Abstract: Hydrophilic polymers using as matrix former in matrix tablets is a common approach and well-known excipient Carbopol is widely used for this reason too. In common case polymer doesn’t interact with drug but Carbopol is weak polyacrylic acid and obvious can interact at physiological enteric conditions with weak base drugs like trimetazidine dihydrochloride. During matrix tablet dissolution at enteric conditions the microenvironment pH inside tablet changed from surface to center. Was found that hydrated matrix has unusual structured in microenvironment pH diapason of possible trimetazidine-Carbopol interaction. This matrix structuration resulted in significant matrix behavior changing and increasing trimetazidine release retardation in comparison with release data at gastric conditions. Thus the example of trimetazidine-Carbopol interaction demonstrates additional mechanism of drug retardation that could be used for another appropriate weak base drugs.

1. Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 72 No. 6 pp. 1259ñ1261, 2015 ISSN 0001-6837
Polish Pharmaceutical Society
In case of soluble matrices, a hydrogel formed
after contact of matrix with medium and drug release
occurs either via drug diffusion through a network of
capillaries formed between compacted matrix former
or/and erosion of the matrix. Dependent on the aque-
ous drug solubility, one of the mechanisms could
dominate or combination of both takes place (1).
Despite that Carbopol 71G is crosslinked polyacrylic
acid and in principle is insoluble, the drug release
occurs similarly to the water soluble matrices includ-
ing erosion (2). Being a weak acid, Carbopol 71G
can interact with weak bases at pH about pKa = 6.1.
Trimetazidine dihydrochloride as a week base (pKa1
4.45, pKa2 9.14 (4)) can interact with Carbopol 71G.
Therefore, the aim of this work was to investigate the
trimetazidine-Carbopol interactions and their effect
on drug release from matrix tablet.
EXPERIMENTAL
Materials
API: Trimetazidine dihydrochloride (TMZ ◊
2HCl, Sochinaz SA, Switzerland); matrix former:
crosslinked polyacrylic acid (Carbopol 71G,
Lubrizol Corp., USA); filler: lactose monohydrate
(Granulac 200, Meggle AG, Germany); glidant: col-
loidal silicon dioxide (Aerosil 200 Ph, Evonik AG,
Germany), lubricant: sodium stearyl fumarate (Pruv,
JRS Pharma, Germany).
Tablets preparation
Direct compression method was applied to
obtain 200 mg biconvex tablets with 8 mm diameter
according to the formulation presented in Table 1
using a mixer (Turbula T2F, Willy A. Bachofen AG,
Switzerland) and eccentric tablet press (Korsch
EKO, Korsch AG, Germany).
Dissolution test
The drug release from tablets was investigated
in a paddle apparatus (Vankel VK 300, Vankel
Industries, Edison., NJ, USA) at following condi-
tions: 900 mL of 0.1 M HCl or PBS pH 6.8, 100
rpm, 37O
C; (n = 3). Samples were withdrawn at pre-
determined time points, filtered through 0.35 µm fil-
ters and measured UV-spectrophotometrically at λ =
269 nm (pH 1: y = 0.0022x, R2
= 0.9999; pH 6.8: y
= 0.0022x + 0.0276, R2
= 0.9993).
Aqueous solubility determination
The shake-flask method was used for TMZ ◊
2HCl and Granulac 200 solubility determination.
INTERACTION OF WEAK BASE DRUG TRIMETAZIDINE AND CARBOPOL
AS FURTHER RETARDATION IN THE MATRIX TABLET
VALENTYN V. MOHYLYUK* and LENA L. DAVTIAN
Department of Pharmaceutical Technology and Biopharmaceutics, Shupyk National Medical Academy of
Postgraduate Education, Kyiv, Ukraine
Abstract: Hydrophilic polymers using as matrix former in matrix tablets is a common approach and well-
known excipient Carbopol is widely used for this reason too. In common case polymer doesnít interact with
drug but Carbopol is a weak polyacrylic acid and obviously can interact at physiological enteric conditions with
weak base drugs like trimetazidine dihydrochloride. During matrix tablet dissolution at enteric conditions, the
microenvironment pH inside tablet changes from surface to center. It was found that hydrated matrix has unusu-
al structured in microenvironment pH diapason of possible trimetazidine-Carbopol interactions. This matrix
structuration resulted in significant matrix behavior changing and increasing trimetazidine release retardation
in comparison with release data at gastric conditions. Thus, the example of trimetazidine-Carbopol interactions
demonstrate additional mechanism of drug retardation that could be used for another appropriate weak base
drugs.
Keywords: Carbopol, trimetazidine, matrix tablet, release retardation
1259
* Corresponding author: e-mail: Valentyn.Mohylyuk@gmail.com

