Kniga na apstrakti book of abstrcts

Preformulation studies as a starting points in selection 
of polymorphic form in generic drug development
Z. Babic, H. Trobradovic, S. Hadzidedic
Bosnalijek d.d., Development Department,Preformulation Studies Jukiceva 53, 71000 Sarajevo
In contrary to adapted opinion, generic drug development is far from being only a routine “copy-paste of
originator” process. One feature where generic formulation may fail to attain regulatory requirements concerning
drug bioavailability and stability may happen in cases where formulation development has to deal with polymor-
phism of active drugs. In such cases, it is necessary to conduct preformulation studies of different polymorphic forms
in order to provide critical information on crystalline structure which will be more appropriate concerning the drug’s
processibility. In this work two polymorphic forms of quinazolina derivative, namely doxazosine mesylate has been
investigated. Polymorphism of doxazosine mesylate is well known. In literature three forms has been described,
though with different nomenclature, Form I, Form II and Form III or A,B and C. Polymorphic form of analysed active
drug has been confirmed by means of thermal analysis (differntial scanning calorimetry) and hot stage microscopic
investigation. Solubility was measured by flask shake method with assay analysed by UV. Possible interactions
between active drug and excipients has been investigated combining DSC (with heating rate of 10°C/min) and HPLC.
HPLC method was also involved for investigation of doxazosine mesylate solutions’ stability. First investigation of
Form I showed that drug is poorly soluble in water and exhibits changes in polymorphic structure after being stored
for two weeks at 55°C/75%RH. Possibly, this conversion may lead to dissolution problems due to unknown proper-
ties of the new crystalline structure after stability testing since its polymorphic form differs from both Form I and
Form II. Further, Form II has been investigated. Surprisingly, no significant difference in solubility of two polymor-
phic forms has been found. Both polymorphic forms exhibit incompatibilities with sodium starch glycolate, corn
starch and croscarmelose. No difference has been found concerning the higroscopicity, lipophilicity and compres-
sion properties between Form I and Form II. 
It was clear so far that none of investigated physical or chemical properties can be interpreted as an advan-
tageous intrinsic property of either Form I or Form II. As a conclusion, Form I has been recommended for formula-
tion development due to better flowability and mixibility with excipients. 
Macedonian pharmaceutical bulletin 53 (1,2) 80 (2007)
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Forced degradation studies for better understanding 
of active pharmaceutical ingredient
L. Zilic Marjanovic, S. Hadzidedic, H. Trobradovic, V. Mekinjic
Development Department, Bosnalijek d.d, , Jukiceva 53, 71000 Sarajevo, Bosnia and Herzegovina
Stress testing is defined as the stability testing of drug substances and drug products under conditions exceed-
ing those used for accelerated testing. Pharmaceutical companies perform stress testing (also called forced-degrada-
tion studies) during preformulation to help select compounds and excipients for further development, to facilitate
salt selection or formulation optimization, and to produce samples for developing stability-indicating analytical meth-
ods. Stress testing provides information about degradation mechanisms and potential degradation products. This in-
formation then can be used to develop manufacturing processes or to select proper packaging. It may also help in
preparing reference material of identified degradation products. Chemical purity is the most important quality char-
acteristic of a pharmaceutical substance. Impurities are unwanted coexisting components in bulk pharmaceutical
chemicals that arise during manufacture and/or subsequent storage. A description of the identified and unidentified
existing impurities in a chemical drug substance is referred to as the impurity profile (IP). The presence of organic
impurities in a drug substance is closely dependent on the process of manufacture. A different route of synthesis will
tend to lead to a different IP.
Stress testing is a critical component of drug development. By generating key stress-testing samples (i.e.,
partially degraded samples stressed under various conditions), predictive degradation information can be obtained
early in the process and can be of significant value to a drug company in terms of time and money. 
The aim of the present study was determined the intrinsic stability of amlodipine besilate by establishing
degradation pathways in order to identify the likely degradation products.
Stress testing of amlodipine besilate was performed under stress conditions (thermal, thermal / humidity,
photolytic, acid / base hydrolitic and oxidative). Impurity testing was performed with isocratic reversed-phase HPLC
with UV-Vis detection analytical procedure. We used next conditions and equipment: thermal and thermal/humidi-
ty test – chamber with controlled temperature and humidity, photolytic – chamber for photostability testing Suntest
– CPS+, acid/base hydrolitic – 1mol/l HCl / 1 mol/l NaOH, oxidation – 3% V/V H2O2.
