Kniga na apstrakti book of abstrcts

Scale-up of fluid-bed granulation of paracetamol 
Natasa Anevska-Stojanovska
1
, Katerina Goracinova
2
1
Research and Development Department, Alkaloid, Aleksandar Makedonski 12, Skopje, Macedonia
2
Faculty of Pharmacy, Vodnjanska 17, Skopje, Macedonia
The correlation among the critical fluid bed process parameters and properties of paracetamol granulates
prepared using pilot equipment Aeromatic-Fielder TSG 2 was used as a guide during the theoretical and experimen-
tal scaling up studies on industrial equipment Aeromatic-Fielder TSG 4.
In  the present study the batch size is increased by a factor of 10. The equipment factor (air distributor area)
and process factors (spray rate, atomizing air pressure and binder droplet size) were used as main scale-up factors..To
maintain the same fluidization velocity, the air flow rate is increased by the equipment factor of  4.56.
The calculated starting process parameters using scale-up factors were little adjusted to achieve the desired
results (Table 1./TSG 4 (Gr 2)). The inlet air temperature and air flow during spraying were increased. In order to keep
the same relative droplet size, correction was made to the ratio of binder spray rate and atomizing air consumption.
Table 1. Scale-up of process parameters 
Granulate size distribution, geometric mean diameter and standard deviation, bulk and tap density (Carr's
index and Hausner ratio), flow rate (angle of repose) and loss on drying were evaluated through the different scale-
up stages. Statistical evaluation of granule size distribution did not showed statistically significant differences between
the granulates prepared on pilot equipment and industrial equipment. Good flowability and compressibility of gran-
ulates prepared at industrial scale have indicated properties optimal for tableting. The granulation process was suc-
cessfully scaled up by the air distributor area and relative droplet size.
Macedonian pharmaceutical bulletin 53 (1,2) 51-52 (2007)
PP - 7
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TSG 2 
 
TSG 4 
(Gr 1) 
TSG 4 
(Gr 2) 
Batch size (kg) 
8,449 
84,49 
84,49 
Area of air distributor (m
2
) 
0,057 
0,26 
0,26 
Mixing: 
 
 
 
Mixing/air flow rate (m
3
/h) 
200 
910 
910 
Mixing/inlet air temperature (
°C) 
50 
50 
60 
Mixing/time (min) 
1 
2 
2 
Spraying: 
 
 
 
Spraying, phase 1/air flow rate (m
3
/h) 
200 
910 
1200 
Spraying, phase2/air flow rate (m
3
/h) 
300 
1400 
1600 
Spraying/inlet air temperature (
°C) 
50 
50 
60 
Spray rate (kg/min) 
0,6 
0,8 
0,7 
Atomizing air pressure (Pa) 
2 
. 
10
5
 
1,5
. 
10
5
 
1,5
. 
10
5
 
Relative droplet size 
0,35 
0,46 
0,40 
Drying: 
 
 
 
Drying phase 1/air flow rate (m
3
/h) 
350 
1600 
1600 
Drying phase 2 air flow rate (m
3
/h) 
100 
500 
500 
Drying/ inlet air temperature (
°C) 
60 
60 
70 

