojih antiadhezivnih i lubrikatnih karakteristika u
poređenju sa komercijalno dostupnim koprocesovanim ekscipijensima na bazi laktoze.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Application of solventless granulation method for developent of novel co‐processed excipeints, Primena metode granulacije bez upotrebe rastvarača u razvoju novih koprocesovanih ekscipijenasa",
volume = "71",
number = "5 suplement",
pages = "S80-S81",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4671"
}

Ćirin-Varađan, S., Đuriš, J., Ibrić, S., Parojčić, J.,& Aleksić, I.. (2021). Application of solventless granulation method for developent of novel co‐processed excipeints. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 71(5 suplement), S80-S81.
https://hdl.handle.net/21.15107/rcub_farfar_4671

Ćirin-Varađan S, Đuriš J, Ibrić S, Parojčić J, Aleksić I. Application of solventless granulation method for developent of novel co‐processed excipeints. in Arhiv za farmaciju. 2021;71(5 suplement):S80-S81.
https://hdl.handle.net/21.15107/rcub_farfar_4671 .

Ćirin-Varađan, Slobodanka, Đuriš, Jelena, Ibrić, Svetlana, Parojčić, Jelena, Aleksić, Ivana, "Application of solventless granulation method for developent of novel co‐processed excipeints" in Arhiv za farmaciju, 71, no. 5 suplement (2021):S80-S81,
https://hdl.handle.net/21.15107/rcub_farfar_4671 .