Stress testing was performed on amlodipine besilate from two manufacturer with different route of synthe-
sis. Results of stress testing are used for select compound (comparison A is more stable than B) and excipients for
further development (Drug/Excipient compatibility). 
Macedonian pharmaceutical bulletin 53 (1,2) 81 (2007)
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Defining primary criteria for the choice of an optimal salt 
for designing of amlodipine tablets formulation
S. Hadzidedic,
1
L. Zilic
1
,V. Mekinjic
1
, S. Kocova El-Arini
1,2
1
Bosnalijek d.d. Development Department, Jukiceva 53,71000 Sarajevo, Bosnia and Herzegovina
2
Nationla Research Centre, Tahrir Street,Cairo, Egypt
Different salts of the same active substance exhibit different chemical and biological profiles that can affect
in different ways the clinical efficacy and safety of the drug product. The salts may differ in their solubility profiles and
dissolution characteristics, which can influence the extent of drug absorption, and consequently the onset, the dura-
tion and the intensity of the drug effect.
Since the salt choice can dramatically change drug characteristics, each salt should be tested in a well designed
optimization study prior to the beginning of the product development phase.
The aim of the present study was to determine the primary criteria for the selection of an optimal salt for
designing of almodipine tablet formulation and to select the optimal salt from the almodipine salts available on the
market. Further aim of the study was to prepare trial tablet formulation of the selected salt for stability testing.
The experimental work consisted of a series of screening tests conducted on samples of different almodip-
ine salts in order to define the primary criteria for selection of the optimal salt.
For all the salts, hygroscopicity was investigated as a screening test. The salts with acceptable hygroscopic-
ity were further tested. They were exposed to extreme conditions of humidity in order to check the changes in the
crystalline structure by means of thermal analysis. Using these methods, the tendency to polymorphic changes and
pseudo polymorphism caused by the presence of solution during the manufacturing process or during the accelerat-
ed stability test were determined. At the following level, water solubility was tested in order to determine a poten-
tial problem in dissolution or product bioavailability. At the final, third level of screening, the chosen salts were
exposed to the thermal conditions of accelerated stability test with the aim to establish their stability. At this level,
tests for compatibility between the drug and the potential excipients were conducted.
With the application of such an approach to the selection of an optimal salt suitable for amlodipine tablet
formulation, the following primary criteria regarding the physical and chemical characteristics of the final product
were defined: stability, solubility and dissolution. Based on the result of the investigations, conclusion was reached
on the most acceptable salt for an amlodipine tablet formulation and trial batches of the formulation were subjected
to stability testing.
Macedonian pharmaceutical bulletin 53 (1,2) 82 (2007)
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Use of thermal analysis and stress test to identify stability problems 
in multicomponent generic products due 
to process change and reformulation
Haris Trobradovic
1
, Seherzada Hadzidedic
1
, Lejla Zilic
1
,Vlado Mekinjic
1
, Hans Leuenberger
2
, 
Silvia Kocova El-Arini
3
, Gabriele Betz
2
1
Bosnalijek d.d., Development Department, Jukiceva 53, 71000 Sarajevo, Bosnia & Herzegovina.
2
Institute of Pharmaceutical Technology, Pharmacenter, 
University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.
3
National Research Centre, Tahrir Street, Cairo – Dokki, Egypt.
Commercial generic product containing five active components presented a stability problem during process
change and reformulation activities. In order to identify the problem and recommend reprocessing methods, a study
was conducted combining thermal analysis and stress test with the use of high pressure liquid chromatography (HPLC)
and gas chromatography (GC). The multicomponent drug system, having the composition of Nomigren
®
, a medica-
ment used in migrane treatment was chosen as a model. Differential scanning calorimetry (DSC) was employed as
a rapid tool in identifying possible interactions between the active components propyphenazone, caffeine, ergota-
mine tartrate, camylofine HCl and mecloxamine citrate. The observed change on the DSC thermogram of the bina-
ry mixture of camylofine HCl and ergotamine tartrate, pointed to interactions between camylofine HCl and ergota-
mine tartrate under the conditions of the test. High pressure liquid chromatography and gas chromatography analyses
of the drugs in the mixtures following the accelerated tests confirmed the results obtained with DSC, that degrada-
tion of ergotamine tartrate took place in the presence of camylofine HCl. Degradation of ergotamine tartrate was
determined to be more than 20% for both temperatures, 25 and 44°C, within the first hour and stayed in this range
for 24 hours, whereas the pure substance was stable under the same conditions. Eutectic melting appeared between
Tp = 113 °C and 120°C for the ratios 0.9:0.1 to 0.7:0.3 of camylofine HCl/mecloxamine citrate. DSC was shown as
a rapid tool to detect interactions and eutectic melting between active compounds. Understanding the nature of the
interactions within multicomponent systems is important for a better control of the manufacturing process and can
be valuable in development of robust formulation. This is in agreement with the basic tenet of quality by design of
FDA's Process Analytical Technology (PAT) Initiative.