Zgolemuvawe na procesot na vrtlo`na granulacija 
na paracetamol 
Nata{a Anevska-Stojanovska
1
, Katerina Gora~inova
2
1
Istra`uvawe i razvoj, Alkaloid, Bul. Aleksandar Makedonski 12, Skopje, Makedonija
2
Farmacevtski fakultet, Vodwanska 17, Skopje, Makedonija
Korelacijata pome|u kriti~nite procesni parametri i svojstvata na paracetamol granulatite
izraboteni na pilot opremata Aeromatic-Fielder TSG 2 be{e iskoristena kako vodi~ pri studijata na teo-
retsko i eksperimentalno zgolemuvawe na procesot na industriskata odrema Aeromatic-Fielder TSG 4.
Vo studijata, goleminata na serijata e zgolemena so faktorot deset. Faktorot na opremata
(popre~na povr{ina na  prenosnikot na vozduh) i procesnite parametri (brzina na nanesuvawe na rastvorot
za granulacija, pritisok na atomizacija i golemina na kapkata na rastvorot) bea iskoristeni kako glavni
faktori vo tekot na studijata na zgolemuvawe. So cel vospostavuvawe na ednakva brzina na fluidizaci-
ja, protokot na vozduhot be{e zgolemen so faktorot na opremata  4.56.
Presmetanite procesni parametri, so koristewe na faktorite na zgolemuvawe bea prilagodeni
zaradi pouspe{na izvedba na procesot (Tabela 1./TSG 4 (gr 2)). Temperaturata i protokot na vlezniot voz-
duh bea zgolemeni
. Zaradi obezbeduvawe na ednakva relativna golemina na kapkata, korekcii bea napraveni
na odnosot brzina na nanesuvawe na rastvorot za granulirawe i protokot na vozduhot niz diznata. 
Tabela 1. Zgolemuvawe na procesnite parametri 
Distribucijata na ~esti~kite spored goleminata, sredniot geometriski dijametar i standardnata
devijacija, prividnata gustina pred i po tapkawe (Karov indeks i Hausnerov indeks), brzinata na proteku-
vawe (nasipen agol) i sodr`inata na vlagata bea sledeni pri razli~nite stepeni na zgolemuvawe na pro-
cesot. Statisti~kata analiza na distribucijata na ~esti~kite ne poka`a prisustvo na statisti~ki zna~ajni
razliki pome|u granulatite proizvedeni na pilot opremata i industriskata oprema. Vrednostite na
proto~nite i kompresibilnite karakteristiki na granulatite proizvedeni na industriskata oprema se vo
granici optimalni za izvedba na procesot na tabletirawe. Procesot na granulacija be{e uspe{no zgole-
men so koristewe na popre~nata povr{ina na  prenosnikot na vozduh i relativnata golemina na kapkata.
Macedonian pharmaceutical bulletin 53 (1,2) 51-52 (2007)
PP - 7
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TSG 2 
TSG 4(Gr 1) 
TSG 4(Gr 2) 
Golemina na serija (kg) 
8,449 
84,49 
84,49 
Popre~na povr{ina na  prenosnikot na vozduh (m
2
) 
0,057 
0,26 
0,26 
Me{awe: 
 
 
 
Me{awe /protok na vlezen vozduh (m
3
/h) 
200 
910 
910 
Me{awe /temperatura na vlezen vozduh (
°C) 
50 
50 
60 
Me{awe /vreme (min) 
1 
2 
2 
Granulacija: 
 
 
 
Granulacija, faza 1/protok na vlezen vozduh (m
3
/h) 
200 
910 
1200 
Granulacija, faza 2/protok na vlezen vozduh (m
3
/h) 
300 
1400 
1600 
Granulacija /temperatura na vlezen vozduh (
°C) 
50 
50 
60 
Brzina na nanesuvawe na rastvorot (kg/min) 
0,6 
0,8 
0,7 
Pritisok na atomizacija (Pa) 
2 
. 
10
5
 
1,5
. 
10
5
 
1,5
. 
10
5
 
Relativna golemina na kapkata 
0,35 
0,46 
0,40 
Su{ewe: 
 
 
 
Su{ewe, faza 1/protok na vlezen vozduh (m
3
/h) 
350 
1600 
1600 
Su{ewe, faza 2/protok na vlezen vozduh  (m
3
/h) 
100 
500 
500 
Su{ewe/temperatura na vlezen vozduh  (
°C) 
60 
60 
70 