2. 1260 VALENTYN V. MOHYLYUK and LENA L. DAVTIAN
The excess of tested substance was added to 50 mL
of medium (0.1 M HCl or PBS pH 6.8). The equi-
librium concentration was achieved in three days.
The substance solubility was calculated after drying
of known quantity of aliquot to constant weight at
105O
C.
RESULTS AND DISCUSSION
TMZ ◊ 2HCl release from matrix tablets at pH
1 was much faster than at pH 6.8 (Fig. 1) or slowed
down upon medium change from pH 1 to pH 6.8
after 2 h.
Since the solubility of Granulac 200 and TMZ
◊ 2HCl is relatively pH independent in the range 1-
6.8 (Tab. 2), the ionic interaction between positive-
ly charged TMZ and negatively charged Carbopol
71G could be a reason for slower drug release.
The swelling/erosion behavior of acidic disso-
lution medium (e.g., pH 1) of Carbopol 71G con-
taining tablets was not affected by the presence of
TMZ ◊ 2HCl (Fig. 2). In this medium, Carbopol
71G was not ionized and no interaction with TMZ ◊
2HCl occurred. The release of freely soluble drug
from swollen tablets was driven by diffusion and
was relatively fast (Fig. 1).
In the medium with pH 6.8, approx. 80 % of
carboxyl groups of Carbopol 71G and almost all ter-
tiary amine groups of TMZ were ionized (according
to pKa1) and can interact with each other forming
salt in a form of erodible gel layer (Fig. 3) on the
surface of the tablet. Tablets containing TMZ (F1)
did not swell in this medium in contrast to drug free
(F2) tablets (Fig. 2).
The increased swelling and viscosity of ionized
Carbopol 71G in the dissolution medium with pH
6.8 is well known phenomenon (3). However, due to
interaction with ionized TMZ, drug containing
tablets did not swell but rather eroded (Fig. 2). pH
measurement of different regions of tablet cross-sec-
tion after 5 h of dissolution test in phosphate buffer
pH 6.8 showed a pH gradient inside of tablets (Fig.
3 D). Cone-shaped rolled strips of indicator paper
which allows inserting the paper into a point was
used to pH determination. The pH decreased from
approx. 7 on the surface to 2-3 in the centre of the
tablet. A thin erodible surface layer which contacts
with PBS pH 6.8 organoleptically looks like mucus
(Fig. 3 A). The pH 5-7 in outer layer corresponds to
ionized state of Carbopol 71G and TMZ ◊ 2HCl,
where the interaction was possible. This outer layer
has rubber-like structure with elastic properties (Fig.
Table 1. Tablet composition (% per 200 mg tablet)
Formulation F1 F2
TMZ ◊ 2HCl 17.5 ó
Granulac 200 31.3 48.8
Carbopol 71G 50
Aerosil 200 Ph. and Pruv 0.2 and 1.0
Table 2. Aqueous solubility of TMZ ◊ 2HCl and Granulac 200 (n = 3, SD ≤ 5%)
Solubility (mg/mL) at pH
Compounds corresponding to
Stomach Small intestine
TMZ ◊ 2HCl 620 (pH 0.6) 340 (pH 6.7)
Granulac 200 210 (pH 0.9) 210 (pH 6.5)
Figure 1. Effect of medium pH on drug release

3. Interaction of weak base drug trimetazidine and carbopol as... 1261
3 B). The central part of tablet cross-section, which
corresponds to pH 2-5, has a form of plastic gel (Fig.
3 C) easy separable from outer layer. In contrast to
TMZ tablets (F1), the drug free tablet (F2) in PBS
pH 6.8 swelled without formation of internal struc-
ture and different way eroded (Fig. 3). After 19 h of
dissolution test in PBS pH 6.8 (Fig. 2), the solid
residue of drug free tablet (F2) was lower than solid
residue of TMZ contain tablet (F1) in spite of lower
solubility of Granulac 200 than TMZ ◊ 2HCl.
The different behavior of TMZ containing
tablet during dissolution test in 0.1 M HCl solution
in contrast to PBS pH 6.8, the behavior difference of
TMZ containing tablet in PBS pH 6.8 in contrast to
drug free tablet, the internal structure formation of
TMZ containing tablet in PBS pH 6.8 in contrast to
drug free tablet allow us to ascertain the presence of
TMZ-Carbopol 71G interaction. It seems that found
interaction of Carbopol 71G and TMZ in the outer
layer could be used for retardation of drug release.
CONCLUSION
Slowdown of release in the release medium
with pH 6.8 was due to the interaction of TMZ ◊
2HCl and Carbopol 71G with rubber-like layer for-
mation. This interaction could be used for further
retardation. Different release rate and mechanical
properties of tablet in different physiological pH
could provide problems for in vitro/in vivo correla-
tion because of unpredictable tablet presence in the
stomach. Therefore, one of the approaches to
achieve this retardation in pH independent manner
would be an enteric coating.
REFERENCES
1. Aulton M.E.: Pharmaceutics: the Science of
Dosage Form Design, 2nd edn., pp. 289-305,
Churchill Livingstone, Edinburgh 2002.
2. Lubrizol Advanced Materials Inc.,
Pharmaceutical Polymers for Oral Solid Dosage
Forms, Technical Data Sheet, 2011.
3. Lubrizol Advanced Materials Inc., Neutralizing
Carbopol and Pemulen Polymers in Aqueous
and Hydroalcoholic Systems, Technical Data
Sheet, 2009.
1. Reymond F. Steyaert G., Carrupt P.A., Morin
D., Tillement J.P. et al.: Pharm. Res. 16, 616
(1999).
Received: 15. 03. 2015
Figure 2. Matrix tablets behavior during dissolution test Figure 3. TMZ ◊ 2HCl containing matrix tablet after 5 h of disso-
lution test at pH 6.8: A) whole tablet, B) separated rubber-like
layer, C) separated gel core, D) cross-section

