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The influence of O/W cream structure on ITS hydration potential: 
in vivo case study
Arsic I.
1
, Homsek I.
2
, Gorgevic S.
1
., Tadic V.
1
1
Institute for medicinal plant research „Dr Josif Pancic“, Belgrade, Serbia
2
Galenika ad, R&D Institute, Batajnicki drum bb, Belgrade, Serbia
Introduction
The traditional o/w emulsions have dispersed drops of oil phase surrounded by the thick multi-layer of liq-
uid crystalline lamellar surfactant, which protect them that way from coalescence by steric or electric repulsion. Such
emulsions can be prepared by using the contemporary emulsifiers. The thick layer consists of: surfactants with both
low and high HLB values, ethoxylated stearyl alcohols and some propoxylated stearyl alcohols, respectively, and
some steryl alcohol. The emulsions should ensure a prolonged skin hydration effect owing to the presence of water
entrapped between the liquid crystal layers. The aim of this study was to establish the effect of the cream structure,
i.e. the type of emulsifiers used, on skin hydration.
Materials and methods
The o/w cream (E1) contained: 77.15% of water phase with emollient Arlamol
®
E (PPG-15 stearyl ether),
17.85% of oil phase with stearyl alcohol, 5%-aliquots of the emulsifiers Brij
®
72 (Steareth-2) and Brij
®
721 (Steareth-
21). According to the literature data, the application of the mentioned emollient and emulsifiers is associated with
the creams having a liquid crystal structure. The o/w cream (E2) was prepared in the same way, only using 5% of
non-ionic emulsifier Emulgin
®
B
2
-(Ceteareth-20) instead of Brij
®
72 and 721. Polyethylene glycol (PG) was used
as the placebo.
The measurements of the skin moisture (Corneometer CM 825, Courage+Khazaka, Germany) and pH value
(Skin-pH-meter PH 900, Courage+Khazaka, Germany) were carried out on 12 volunteers of the average 45±0.5 years
of age. Prior to each measurement they stayed in controlled room conditions (24±2°C and 55±5% RH). The volun-
teers were requested not to use either cosmetic or any other products on the insides of their forearms during the test.
2 mg/cm
2
doses of the samples (E
1
, E
2
and PG) were applied on 9 cm
2
skin areas inside the forearm of each subject
once a day (in the morning). The skin pH and moisture content were evaluated before the application (baseline value)
and 30, 60, 120, 240 and 360 minutes after the application.
Statistics: The Student’s t-test (p<0.05) was used to evaluate the statistical significance of the measured differ-
ences for each sample compared to baselines. For the evaluation of the efficiency of the samples based on mutual com-
parison of percentage change of parameters tested, ANOVA test (p<0.05) and post-hock Tukey HSD test were used.
Results and discussion
No allergic symptoms or other adverse effects were observed during the experiment. After the application
of E
1
, E
2
and PG the statistically significant differences in relative skin moisture content of the volunteers were
obtained at each checkpoint compared to baseline value (p<0.05). The greatest change was measured one hour after
the application of E
1
, E
2
and PG (12.5%, 11.4% and 6.1%, respectively). At the same time, the skin pH value was
unchanged. 
Both tested formulations, E
1
and E
2
, caused much more pronounced moisturizing effect on the skin com-
pared to the placebo. A statistically significant increase in skin moisture content was registered from 4th to 6th hour
after the application of E
1
compared to E
2.
As expected, the cream E
1
showed a prolonged moisturizing effect (during 360 minutes) compared to the
cream E
2
, which lasted for 240 minutes. The results indicated that duration of this provoked effect depended of the
formulation structure.
Macedonian pharmaceutical bulletin 53 (1,2) 73 (2007)
PP - 21
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Making a jelly with Bensoyl peroxide and Erythromycin
Slavica Maleska Stojadinovic
JZU Opsta bolnica, Ohrid, Macedonia
Always actual and painful problem in the young population is having a healthy and clear skin, lead us to the
idea to create a magistral preparation which acts fast and effectively over the skin with acnes, and to stop secondary
infections. Acnes could be greater psychological barrier in some cases, and with squeezing them, it just makes the
situation to become worse.