Optimization of Metronidazole Tablet formulation 
using Response Surface Experimental Design
Meri Davceva, M. Simonoska Crcarevska, N. Geskovski, Katerina Goracinova
Institute of Pharmaceutical Technology, Faculty of Pharmacy, 
University "Ss Cyril and Methodious", Vodnjanska 17, 1000 Skopje, Macedonia
The aim of the study was to evaluate individual and the effects of the binder (B) and disintegrant (D) on the
properties of Metronidazole tablets (hardness, friability, disintegration and dissolution) using Response Surface exper-
imental design. 
Methods: Polyvinylpyrrolidone (Kollidon K-25) was used as a binding agent at concentrations 1-4%, and
cross-linked polyvinylpyrrolidone (Kollidon CL) as disintegrant at concentration 0,2-1,2% in a metronidazole tablet
formulation. During the preformulation studies both methods, wet granulation and direct compression were evalu-
ated and compared. Direct compression method was used in further formulation and optimization studies as the pro-
duced by direct compression methods showed better mechanical and dissolution properties. Formulation optimiza-
tion was performed using Response Surface design, with three levels and two variable factors, which resulted in nine
complete formulations that were studied. 
Results: The amounts of binder and disintegrant have significant effect on the tablet's hardness. The tablet
hardness increases when the amount of disintegrant was decreased and the amount of binder increased. Tablets' fri-
ability also depends on the presence of binder and disintegrant. Reduction in tablets friability was noticed when the
binder amount was increased and the disintegrant amount was decreased. 
The amount of binder and disintegrant in the tablets has the most significant effect over tablet disintegration.
However, the interaction between these two components also plays a significant role. The dissolution at acidic pH
depends on the amount of disintegrant. With the increase of the pH value, the binder, apart from the disintegrant, plays
an important role. The ranking of the individual and interaction coefficient values for the formulations was D > B for
hardness, D >but 
≅ B for friability, B >> B-D > D for disintegration. 
Conclusion: The optimal formulation should take into consideration the mechanical properties of the tablet
as well as the disintegration and dissolution of metronidazole. The minimum concentration of disintegrant required
in order to provide appropriate disintegration rate and to decrease the effect of the binder was confirmed during the
optimization studies. Also the amount of binder needed to provide certain mechanical tablet properties and mutual
interaction among the binder and disintegrant concentration and influence on the tablet properties were established
and discussed.
Macedonian pharmaceutical bulletin 53 (1,2) 53-54 (2007)
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Formulacija na Metronidazol tableti so brzo osloboduvawe
Meri Dav~eva, M. Simonoska Crcarevska, N. Ge{kovski, Katerina Gora~inova
Institut za farmacevstka tehnologija, Farmacevtski fakultet, 
Univerzitet Sv. Kiril i Metodij, Vodwanska 17,Skopje,Makedonija
Cel: Da se formulira i optimizira  tabletna formulacija so brzo osloboduvawe, so model lekovi-
ta supstancia-metronidazol. Vo tekot na preformulaciskite ispituvawa be{e izbrana formulacija koja
ponatamu }e se optimizira. Vo tekot na optimizacijata bea ispituvani vlijanijata na nezavisnite promen-
livi, koncentracijata na vrzuva~ot i dezintegransot vrz farmacevtsko-tehnolo{kite i biofarmacevt-
skite osobini na tabletnata formulacija.
Metodi:  Dvata proizvodni procesi vla`na granulacija (VG) i direktna kompresija (DC) bea
primeneti vo preformulaciskite ispituvawa. VG be{e izveduvana so rastvor na vrzivno sredstvo, no i
samo so vehikulum. Vo site formulacii bea vklu~eni Kollidon K-25, kako vrzuva~ vo koncentracija od 5%,
kalcium stearat i natrium lauril sulfat kako lubrikanti podednakvo zastapeni so 0,5% poedine~no. So
cel da se sogleda ulogata na polnitelot, bea upotrebeni tri naj~esto koristeni polniteli vo prvite 4
formulacii: laktoza, mikrokristalna celuloza (MCC) i dikalcium fosfat vo koncentracija od 34%, vo
procesot vla`na granulacija, so rastvor na vrzivno sredstvo. Za da se prou~i ulogata na dezintegransot-