Macedonian pharmaceutical bulletin 53 (1,2) 83 (2007)
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Factorial design evaluation of formulation of factors on the drug
release from HPMC matrices
Aleksandra Petrovic
1
, Svetlana Ibric
2
, Svetlana Trajkovic
1
, Radmila Popovic
1
,
Dragica Popadic
1
, Zorica Guric
2
1
Galenika a.d., Institute for R&D, Batajnicki drum b.b, Belgrade, Serbia 
2
Department of Pharmaceutical Technology, Faculty of Pharmacy, Belgrade, Serbia
The purpose of this study was to evaluate the influence of formulation factors on the release properties of
theophylline (TP) from aminophylline (AP) matrices based on different hydroxypropylmethylcellulose (HPMC) ratio
and viscosity grades. The General full factorial experimental design 3 x 3 x 3 was used based on three independent
variables: applied in vitro test (X1), HPMC/drug ratio (X2) and polymer viscosity grade (X3). The drug release per-
cent at 2h (Y
2h
), 4h (Y
4h
) and 8 h (Y
8h
) and time for 50% of TP release from matrices (Y
T50
%) were response vari-
ables. Three in vitro tests were used: Test 1 and Test 4 (Theophylline Extended-release Capsules, USP XXVI) and
Half-change method. The concentration of TP was determined by UV-VIS spectrophotometric method, at 271 nm. 
According to factorial design analyses, in vitro test was the most significant factor influencing drug release
after 4h and 8h examination, while HPMC/drug ratio and viscosity grade of polymer have great influence on the
release of the drug. The evaluation of the release mechanism showed the most significant effect was that of in vitro
test applied, followed by the polymer/drug ratio. For Half Change method erosion was the predominant mechanism
of TP release indicating Case – II transport, while for Test 1 the release mechanism were followed by both diffusion
and erosion. The lowest release exponent n values, obtained from Ritger-Pepass equation, for Test 4 indicate diffu-
sion process inclining from Fickian diffusion to Anomalous transport. These results emphasized the importance of
adequate in vitro test selection as biorelevant drug release media. 
Acknowledgements: This work was done under Project No TR-6719B, supported by the Ministry of Science
and Environmental Protection, Republic of Serbia.
Macedonian pharmaceutical bulletin 53 (1,2) 84 (2007)
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Pharmaceutical forms Anantidotarioum Nicolai
Marta Pocuca
1
, Dragan Stupar
2
1
Department of Pharmacy, Faculty of Medicine Novi Sad, Hajduk Veljkova 3, Novi Sad, Serbia
2
Faculty of Pharmacy, Vojvode Stepe 450, Beograd, Serbia
Pharmaceutical forms are equally important as pharmacodinamic effect of drug for expression of therapeu-
tic effect. Antidotarium Nicolai is the first pharmacopoeia written at the beginning of XII c. by Nicolaus Salernitanus.
Pharmaceutical forms were not described clearly in terms of type, structure, technological process and application.
Salerno’s pharmacotherapy, as it can be seen from the Antidotarium, was based on “sugar-honey pharmacy” and the
only difference between pharmaceutical forms was viscosity of forms. 
The following forms are described in the Antidotarium: 
•
Electuaria: It is difficult to define technological process as type and origin of honey are usually described
in stead of a preparation. Electuaria hasn’t presented the unique pharmaceutical form which could have been applied
uniquely but more a way of conservation. Preparations described in the Antidotarium could have been applied as
supositoria, unguenta or tablets.
•
Morsuli: This form was very similar to electuaria. The only difference is viscosity which is much higher
in the case of morsuli. Together with the pillules, morsuli were a precursor of tablets.