Aim of this work is to create preparation which will be effective to the young persons' problematic skin, easy
for application and with extended realizing of active components. In modern dermotherapy, jellies have important
position among the other bases. That was our starting point for the expected effectiveness of the preparation.
The preparation that we are made, should penetrate into the skin and to effect locally - keratolytical and anti-
inflammatory. To achieve keratolytical effect, we used Bensoyl peroxide. For anti-inflammatory effect of the prepa-
ration, we used the antibiotic Erythromycin, because of the data found in the literature.
Jelly with Bensoyl peroxide and Erythromycin was made in Galen's laboratory in Public Health Organization
"Opsta bolnica" - Ohrid.
According to the European Pharmacopeia, the jellies are divided into:
•
Hydrophobic jellies /Oleogels/ and
•
Hydrophilic jellies /Hydrogels/.
For preparation of this jelly, we used Polyacrylic acid, from the possible jellifying agents, which is polymer
of Acrylic acid and belongs to a group of organic jellies. Jellies based on Polyacrylic acid are with stable viscosity
even after longer exposure to room temperature. For preparation of the jelly we used the following substances:
Bensoyl peroxide, Erythromycin, Sodium hydroxide 10%, Polyacrylic acid, Distillated water, Propylen glycol.
Titrimetric method, described in BP 93 was used for controlling the concentration of the Bensoyl peroxide
in the jelly.
Controlling the concentration of Erythromycin in the jelly was done using BP 88 Appendix XIV (Microbial
controlling of antibiotics).
During the preparation of the jelly with Bensoyl peroxide and Erythromycin, aging test was done, where the
preparation was liable to different temperatures (4
°
C, 41
°
C, 50
°
C and normal temperature), during six months. During
this, we were checking the following parameters: concentration of active components, pH changes and organolep-
tical changes. The results for concentration of active ingredients, test for fast ageing, sterility test and checking the
jellies made only with Bensoyl peroxide and only with Erythromycin, are satisfactory.
Results of the treatment with the jelly with Bensoyl peroxide and Erythromycin incorporated largely become
better, which is result of synergistic action of Bensoyl peroxide and Erythromycin. Jelly is stable in period of six
months, it has milky profile, has pleasant feel to the skin and can be easily removed. Preparation is non-toxic and
does not cause irritations to the skin.
Preparation can be made in Pharmacy and Galen's laboratory, and easy applicability and efficacy makes this
preparation acceptable for the patients.
Macedonian pharmaceutical bulletin 53 (1,2) 74-75 (2007)
PP - 22
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Izrabotka na gel so Benzoyl peroxyd i Erytromycin
Slavica Maleska Stojadinovi}
JZU Op{ta bolnica, Ohrid, Makedonija
Sekoga{ aktuelnoto i bolno pra{awe kaj mladite da imaat ubava i ~ista ko`a ne navede na ideja-
ta da pripremime magistralen preparat koj na brz i efikasen na~in }e deluva na akneti~astata ko`a, a
pri toa da se spre~i da dojde do sekundarana infekcija. Aknite mo`at da bidat pogolema psihi~ka prepre-
ka kaj nekoi bolni,{to pri grubo istiskuvawe na komedonite samo ja vlo{uvaat sostojbata.
Celta na trudot e da napravime preparat koj }e bide efikasen kaj problemati~nata ko`a kaj mla-
dite, lesno aplikativen i so prodol`eno dejstvo na aktivnite komponenti. Vo sovremenata dermoterapi-
ja, gelovite so svoite prednosti koi gi imaat nad drugite podlogi zazemaat zna~ajno mesto. Toa ni be{e
osnovna pojdovna to~ka za ishodot na o~ekuvanata delotvornost na izgotveniot preparat.
Preparatot koj nie treba da go podgotvime treba da prodre vo ko`ata i da deluva lokalno, taka
{to }e dejstvuva keratoliti~ki i antiinflamatorno. Za da se postigne keratoliti~koto dejstvo, se odlu-
~ivme da toa bide benzoyl peroxyd. Preparatot da bide so antiinflamatorno dejstvo,se odlu~ivme na antibio-
tikot erytromycin, spored podatocite koi gi crpevme od literaturata.
Gelot so benzoyl peroxyd i erytromycin go izrabotivme vo Galenskata laboratorija pri JZU Op{ta
bolnica Ohrid.