krospovidon (Kollidon CL) go vklu~ivme vo slednite 4 formulacii vo koncentracija od 3%, za smetka na
polnitelot. MCC i dikalcium fosfat kako polniteli bea vklu~eni vo formulaciite pripremeni so VG
so vehikulum. MCC kako polnitel be{e vklu~en i vo formulaciite pripremeni so direktna kompresija.
Site pripremeni granulati i suvi smesi bea ispituvani na nasipen agol, brzina na protekuvawe, nasipna
gustina, gustina po tapkawe, indeks na kompresibilnost i vlaga. Podgotvenite tableti bea ispituvani vo
pogled na cvrstinata, frijabilnosta, mehani~kata jakost, vremeto na dezintegracija i disolucija na aktiv-
nata supstancija.
Rezultati:  So primena na VG dobieni bea izvonredno dobro proto~ni granulati, sporedeno so
suvite smesi za DC, koi imaa zadovolitelni vrednosti. Tabletite dobieni so VG - so rastvor na vrzivno
sredstvo, poka`uvaat nezadovolitelna mehani~ka jakost, so pojava na listawe pri odreduvawe na frija-
bilnosta i nezadovolitelna cvrstina, {to najverojatno se dol`i na nevoedna~ena distribucija na vrzivno-
to sredstvo. Povoedna~ena raspredelba na vrzuva~ot e dobiena kaj formulaciite so VG-so vehikulum, {to
rezultira{e so pogolema mehani~ka jakost, cvrstina i odli~ni vrednosti na frijabilnost na tabletite.
Site formulacii dobieni so DC, imaa zadovolitelna mehani~ka jakost, cvrstina i frijabilnost. Jasno
se zabele`uva ulogata na dezintegransot kaj site formulacii kade e vklu~en, namaluvawe na vremeto na
raspa|awe od minuti do sekundi, no i negovoto vlijanie vrz cvrstinata i frijabilnosta na tabletite.
Prirodata na polnitelot ima vlijanie vrz dezintegracijata i disolucijata, no e nezna~itelno vo odnos
na vlijanieto na dezintegransot, so isklu~ok na MCC, koja pokraj uloga na polnitel ima svojstvo i na vrzu-
va~ i dezintegrans.
Zaklu~ok:
  Rezultatite uka`uvaat deka DC mo`e da se primeni kako metod za podotovka na ispitu-
vanata formulacija na metronidazol tableti. MCC e superioren polnitel vo odnos na mehani~kite svo-
jstva, no i vo odnos na dezintegracijata i disolucijata na tabletite.
Macedonian pharmaceutical bulletin 53 (1,2) 53-54 (2007)
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Enteric coated chitosan-Ca-alginate microparticles 
for colon drug delivery
M. Simonoska Crcarevska, M. Glavas Dodov, K. Goracinova
Institute of Pharmaceutical technology, Faculty of Pharmacy, Vodnjanska 17, 1000, Skopje, Macedonia
Budesonide, a highly hydrophobic drug, is one of the most used in the treatment of active colon diseases. A
novel formulation that will offer efficient treatment of colon diseases should combine biopolymer colloidal drug car-
riers that offer prolonged residence time and controlled release at the site of action. By modifying drug residence
time and drug release rate, increased therapeutic concentration at the site of inflammation and increased therapeutic
activity might be achieved. Having in mind bio/mucoadhesive properties of natural biopolymers, chitosan-alginate
microparticulated systems should have potential for colon targeting. Coating the MP`s by polymer with pH depend-
ent properties such as eudragit might obtain direct targeting of the microparticles to the colon region whereby increased
drug control release will be present. Using a novel one step spray-drying procedure [1] chitosan-Ca-alginate micropar-
ticles (sample 1) budesonide loaded, were prepared. MP`s were further coated using Eudragit
®
S 100 (sample 2), by
the same procedure. Eudragit:MP`s mass ratio was 2:1. Microparticles were spherical with mean particle size of
4.454±9*10
-3
µm (sample 1), and 4.261±0.03µm (sample 2), narrow unimodal distribution and positive surface
charge which favours expected mucoadhesivness of MP`s. The in vitro release of budesonide from uncoated and
coated MP`s was carried out at 37
0
C for 24h in acidic buffer (pH 2.0) and phospate buffer (pH 7.4). Eudragit coat-
ing has sustained release of budesonide in acidic media. In pH 7.4 budesonide was released faster from coated than
the uncoated beads, one might be suspected that redistribution of budesonide in the hydrophilic matrix will be trig-
gered by eudragit solvent (acetone) and hence influenced the release rate at pH 7.4.
In vivo experiments on male Wistar rats followed. Coated MP`s significantly improved efficacy of budes-
