Kniga na apstrakti book of abstrcts

New concepts in process technology 
and Pharmaceutical Drug formulation Design
Gabriele Betz
Institute of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 
Klingelbergstr. 50, 4056 Basel, Switzerland.
The Industrial Pharmacy Lab (IPL) is focusing on research in process technology and pharmaceutical drug
formulation design and was found in 2001 as a turning platform between the university and the pharmaceutical indus-
try at the Pharma Hub Basel. In close cooperation with the pharmaceutical industry this is a very unique concept
1
aiming to understand and control pharmaceutical processes, which is in agreement with the basic tenet of quality by
design of FDA’s PAT (Proscess Analytical Technology) initiative. Over 80% of the active drugs that are formulated
to produce systemic effects in patients are marketed as solid dosage forms, due to the great acceptance of patients to
take tablets. In the present research overview of the IPL tools for robust solid dosage form design are introduced,
such as granulation in-process control and compaction simulation for tabletting scale-up. Finally, recent results about
multiple dosage forms, such as a floating drug delivery system and a multiple pellet system is presented. These dosage
forms are less affected by variation in the gastric emptying rate and moreover by gastrointestinal transit time com-
pared to a single unit form.
1
NETS Award 2004 sponsored by Gebert Rüf Foundation, Switzerland.
Macedonian pharmaceutical bulletin 53 (1,2) 65 (2007)
PP - 15
65
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Non-invasive drug delivery
Gabriele Betz
Institute of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 
Klingelbergstr. 50, 4056 Basel, Switzerland.
The number of new therapeutic proteins (biopharmaceutical or biologicals) is increasing, in particular mon-
oclonal antibodies and vaccines dominate the list of new biopharmaceuticals.
The formulation process of biopharmaceuticals requires specific expertise and should take into account the
sensitivity of the molecules to physical and chemical degradation reactions. Biopharmaceuticals have a number of
special properties, such as high molecular weight, formation of secondary, tertiary, and sometimes quaternary struc-
ture, which are mainly stabilized by weak physical forces and not by covalent bonds. Therefore, preservation of the
delicate structure of the protein is the challenge of a formulation scientist.
Therapeutic proteins should not be administered via the oral route, because of the presence of proteases in
the GI tract. Moreover, the gut wall presents an efficient barrier against protein permeation. 
There is the need to search for alternative routes of administration, such as nasal, rectal, vaginal, pulmonary,
dermal, and through nails. This presentation analyses the opportunities and limitations of alternative non-invasive
drug delivery routes.
Macedonian pharmaceutical bulletin 53 (1,2) 66 (2007)
PP - 16
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Orally Disintegrating Tablets (ODT) - Trends 
and Recent Developments 
E. Adamova
1
, R. Dameska
1
, M. Anevska
1
, D.Lepcevska
1
, E. Spaseska-Aleksovska
1
1
ReplekFarm, Ul. Kozle 188, 1000 Skopje, MK 
In recent years there has been an expansion in development of orally disintegrating tablets (ODT) in the
pharmaceutical industry. ODTs are listed in the European Pharmacopoeia as solid dosage forms administered oral-
ly, that disintegrate and dissolve in 3 min., without chewing or additional water consumption. 
Main advantage of these forms is ease of administration in patients that have swallowing difficulties, geri-