•
Pillules: Technological process was very simple; drug should have been mixed with an adequate quantity
of vehiculum i.e. viscose liquids (honey, plant juices). Pillules were symbol of pharmacy and were privileged phar-
maceutical form until XX c. when tablets suppressed their importance.
•
Trochisci: This form was very similar to pillules but it hasn’t been applied but has been only a way of con-
versation. Technological process was equal for all trochici preparations; drug was mixed with some liquids (vine,
plant juice), run dry in a shadow and kept until usage.
•
Sirupi: It is interesting that technological process required evaluations and testing with regards to viscos-
ity. This was important for a proper conservation of preparation, as sirupus could keep proper quality only if con-
centration is high enough.
•
Emplastrum: Described preparations show that it was very difficult to prepare this form, technological
process was very complex and described in details in contrary to other forms where description is very poor. This
form was less used comparing to other forms described in the Antidotarium.
•
Unguenta: There were no general rules for technological process for unguenta and each was prepared
according to separate prescription. Generally, this was form that contained fatness and was applied externally.
•
Olea: Technological processes described in the Antidotarium were different for olea prepared from dried
and from fresh plant drugs. There are also two different types that are described: olea prepared from only one plant
and complex olea.
Antidotarium Nicolai is of unique importance because it represents the first attempt of systematisation of
pharmaceutical forms. Although today's criteria differ significantly from Nicolaus's, this book still has a great value
as it represents the base for all further pharmacopoeias written many years after Antidotarium Nicolaus.
Macedonian pharmaceutical bulletin 53 (1,2) 85 (2007)
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Adrenaline injection, formulation and pharmacodinamic efficasy
E. Najdovska, Z. Veljanova
Sluzba za infuzioni rastvori, Klinicka bolnica Dr. Trifun Panovski – Bitola, Makedonia
Adrenaline is a direct-acting sympatomimetic agent with pronounced effects on alpha and beta adrenergic
receptors.Its effects are similar to most of those of sympathetic nerve stimulation. Its action should be likened to the
hormonal role of endogenous adrenaline ,released from the adrenal medulla in response to severe physiological
stress.Adrenaline has a more marked effect on beta-adrenoreceptors than on alpha, and this property explains many
aspects of its pharmacology.In practice ,major effects of adrenaline include increased speed and force of cardiac con-
traction, blood flow to skeletal muscle is increased, hepatic blood flow is increased and metabolic effects include
increased glucose output as well as markedly increased oxygen consumption: blood flow in the kidneys mucosa and
skin is reduced: there is little direct effects on cerebral blood flow. Adrenalin relaxes the bronchial musculature and
may be injected subcutaneously to relieve bronchial spasm in acute attack of bronchial asthma subcutaneous or intra-
muscular injection of 0,2-0,5 ml of adrenaline (1 in 1 000) gives symptomatic relief in acute allergy and may be life-
saving in anaphylactic shock. Subcutaneous or intramuscular injection is also indicated for cardiovascular resusci-
tation procedures. The extreme emergencies a dilute solution may be given by very slow intravenous injection.
Intramuscular injection is idicated in the emergency treatment of hypoglycaemia. Adrenalin is frequently added to
local anaesthetics to retard diffusionand limit absorption, to prolong the duration of effect and to lessen the danger
of toxicity. Its has also been added to injections for spinal anaesthesia to delay apsorption and prolong the effect.adren-
aline constricts arterioles and capillaries and causes blanching when applied locally to mucous membranes and
exposed tissues. It is used to check capillary bleeding. In ophthalmology, adrenaline is used to reduce conjuctival
congestion and to reduce intra-ocular preasure in simple glaucoma.
The fact that there is lack of adrenaline injection on the drug market in our contry, the aim of presented work
was to formulated adrenalin injection and to evaluate its quality and stability. Adrenaline injection is a steril solu-
tion of adrenalin in water for injection. It contains 95-105% of adrenaline. Packaging and storage in well closed,
light resistant containers as a single dose or multiple dose, preferably of Tipe I glass. The formulation manifested
good quality in respect to Physical properties, physicochemical parameters and microbiological quality according
to BP and USP. The dosage form was stable for a year storage protect from light in a cold place.