onide in the healing of TNBS induced colitis in rats. Moreover, the sustained drug release allows pharmacological
effects to be extended due to the prolonged residence time of the carrier system at the targeted inflamed area. In this
way, IBD could be treated locally, opening a new therapeutic use for this drug in inflammatory diseases.
Acknowlwdgements:
The authors would like to acknowledge the support of NATO SfP: 978023
Macedonian pharmaceutical bulletin 53 (1,2) 55-56 (2007)
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Enterosolventni citozan-Ca-alginatni mikro~esti~ki za naso~eno
i kontrolirano osloboduvawe na lekovita supstancija vo kolon
M. Simonoska Crcarevska, M. Glava{ Dodov, K. Gora~inova
Institut za Farmacevtska tehnologija, Farmacevtski fakultet, 
Univerzitet Sv. Kiril i Metodij, Vodwanska 17, Skopje 1000, Makedonija
Sovremenite trendovi pri tretman na bolesti na debeloto crevo (ulcerativen kolit, Kronovo
zaboluvawe) se naso~eni kon formulirawe na dozirani formi so naso~eno i kontrolirano osloboduvawe
na lekovitata supstancija lokalno vo debeloto crevo. Od ovie sistemi se o~ekuva zna~ajno da vlijaat na
namaluvawe na intenzitetot i za~estenosta na potencijalnite nesakani efekti, karakteristi~ni za kon-
vencionalnite dozirani formi, kako i na pogolemata efikasnost, vo terapijata na inflamatornite crevni
zaboluvawa kako rezultat na zgolemenata koncentracija na lekovitata supstancija i nivniot prodol`en
period na prestoj na mestoto na aplikacija. Imaj}i gi vo predvid bio/mukoadhezivnite osobini na prirod-
nite biopolimeri, mikropartikuliranite sistemi bazirani na citozan i alginat pretstavuvaat vetuva~ki
sistemi za specifi~no naso~uvawe na lekoviti supstancii vo kolonot. So oblo`uvawe na mikro~esti~kite
so enterosolventen polimer kako {to e eudra`itot se o~ekuva da se postigne naso~uvawe, efikasna kon-
trola na osloboduvaweto na budezonidot i lokalizirawe na negovoto dejstvo vo kolonot. 
Citozan-Ca-alginatnite mikro~esti~ki so enkapsuliran budezonid (primerok 1) se izraboteni so
ednostepena postapka na rasprsnuvawe so su{ewe [1]. Mikro~esti~kite se oblo`ni so Eudragit
®
S 100
(primerok 2) so primena na istata postapka. Eudra`it:MP maseniot odnos e 2:1. Mikro~esti~kite se sfer-
ni so sreden dijametar od 4.454±9*10
-3
µm (primerok 1) i 4.261±0.03µm (primerok 2), tesna unimodalna dis-
tribucija i pozitivni vrednosti za povr{inskata naelektriziranost, {to e vo prilog na nivnata o~eku-
vana mukoadhezivnost. In vitro testovite za disolucija od neoblo`enite i oblo`nite MP se izvedeni na
37
0
C vo tek na 24h vo kisel (pH 2.0)  i fosfaten pufer (pH 7.4). Od dobienite rezultati jasno se gleda poten-
cijalot na oblo`enite so eudra`it mikro~esti~ki uspe{no da ja suprimiraat brzinata na osloboduvawe
na budezonidot vo kisel medium. Pobrzoto osloboduvawe na budezonidot od oblo`enite so eudra`it vo
odnos na neoblo`enite mikro~esti~ki vo pH 7.4 najverojatno se dol`i na preraspredelbata na budezonidot
vo hidrofilniot matriks predizvikana od vehikulumot za enterosolventniot polimer (aceton).
Napraveni se i in vivo eksperimenti na ma{ki Wistar staorci. Dobienite rezultati se vo prilog na
efikasnosta na oblo`enite so eudra`it citozan-Ca-alginatni mikro~esti~ki so budezonid vo tretman-
ot na TNBS induciraniot kolit kaj staorci. Naso~enoto deluvawe i lokaliziranoto i kontrolirano oslo-
boduvawe na budezonid od mikro~esti~kite oblo`eni so eudra`it rezultiraat so zna~ajno namaluvawe
na parametrite na o{tetuvawe na debeloto crevo i inflamacijata kaj eksperimentalniot `ivotinski
model na inflamacija vo sporedba so kontrolnite formulacii i nelekuvanite `ivotni.
Site prethodno izneseni rezultati uka`uvaat deka posle per oralna aplikacija oblo`enite so
eudra`it citozan-Ca-alginatni mikro~esti~ki so budezonid, kako rezultat na nivnite osobini za naso~eno
i kontrolirano osloboduvawe, odnosno obezbeduvawe na lokalno dejstvo na budezonidot vo GIT, imaat
potencijal za efikasnost vo terapijata na humanite inflamatorni crevni zaboluvawa.
Blagodarnost:
Avtorite se zablagodaruvaat na podr{kata na  NATO SfP: 978023
Macedonian pharmaceutical bulletin 53 (1,2) 55-56 (2007)
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Experimental design of cetirizine dihidrochloride 
chewable tablets formulation
Suncica Jordanoska, Marija Glavas Dodov, Katerina Goracinova