atric patients and children. Also ODTs are marketing tool of the pharmaceutical companies in extension of exclu-
sivity on active substances. Disadvantage of these forms is difficulty of incorporation of high doses of active sub-
stance, achieving fast disintegration, successful taste masking and achieving satisfying organoleptic characteristics
of the tablet. 
ODTs are dosage forms in which up to 500 mg of active substance can be incorporated, and good tablet
parameters could be achieved. There are few known technologies for production of ODT: moulding, lyophilization
(Zydis
®
i Lyoc
®
), and direct compression (Orasolv
®
, Durasolv
®
, Wowtab
®
), and every method has its advantages and
disadvantages. Direct compression is most widely used technology, because it employs conventional tablet-press-
es, it doesn’t require special manufacturing equipment, utilizes known excipients, and provides tablets with good
physical parameters, due to which no special packaging is required. 
ODT formulation in direct compression includes diluent, disintegrant, lubricant, antistatic, sweetener, aro-
mas and colors. Most frequently used diluent is mannitol, directly compressible grade, which has good solubility
(quick and easy moisturization), sweet enough taste and other convenient organoleptic characteristics. 
• 
Due to the fast disintegration requirement, ODT formulations include high percent of super disintegrator,
often 10-20%. Therefore the choice and amount of disintegrator is a critical moment. Most important requirements
that need to be addressed when choosing disintegrator are: 
• 
Disintegration capacity- by capillary forces fast and efficient conduction of small volumes of saliva, increase
of volume and hydrostatic pressure in the tablet for disintegration of the same. 
• 
Compressibility- good compressibility of the disintegrator would provide good hardness of the tablet
achieved by relatively low compression force, on the other hand by lowering the compression force one would achieve
more porous tablets and faster disintegration. 
• 
Particle size- by lower particle size increased contact surface would be achieved and therefore disintegra-
tion to granules/ particles with smaller size. 
Flowability- particle shape (spherical compared to elongated) and particle size distribution (similarity in size).
Many actives have been formulated as ODT: antipsychotic/antidepressant agents, antipyretic/analgesic/anti-
inflammatory agents, hypnotic/sedative agents, GIT agents, antitussive agents, antihypertensive/cardiovascular sys-
tem conditioning agents, antiasthmatic/antiallergic agents, antiparkinskonic/anti-Alzheimer agents, hypolipidemic
agents, antimicrobial or antiviral agents. 
Macedonian pharmaceutical bulletin 53 (1,2) 67-68 (2007)
PP - 17
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Oralno Dezintegrira~ki Tableti (ODT)
- trendovi i najnovi soznanija
E. Adamova
1
, R. Dameska
1
, M. Anevska
1
, D. Lep~evska
1
, E. Spaseska-Aleksovska
1
1
ReplekFarm, Ul. Kozle 188, 1000 Skopje, MK
Vo poslednite nekolku godini vo farmacevtskata industrija postoi ekspanzija vo razvojot na oral-
no dezintegrira~ki tableti (ODT). Tie se propi{ani vo Evropska Farmakopea kako cvrsti doza`ni formi
koi se administriraat oralno, a se dezintegriraat i se rastvoraat za 3 minuti, bez xvakawe i bez dopol-
nitelno zemawe na voda.
Glavna prednost e olesnetata administracija kaj pacienti koi imaaat problemi so goltawe, stari
lica i deca. Isto taka ovie doza`ni formi pretstavuvaat marketing alatka na farmacevtskite kompanii
za prodol`uvawe na ekskluzivnosta vrz svoite aktivni supstancii. Nedostatok pri formulirawe na ovie
doza`ni formi e inkorporiraweto na visoki dozi na aktivna supstancija, postignuvawe na brza dezinte-