Macedonian pharmaceutical bulletin 53 (1,2) 86-87 (2007)
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Adrenalin ampula – formulacija i farmakodinamski efekt
E. Najdovska, Z. Veljanova 
Slu`ba za infuzioni rastvori, Klini~ka bolnica Dr. Trifun Panovski, Bitola
Adrenalinot e simpatomimetik so mo}no izrazeno deluvawe na alfa i beta adrinergi~nite recep-
tori. Negovoto deluvawe e soodvetno na deluvaweto na endogeniot adrenalin koj se osloboduva od sr`ta
na nadbubre`nata `lezda.
Vo praksa, najzna~ajniot efekt na adrenalinot e zgolemuvaweto na brzinata i snagata na srceva-
ta kontrakcija, se zgolemuva snabduvaweto na skeletnite muskuli i crniot drob so krv, se stimulira metab-
olizmot i se zgolemuva potro{uva~kata na kislorod. Se zabrzuva sogoruvaweto na jaglenohidratite, raste
respiratorniot koli~nik i bazalniot metabolizam. Protokot na krv vo bubrezite i ko`ata se namaluva
a ima i mal direkten efekt vrz cerebralniot protok na krv. Adrenalinot naj~esto se aplicira potko`no
ili intramuskulno. Dozite za vozrasni se 0,2-0,5 mg. Intravenski se dava poretko, samo vo forma na voden
rastvor, injiciraweto e sporo a poedine~nata doza ne smee da bide pogolema od 0,05 mg. Adrenalinot se
dava i intrakardialno so cel o`ivuvawe na pacientot - pri kardialen arest. Subkutano ili intramuskul-
no se dava pri akutni alergii i go spasuva `ivotot na pacientot pri anafilakti~en {ok. Adrenalinot
gi kontrahira arteriolite i kapilarite i predizvikuva bledilo-{to nao|a primena pri proverka na kapi-
larno krvarewe vo otorinolaringologijata. Vo oftalmologijata, adrenalinot se koristi da ja namali
kowuktivalnata kongestija i da go namali intraokularniot pritisok.
Neredovnoto snabduvawe na na{iot pazar so ampularna forma na adrenalin koj e neophoden pri
hirur{ki intervencii i akutni alergiski sostojbi, navede na postavuvawe cel: formulirawe na ampular-
na forma na adrenalin. Adrenalinot vo ampularna forma e oficinelen po USP i BP. USP go definira
kako epinefrin-inj.-sterilen rastvor na epinefrin vo voda za inekcii, pripremeno so pomo{ na
hlorovodorodna kiselina. Se ~uva vo ednodozna ili pove}edozna ambala`a, tip I staklo, za{titeno od
svetlost pH = 2,5-5. Se sterilizira so avtoklavirawe ili filtracija. BP go definira kako adrenalin-
hidrogentartrat, isto taka edno ili pove}edozna ampula, tip I staklo, za{titeno od svetlost. pH=2,8-3.6.
Se sterilizira so avtoklavirawe. Adrenalin ampulata sod`i ekvivalent od 0,1 %w/v na adrenalin (odnos-
no 0,18 g adrenalin hidrogentartarat). Vodeniot rastvor na adrenalin e optimalno stabilen pri pH=3,6.
Zaradi toa se priprema ili kako adrenalin hidrogentartrat ili so upotreba na hlorovodorodna kiseli-
na, no dozata e sekoga{ izrazena na ekvivalentna sodr`ina na adrenalin 1 vo 1 000 (1 mg/ml). Rastvorot
mora da bide bister i bezboen. Obojuvaweto e znak deka po~nal raspadot na adrenalinot a kafeava boja na
rastvorot e znak deka adrenalinot kompletno e raspadnat. Stabilnosta na preparatot e zavisna od pH na
rastvorot i uslovite na ~uvawe. Pri pH = 3,6 i ~uvawe za{titeno od svetlost, vo temna ambala`a, staklo
tip I i na ladno mesto, mo`e da se garantira rok na upotreba od 1 godina. So promenata na pH se zabrzuva
i raspadot na adrenalinot duri i ako se ~uva na ladno i za{titeno od svetlost. [tom pH porasne nad 4,5
mnogu brzo se pojavuva obojuvawe na rastvorot.
I dvete proskripcii se primenlivi vo na{i uslovi i davaat proizvod koj go zadovoluva kvalite-
tot vo soglasnost so USP i BP.
Macedonian pharmaceutical bulletin 53 (1,2) 86-87 (2007)
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