Spored Evropskata farmakopea podelbata na gelovite e na:
•
hidrofobni gelovi/Oleogels/ i
•
hidrofilni gelovi/Hydrogels/.
Od gelira~kite komponenti za prigotvuvawe na ovoj gel, se odlu~ivme da upotrebime Polyacrillic
acid, koja kako polimer na akrilnata kiselina, ovoj gel go ~ini da go vbroime vo grupata na organski gelovi.
Gelovi na baza na poliakrilna kiselina se so stabilen viskozitet i posle podolgo stoewe na sobna tempe-
ratura. Pri izgotvuvawe na gelot se koristevme so slednite supstancii: benzoyl peroxyd, erytromycin, natrium
hydroxide 10%, Polyacrilic acid, Aqua destilata, Propylen glycol.
Za odreduvaweto na koncentracijata na benzoyl peroxyd vo gelot koj ni be{e za izrabotka, se
slu`evme so titrimetriska metoda propi{ana vo BP 93.
Odreduvaweto na erytromycin vo gel e izvr{eno po BP 88 Apendix XIV(mikrobno odreduvawe na
antibiotici).
Pri izrabotka na gelot benzoyl peroxyd so erytromycin, raboten e test na brzo stareewe, pri {to prepa-
ratot e podlo`en na razli~ni temperaturi (4
°
C, 41
°
C, 50
°
C i sobna t
°
), vo traewe od 6 meseci.Pri toa gi
sledevme slednite parametri: koncentracija na aktivni komponenti, pH promeni i organolepti~ki promeni.
Dobienite rezultati po odnos na koncetracijata na aktivnite komponenti, testot za brzo stareewe,
ispituvaweto na sterilnosta i ispituvaweto na gel samo so benzoyl peroxyd i gel so benzoyl peroxyd i ery-
tromycin se zadovolitelni.
Rezultatite od tretiraweto so gelot vo koj se inkorporirani benzoyl peroxyd i erytromycin se zna-
~itelno podobri, {to zboruva za edno sinergisti~ko dejstvo na benzoyl peroxyd-ot i erytromycin-ot. Stabilen
e vo rok od {est meseci, gelot e so mle~en izgled, ima prijaten oset na ko`ata i lesno se isperuva od ko-
`ata. Preparatot e netoksi~en i ne predizvikuva reakcii na iritacii na ko`ata.
Preparatot mo`e da se izraboti vo apteka i vo galenska laboratorija, a lesnata aplikativnost i
efikasnost go pravi ovoj preparat prifatliv za pacientite.
Macedonian pharmaceutical bulletin 53 (1,2) 74-75 (2007)
PP - 22
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Defining critical steps during formulation development of semisolids
using rheology measurement
S. Kostic, D. Jagodic, S. Hadzidedic
Bosnalijek d.d., Development Department Jukiceva 53, 71000 Sarajevo, Bosnia and Herzegovina
One of the critical steps in producing of semisolid dosage forms is connected with type of equipment.
Generally, ointments are greasy, semisolid preparations, often anhydrous and containing dissolved or dis-
persed active substance. Practice shows that during the production of ointment is necessary to get much more atten-
tion on define critical steps and using rheology it becomes possible.
Formulation of ointment contained corticosteroid drug and ointment base with white soft paraffin and paraf-
fin, liquid. However well we design a topical vehicle for maximum drug bioavailability we must still make the prepa-
ration acceptable to the patient. All this and physical and chemical behaviour of the drug in oil phase we decide to
develop ointment and define critical steps to accomplish all needed conditions.
The aim of the study was to define critical steps during production of ointment in phase of scale up, using
rheological measurement. The main steps in production of ointment were mixing, homogenizing and filling in the
tube. Application of rheology in this case was to improve that there were no changes in rheology behavior during
the production of ointments. Five rheological methods: single point viscosity, viscosity profile-shear rate and shear
stress, viscoelastic profile-oscillation frequency and oscillation sweep test were used.
According to this, rheological measurements are applied on these critical steps: mixing, homogenizing,
process outlet, before filling and after filling the ointment into the tubes.
It was used rheometar RheoStress 1 from Haake with software RheoWin 3.2. and sensor type PP35 –I ser-
ated plate for rheological measurements. Equipment which was used in production of scale up batches was mixer-
homogenizer Vakumix, type HM 15-008.