gracija kako i uspe{no maskirawe na vkusot i postignuvawe na zadovolitelni organolepti~ki osobini
na tableta.
ODT se doza`ni formi vo koi mo`e da bide inkorporirano do 500 mg aktivna supstanca, so koja
bi se obezbedile dobri tabletni parametri. Postojat pove}e metodi za dobivawe ODT : postapka so
izvlekuvawe (molding), liofilizacija (Zydis
®
i Lyoc
®
) i direktna kompresija (Orasolv
®
, Durasolv
®
, Wowtab
®
)
pri {to sekoja metoda ima svoi prednosti i nedostatoci. Direktna kompresija e naj~esto koristena
tehnologija, bidej}i koristi konvencionalni tablet-ma{ini, pri {to ne e potrebna posebna oprema za
proizvodstvo, se koristat voobi~aeni i poznati ekscipiensi, i se dobivaat tableti so zadovolitelni
fizi~ki parametri, pri {to ne se potrebni specijalni pakuvawa. 
Formulacija na ODT za direktna kompresija, sodr`i polnitel, dezintegrator, lubrikant, antis-
tatik, zasladuva~i, aromi i boi. Naj~esto koristen diluent e manitol, so direktno kompresibilen kvalitet,
koj ima zadovolitelna rastvorlivost (brzo i lesno se vla`ni), sladok vkus i drugi pogodni organolep-
ti~ki svojstva.
Poradi baraweto za brza dezintegracija, vo ODT formulaciite e potrebno vmetnuvawe na visok
procent na superdezintegratori, naj~esto 10-20%, poradi {to izborot na dezintegrator i negoviot uddel
e kriti~en moment. Glavni karakteristiki na koi treba da se vnimava pri izbor na dezintegrator se: 
•
sposobnost za vla`newe i raspa|awe- treba brzo i efikasno so kapilarni sili da sproveduva mal
volumen na plunka, zaradi zgolemuvawe na volumen i hidrostatski pritisok vo tabletata pod ~ie dejstvo
bi se raspadnala istata.
•
kompresibilnost- podobri kompresibilni svojstva na dezintegratorot bi ovozmo`ile dobivawe
dovolno cvrsti tableti pri relativno mala sila na kompresija, dodeka pri poniski sili na kompresija
bi se dobile poporozni tableti i pobrza dezintegracija.
•
golemina na ~esti~ki- dovolna usitnetost so cel zgolemena dopirna povr{ina i raspa|awe do
granuli/~esti~ki so soodvetna golemina vo usnata praznina. 
•
proto~nost- karakteristiki na koi se vnimava se oblik na ~estici (sferi~ni vo odnos na vlak-
nesti) i distribucija na golemina na ~estici (voedna~enost na golemina). 
Golem broj na aktivni supstancii veke se formulirani kako ODT: 
Anti-psihotici i anti-depresivi; antipiretici, analgetici i anti-inflamatorni supstanci; hip-
notici i sedativi; antitusici; GIT lekovi; anti-astmatici i anti-alergeni; anti-hipertenzivi i kardio-
vaskularni; hipolipidemici; anti-mikrobni i anti-viralni; lekovi protiv Parkinsonova i Alchajmerova
bolest.
Macedonian pharmaceutical bulletin 53 (1,2) 67-68 (2007)
PP - 17
68
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Inffluence of Methylcellulose and Hypromellose on the physical 
properties of the Metformin HCl tablet cores 850 mg
V. Dinik
1
, L. Makraduli
1
, D. Dimova
1
, E. Spaseska - Aleksovska
1
1
ReplekFarm, Kozle 188, 1000 Skopje, R. Macedonia
The active substance Metformin Hydrochloride has poor compressibility as a result of the strong intra-crys-
tal adhesive forces. It is considered as a high dose drug in the oral dosage forms which combined with its poor com-
pressibility makes the process of developing a tablet, as an oral dosage form more difficult.
Considering the objective to produce a film coated tablet as a final product, the hardness and friability of the
gained tablet cores are very important in the performing of continuous and successful process of film coating of the
tablet cores.
The aim of this work is to show the difference in the physical properties of tablet cores produced with
Methylcellulose as a filler/binder compared to tablet cores with Hypromellose as a filler/binder in their composition.