1
Institute of Pharmaceutical Technology, Faculty of Pharmacy, 
University "Ss Cyril and Methodious", Vodnjanska 17, 1000 Skopje, Macedonia
The purpose of the present study was to formulate a chewable tablet containing cetirizine dihidrochloride, includ-
ing correction of taste of the active substance by coating it with polymer, without harming the dissolution profile.
A granulate containing cetirizine was coated with polymer of 5%, 10% and 20% weight gain, which is resist-
ant in neutral pH and is instantly dissolved in the acidic pH in the stomach.  
The effect of the polymer weight gain on the physical, technological and the biopharmaceutical characteris-
tics of the granules was examined. Also, the consequences of the polymer weight gain on the improvement of the taste,
on the physical, technological and biopharmaceutical characteristics of the tablets were examined. The effect of the
independent variables was analyzed applying a "screening" experimental design. 
During the analysis of the granules, the percentage of the coating material and the size of the granules were cho-
sen as independent variables. The effect of these factors on the flowability and the compressibility of the granules, was
examined through the following measured variables: Carr's index and angle of repose. Also, the effect of the independ-
ent variables on the dissolution rate of the active substance in different pH was analyzed.(pH 1.2, pH 4.6 and pH 6.8)
From the physical and the biopharmaceutical aspects of the granules, the following conclusions could be made: 
The physical characteristics of the granules (flowability and compressibility) depend on the coating percentage
(polymer weight gain), the particle size and on the mutual effect of the both factors. According to the obtained mathe-
matical dependence, the flowability and the compressibility of the granules is improving by increasing the polymer weight.
It was concluded that in the acidic pH, the particle size has the greatest effect on the dissolution rate. Despite
this, the percentage of the polymer coating in acidic pH has no effect on the dissolution rate because of the rapid dis-
solution of the coating material in the acidic environment. 
In the neutral pH, which simulates the pH environment of the saliva, the greatest effect on the dissolution
rate belongs to the particle size and the mutual effect between the size of the particles and the percentage of the poly-
mer coating.
During the analysis of the tablets, the percentage of the granule coating and the presence of the excipients
/disintegrant were taken as independent variables. 
The effect of the independent variables on the disintegration time, taste improvement and the dissolution rate
in different pH environments was examined. 
From the aspect of the physical and the biopharmaceutical characteristics of the chewable tablets, as we expect-
ed, the disintegration time depends on the quantity of the incorporated disintegrant.
The dissolution rate depends on the presence of the disintegrant and the percentage of the coating material in
all the pH environments. 
The contact of the active substance during the presence in the mouth is avoided by the coating process. 
Because of the insolubility of the coating material - Eudragit E in the neutral pH, which corresponds to the
pH in the mouth, the contact of cetirizine is avoided  and the dissolution in the salivary liquids is disabled, which also
prevents the contact with the taste receptors.  
Still, the excipients play a very important role in taste masking, and they give the chewable tablets a much
more pleasant taste.
The excellent dissolution characteristics of cetirizine dihidrochloride is not compromised by increasing the
polymer percentage, although the taste is improved. 
A formulation of a palatable chewable tablet was achieved completely by incorporating a granulate with 20%
polymer weight gain.
Formulations of chewable tablets which have an excellent taste and a dissolution rate which exceeds  90%
in the 30-th minute in all the three pH media were achieved.
Macedonian pharmaceutical bulletin 53 (1,2) 57-58 (2007)
PP - 10
57
^ETVRTI KONGRES NA FARMACIJATA NA MAKEDONIJA SO ME\UNARODNO U^ESTVO
FOURTH CONGRESS OF PHARMACY OF MACEDONIA WITH INTERNATIONAL PARTICIPATION