The results of this study, presented by rheogram, has shown that there were no significant different in rheo-
logical behaviors in defined critical steps. This was very useful as confirmation that equipment and defined process
steps in production of scale up batches gave us a product with specified quality. Study with this kind of results
improved that rheology could have application as in development phase and also as very useful parameter during
production.
Macedonian pharmaceutical bulletin 53 (1,2) 76 (2007)
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New copolymer zwitterionic matrices for drugs release 
with basic properties
Dimitar Rachev, Bistra Kostova
Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, Medical University, 
2
Dunav Str., 1000 Sofia, Bulgaria
Although there are publications for polyzwitterions (PZI) applications as polymer matrices for sustained
drug release in the literature, data about the usage of the copolymer of vinyl acetate (VA) and 3-dimethyl(methacry-
loyloxyethyl) ammonium propane sulf?nate (DMAPS) as a drug release matrix are not found. This was the first rea-
son for the synthesis of poly(vinyl acetate-co-3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate)
(p(VA-co-DMAPS)) with different compositions, their characterization, properties investigation and their applica-
tion as polymer matrices for sustained drug release. The second reason for the study was the investigation of (p(VA-
co-DMAPS)as matrix for drugs with basic properties. 
Emulsifier-free emulsion copolymerization of VA and DMAPS was performed in distilled water. The total
monomer concentration was 7.5 x 10-2 mol/l. The VA to DMAPS mole fraction ratios in the initial monomer feed
were 90/10 (copolymer 1), 85/15 (copolymer 2) and 80/20 (copolymer 3). The purified copolymer microspheres
were lyophilized. 
The lyophilized copolymers were molded into tablets with diameter of 7 mm and height of 2 mm. The swelling
degree (Q) of the copolymer samples was determined. 
Sustained release (SR) tablets were prepared using polymer carriers: (i) p(VA-co-DMAPS); (ii) Kollidon
®
SR. The Verapamil hydrochloride was included as a model drug. Tablets were prepared by compression after wet
granulation with a single punch tablet press 
Drug release profiles were evaluated using a dissolution test apparatus. The USP paddle method was select-
ed in aqueous medium at three different pH values.
Stable copolymer (vinyl acetate-co-3-dimethyl-(methacryloyloxyethyl)ammonium propane sulfînate, p(VA-
co-DMAPS)) latexes with different compositions were synthesised for the first time by the emulsifier-free emulsion
copolymerization. The explanation proposed for an unusual "overshooting" behaviour of the copolymer tablets is
based on the formation of the specific clusters from the opposite oriented dipoles - zwitterions species. The varia-
tion of their concentration with the DMAPS unit fraction (m
DMAPS
), pH, ionic strength (I) is responsible for the dif-
ferences in the swelling kinetics established. The results obtained prove that mDMAPS and I could be used for an
effective control on the p(VA-co-DMAPS) matrices swelling degree and sustained Verapamil hydrochloride release
from model tablets. In this way, p(VA-co-DMAPS) matrices afford an good opportunity for the effective usage for
controlling the sustained release of drugs with basic properties such as Verapamil hydrochloride.
Macedonian pharmaceutical bulletin 53 (1,2) 77 (2007)
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Discriminatory dissolution profile for Diclofenac sodium 
retard tablets 100 mg
A. Nalo, S. Miljus, E. Vranjes, S. Hadzidedic
Bosnalijek d.d., Development Department, Jukiceva 53, 71000 Sarajevo, Bosnia and Herzegovina
Diclofenac belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). It works
by blocking the action of a substance in the body called cyclo-oxygenase.
Diclofenac is used to relieve pain and inflammation in a wide range of conditions, including arthritis, gout,
sprains, fractures, back pain and following minor surgery.
Controlled release tablets regulate release of active substance in specified time intervals leading to an extend-
ed period of drug delivery. An appropriate drug release test is required to characterize the drug product and assure
batch-to-batch reproducibility for consistent pharmacological activity. 
For formulation of Diclofenac sodium retard tablets diferent systems can be used, such as Hydroxypropil
methycellulose HPMC system matrix. It is widely used agent which modify release of active substance because of
swelling properties.