The used polymers have same methoxyl content (28 - 31 %) as well as same apparent viscosity.
Used materials in the test formulations are:
Metformin Hydrochloride - Aarti Dugs Ltd., India,
Hypromellose (Methoxyl content 28-30%)-Colorcon, USA, 
Methylcellulose (Methoxyl content 28-30%)-Colorcon, USA
In the production, in-process control and quality control of the granulates before the process of tablet com-
paction and tablet cores the following apparatus was used: 
Balance, TE 1502S; Moisture analyzer MA 45, Sartorius Germany,
High shear mixer MIC 5C - Developer, Comasa s.a., Argentina, 
Dryer- incubator, IP60-MF 60L LTE Scientific Ltd, England, 
Tablet press, Unipress Diamond 20, Manesty, England, 
Calibrator-FGS; 
Tapped/bulk density tester -SVM 102; 
Granulate flow tester -GT-L; Tablet Hardness tester-TBH 100; 
Disintegration tester- ZT 70 Series; 
Tablet friability tester -TAR 100, ERWEKA, Germany, 
Tablet dissolution tester -“Sotax AT7 Smart” USP Apparatus 2, 
with “Perkin Elmer Lambda 45” UV/VIS Spectrophotometer.
Regarding the type of the used polymer, granulates with different flowing characteristics as well as differ-
ent compressibility were obtained.
The tablet cores produced by two different formulations have different physical characteristics (hardness,
friability, disintegration). Regarding the dissolution profile the tablets made with the both formulations complied
with the In House specification for the Dissolution of Metformin Hydrochloride tablet cores 850 mg. 
Following the results we can conclude that Methylcellulose has significantly higher binding properties than
Hypromelose with similar methoxyl content as well as similar apparent viscosity when used as a binder/filler in the
formulation of Metformin hydrochloride film coated tablets 850 mg.
The obtained tablet cores with Methylcellulose in the composition are significantly harder, less friable and
more comfortable for manipulation during the film coating process.
Macedonian pharmaceutical bulletin 53 (1,2) 69-70 (2007)
PP - 18
69
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Vlijanie na Methylcellulose i Hypromellose
na fizi~kite karakteristiki na Metformin hidrohlorid
tabletni jadra 850 mg
V. Dini}
1
, L. Makraduli
1
, D. Dimova
1
, E. Spaseska - Aleksovska
1
1
ReplekFarm, Kozle 188, 1000 Skopje, R. Makedonija
Aktivnata supstancija Metformin Hydrochloride poka`uva isklu~itelno lo{i kompresibilni karak-
teristiki, poradi silnite adhezivni sili vo sklop na samata kristalna struktura. Isto taka stanuva zbor
za aktivna supstancija koja se javuva vo visoka doza vo doza`nite formi za peroralna primena, {to dopol-
nitelno go ote`nuva tehnolo{kiot razvoj na soodveten preparat - tableta. 
So ogled na toa {to celta e proizveduvawe na gotov lek - film oblo`ena tableta cvrstinata i
tro{nosta na dobienite tabletni jadra igraat isklu~itelno va`na uloga za ovozmo`uvawe na nepreki-
nat i uspe{en proces na oblo`uvawe na tabletnite jadra so film obvivka. 
Celta na ovoj trud e da ja poka`e razlikata vo dobienite parametri na tabletnite jadra koga
kako polnitel/vrzuva~ se koristi Methylcellulose nasproti  Hypromellose. Koristeni se polimeri so ist
udel na Metoxyl grupi (28 - 31%) i so ista viskoznost. Koristeni se slednite materijali i aparatura: 
Metformin Hydrochloride - Aarti Dugs Ltd., India, 
Hypromellose (Methoxyl content 28-30%)-Colorcon, USA,
Methylcellulose (Methoxyl content 28-30%)-Colorcon, USA, 
Vaga, TE 1502S; Vlagomer MA 45, Sartorius Germany, 
Vertikalen granulator, brz me{a~, MIC 5C - Developer, Comasa s.a., Argentina,
Su{nica - inkubator, IP60-MF 60L LTE Scientific Ltd, Greenfield, England, 
Ma{ina za tabletirawe, Unipress Diamond 20, Manesty, England,
Granulator/kalibrator-FGS; 
Tester za odreduvawe na volumen na granulat pred i po tapkawe-SVM 102; 
Tester za odreduvawe na proto~nost na granulat-GT-L; 
Tester za merewe na cvrstina na tableti-TBH 100; 
Tester za merewe na raspadlivost na tableti- ZT 70 Series; 
Tester za odreduvawe na tro{nost na tableti-TAR 100, ERWEKA, Germany, 
Aparat za odreduvawe na rastvorlivost na tableti -“Sotax AT7 Smart” USP Apparatus 2, 
so koristewe na “Perkin Elmer Lambda 45” UV/VIS Spektrofotometar.
Granulatite dobieni so dve razli:ni formulacii pred procest na tabletirawe se razlikuvaat vo
odnos na proto~nite i kompresibilnite osobini i vo tek na in process kontrolite i vo tekot na proce-
sot na tabletirawe. 
Tabletnite jadra dobieni so dvete razli~ni formulacii zna~itelno se razlikuvaat vo odnos na
fizi~kite karakteristiki (cvrstina, tro{nost, raspadlivost), dodeka vo odnos na rastvorlivosta i dvete
formulacii dadoa rezultati koi odgovaraat na prethodno zadadenata specifikacija. 
Rezultatite poka`aa deka Methylcellulose ima zna~itelno pogolema vrzuva~ka mo} vo odnos na Hypro-
mellose, so ista viskoznost i ist uddel na Metoxyl-grupi, koga se koristi kako sredstvo za vrzuvawe pri izra-
botkata na tabletni jadra od preparatot Metformin hidrohlorid film-obo`eni tableti 850 mg. Dobi-
enite tabletni jadra vo ~ij {to sostav se nao|a Methylcellulos se zna~itelno pocvrsti, neronlivi, i polesni
za manipulacija vo tek na procesot na oblo`uvawe so film obvivka.
Macedonian pharmaceutical bulletin 53 (1,2) 69-70 (2007)
PP - 18
70
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Effect of packaging and storage on the stability 
of Amlodipine besylate tablets 
S. Fako, E. Satrovic, S. Bojo-Omeragic, M. Dzambic, L. Zilic Marjanovic, S. Hadzidedic
Bosnalijek d.d., Development Department, Jukiceva 53, 71000 Sarajevo, Bosnia and Herzegovina
The increasing intervention by regulatory agencies stimulated standard approaches to stability testing. The sta-
bility of pharmaceutical ingredients and the products containing them depends on (a) the chemical and physical prop-
erties of the materials concerned (including the excipients and container systems used for formulated products) and (b)
environmental factors such as temperature, humidity, and light and their effect on the substances in the product.
Amlodipine is a blocker of calcium channels and a dihydropyridine derivative that has a specific strong effect
on transmembrane passing of calcium ions and reducing of calcium concentration in myocardial cells and soft mus-
cles. Amlodipine primarily affects the peripheral blood vessels, although it widens the coronary blood vessels too.
Amlodipine reduces peripheral resistance by peripheral vasodilatation, thus reducing blood pressure. Therapeutic
indications are Arterial hypertension; Vasospastic angina and Stable angina pectoris.
The effect of packaging and storage on Amlodipine tablets was examined in cold-form aluminium blisters
and PVC/PVDC blisters.The tablets were stored at 25°C at relative humidity 60 % (RH), 30°C at relative humidity
65 % (RH) and 40°C at relative humidity 75% (RH), for six months. The physical and chemical stability of the prod-
ucts were measured after 1, 3 and 6 months at ICH conditions.Dissolution was used to asses in vitro tablet perform-
ance using spectrophotometar (Shimadzu UV-1700). High performance liquide chromatography (HPLC Agilent
1100) was used to evaluate chemical stability of Amlodipine tablets such as assay and related substances.Water con-
tent of tablets was also examined by Karl Fischer titration. Photostability of the product was evaluated by Sun test
CPS+ acording to ICH guidelance (Q1B).
Results showed significant changes for tablets packaged in cold- form aluminium due to PVC/PVDC blis-