Chosen formulation contains 39.37 % of active substance, 15.5% of HPMC as sustained release agent, 37.12%
of Lactose as a filler, 5% of Copovidone as binder , 1.5 % Aerosil as a glidant and 1.5 % of Magnesium stearate as
a lubricant. Active ingredient, release retardant, filler and flow promoters were blended together by dry mixing and
made into tablets by direct compression at a fixed compression force.
Drug dissolution profiles are increasingly used to evaluate drug release characteristics of pharmaceutical
products. Discriminatory dissolution profiles are highly desirable for differentiating between products having dif-
ferences in pharmaceutical attributes (formulation and/or manufacturing processes differences) that may reflect cor-
responding differences in vivo.
This study of discriminatory dissolution profile of Diclofenac sodium retard tablets 100 mg was performed
according to general discriminatory dissolution profile apparatus 1 and 2, Method of rotating basket and Method of
rotating paddle. 
Four dissolution medium were used: water, Acetate buffer pH= 4.6, Phosphate buffer pH=6,8 and Phosphate
buffer pH=7,5; 900 ml, at temperature 37 °C ± 0,5 °C, with mixing speed 50 rpm, 75 rpm and 100 rpm. Sample medi-
um is to be taken every 1 hour with duration of 24 hours. 
Diclofenac sodium assay is to be determined by Spectrophotometric method at 276 nm, using medium as
blank in 0,2 cm quartz cells.
In this study we concluded that a Phosphate buffer pH=7,5 as a medium, apparatus 2 (method of rotating
paddles), and stirring speed of 50 rpm appear to be the best conditions for dissolution of Diclofenac sodium retard
tablets 100 mg which is recommended method in Pharmacopeial forum.
Macedonian pharmaceutical bulletin 53 (1,2) 78 (2007)
PP - 25
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Comparative rheological measurements on corticosteroid ointments
from the manufacturers available on the market 
S. Kostic, M. Mihajljica, N. Saric, S. Hadzidedic
Bosnalijek d.d., Development Department, Jukiceva 53, 71000 Sarajevo, Bosnia and Herzegovina
Rheology is the study of the deformation and flow of matter under the influence of an applied stress. One
of the tasks of rheology is to empirically establish the relationships between deformations and stresses, respective-
ly their derivatives by adequate measurements. These experimental techniques are known as rheometry.
A knowledge of rheological techniques plays an important role in pharmaceutical development and manu-
facture. According to raising a number of sophisticated rheological instruments different approach has become nec-
essary in research of rheological behaviour in semisolids. A rheological properties of raw materials causes more and
more problems during the development and manufacture process of semisolid dosage forms. 
The aim of the study was to investigate the rheological behavior and compare obtained results between five
different ointments available on the market using basic rheological technique. 
All chosen manufacturers from the market had the same corticosteroid drug and similarly ointment base with
white soft paraffin and paraffin, liquid. Obtained results were used for process development of corticosteroid oint-
ment in R&D department in Bosnalijek.
In these rheological experiments it was main role to choose the right methods since the specific way of meas-
urement and right application of sensors using very sophisticated new rheometar and this was a reason that this five
methods are for compartion after numerous practical experiments.
Five rheological methods are single point viscosity, viscosity profile-shear rate and shear stress, viscoelas-
tic profile-oscillation frequency and oscillation sweep test. They were applied on corticosteroid ointment from man-
ufacturer-Bosnalijek and four others from market. 
The relationship between stress, strain and viscoelastic behaviour are depicted in the so called rheograms.
Typical flow curves are presented through 
τ = f (γ) , viscosity is drawn as a function of the shear stress η= f (τ) and
viscoelastic behaviour in function of G′, G′′, G* =f (f, tan 
δ).
It was used rheometar RheoStress 1 from Haake with softwer RheoWin 3.2. and sensor type PP35 –I serated
plate. This type of sensors has shown the best results according to it 
′s similarity to way of application on human skin.
The results of this study shown that there are differents in rheological behaviors between selected ointments.
The rheograms give us very useful and practical information how to select the right type of excipients also how to
choose right technological process during development of semisolid generics.
Macedonian pharmaceutical bulletin 53 (1,2) 79 (2007)
PP - 26
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