ters. It was observed that tablets packed in PVC/PVDC blisters had increased their degradation products and water
content. Also the appearance of tablets was changed from white coloured to yellow spotted.
Therefore, it may be concluded that for this product the choice of packaging material should be cold-form
aluminium blister.
Macedonian pharmaceutical bulletin 53 (1,2) 71 (2007)
PP - 19
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Application of experimental design for screening study of 
dissolution testconditions: carbamazepine immediate-release tablets
I. Homsek
1
, J. Parojcic
2
, N. Cvetkovic
1
, Z. Guric
2
1
Galenika a. d., R
&D Institute, Belgrade, Serbia
2
Dept. of Pharmaceutical Technology, Faculty of Pharmacy, Belgrade, Serbia
Objective: The objective of this paper was to present an example of experimental design application to set up
the dissolution test conditions for the two immediate-release products containing 200 mg of CBZ with proven bioe-
quivalence (in-house data on file): Galepsin
®
tablets (product A) and Tegretol
®
tablets (the reference product B).
Materials and methods: In vitro study was performed in the rotating paddle apparatus (Erweka DT6, Germany)
using sodium lauryl sulfate (SLS) aqueous solution according to the chosen 2
3
factorial design (FD) with the follow-
ing independent variables: concentration of surfactant used (X
1
), volume of dissolution medium (X
2
), and paddle stir-
ring speed (X
3
), as shown in Table 1. The amounts of dissolved CBZ were determined spectrophotometrically at 285±2
nm, after 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes. The mean dissolution times (MDT) for each product were
calculated from the obtained results and compared with mean absorption time (MAT) calculated from in vivo plas-
ma concentration data by the Wagner-Nelson deconvolution method. Dependent variables were set up as a differ-
ence between the MDT observed under various experimental conditions for the investigated products (Y
1
), as well as the
difference between MDT and MAT for each product (Y
2
= MDT
prod. A
- MAT
prod. A
; Y3 =MDT
prod. B
- MAT
prod. B
).
Table 1. Levels of factors.
Table 2. The matrices of 2
3
FD and responses.
Results and discussion: Statistical models connecting dependent and independent variables are presented
using the following equations:
Y
1
= -7.94 - 3.27X
1
- 0.061X
2
- 6.34X
3
Y
2
= +15.30 - 3.80X
1
- 0.56X
2
- 19.29X
3
Y
3
= +23.61 - 0.53X
1
- 0.49X
2
- 12.95X
3
The obtained results indicated that the paddle rotation speed had the most significant effect on the examined
parameters. In general, the applicability of experimental design in the optimization of the dissolution test conditions
in this particular case was shown to be of limited value, because it was not possible to estimate the unique condi-
tions to carry out the "biorelevant" dissolution test for both the products tested. 
Acknowledgement: This study was carried out within the project TR 6719 supported by the Ministry of
Science and Environmental Protection, The Republic of Serbia.
Macedonian pharmaceutical bulletin 53 (1,2) 72 (2007)
PP - 20
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Independent variables  
Low (-) 
High (+) 
X
1
:
 
SLS conc. (%)  
0.1 
1 
X
2
: volume (ml)  
750 
900 
X
3
: speed (rpm) 
25 
75 
 
 
X
1
 
X
2
 
X
3
 
Y
1
 
Y
2
 
Y
3
 
F
1
 
- 
- 
- 
0.60 
41.30 
41.08 
F
2
 
- 
+ 
- 
5.28 
34.66 
29.76 
F
3
 
+ 
+ 
- 
-8.83 
0.05 
9.26 
F
4
 
+ 
+ 
- 
-7.64 
31.58 
39.60 
F
5
 
+ 
- 
+ 
-18.64 
-8.76 
10.26 
F
6
 
+ 
+ 
+ 
-13.91 
-7.63 
6.66 
F
7
 
+ 
- 
- 
-4.64 
30.81 
35.83 
Ek
sp
erimen
t 
F
8
 
- 
+ 
+ 
-15.73 
0.35 
16.46