4. Drug Research
ACTA POLONIAE
PHARMACEUTICA
VOL. 72 No. 6 November/December 2015 ISSN 2353-5288

5. EDITOR
Aleksander P. Mazurek
National Medicines Institute, The Medical University of Warsaw
ASSISTANT EDITOR
Jacek Bojarski
Medical College, Jagiellonian University, KrakÛw
EXECUTIVE EDITORIAL BOARD
The Medical University of Warsaw
The Medical University of Warsaw
The Medical University of GdaÒsk
The Medical University of Warsaw
K. Marcinkowski University of Medical Sciences, PoznaÒ
The Medical University of Wroc≥aw
Polish Pharmaceutical Society, Warsaw
Czech Pharmaceutical Society
Charles Sturt University, Sydney
Pharmazeutisches Institut der Universit‰t, Bonn
DOV Pharmaceutical, Inc.
Semmelweis University of Medicine, Budapest
Miros≥awa Furmanowa
Boøenna Gutkowska
Roman Kaliszan
Jan Pachecka
Jan Pawlaczyk
Janusz Pluta
Witold Wieniawski
Pavel Komarek
Henry Ostrowski-Meissner
Erhard Rˆder
Phil Skolnick
Zolt·n Vincze
This Journal is published bimonthly by the Polish Pharmaceutical Society (Issued since 1937)
Charges
Annual subscription rate for 2016 is US $ 210 including postage and handling charges. Prices subject to change.
Back issues of previously published volumes are available directly from Polish Pharmaceutical Society, 16 D≥uga St.,
00-238 Warsaw, Poland.
Payment should be made either by bankerís draft (money order) issued to ÑPTFarmî or to our account Millennium S.A.
No. 29 1160 2202 0000 0000 2770 0281, Polskie Towarzystwo Farmaceutyczne, ul. D≥uga 16, 00-238 Warszawa, Poland,
with the memo Acta Poloniae Pharmaceutica - Drug Research.
Warunki prenumeraty
Czasopismo Acta Poloniae Pharmaceutica - Drug Research wydaje i kolportaø prowadzi Polskie Towarzystwo
Farmaceutyczne, ul. D≥uga 16, 00-238 Warszawa.
Cena prenumeraty krajowej za rocznik 2016 wynosi 207,90 z≥ (w tym 5% VAT). PrenumeratÍ naleøy wp≥acaÊ w dowol-
nym banku lub UrzÍdzie Pocztowym na rachunek bankowy Wydawcy:
Millennium S.A.
29 1160 2202 0000 0000 2770 0281
Polskie Towarzystwo Farmaceutyczne
ul. D≥uga 16, 00-238 Warszawa
z dopiskiem: prenumerata Acta Poloniae Pharmaceutica - Drug Research.
Warunki prenumeraty zagranicznej - patrz tekst angielski.
Typeset by RADIUS, Warszawa; Printed by Oficyna Wydawniczo-Poligraficzna Prestige, Zπbki
The paper version of the Publisher magazine is a prime version.
The electronic version can be found in the Internet on page
www.actapoloniaepharmaceutica.pl
An access to the journal in its electronics version is free of charge
Impact factor (2014): 0.737
MNiSW score (2013): 15 points
Index Copernicus (2014): 14.75

6. Acta Poloniae Pharmaceutica ñ Drug Research
Volume 72, Number 6 November/December 2015
CONTENTS
REVIEW
1059. Syed Majid Bukhari, Iftikhar Ali, Asma Zaidi, Pharmacology and synthesis of daurichromenic acid as a
Naseem Iqbal, Tayyaba Noor, Rashad Mehmood, potent anti-HIV agent.
Muhammad Salman Chishti, Basit Niaz, Umer Rashid,
Muhammad Atif
1073. Mingwei Mou, Chungen Li, Minghua Huang, Antiosteoporotic effect of the rhizome of Drynaria fortunei
Ziyi Zhao, Huadong Ling, Xiang Zhang, (Kunze) (Polypodiaceae) with special emphasis on its modes
Fengxian Wang, Xincheng Yin, Yanxu Ma of action.
ANALYSIS
1081. Robert Piech, Beata Paczosa-Bator Application of glassy carbon electrode modified with
naftion/MWCNTS for sensitive voltammetric determination
of thymol.
1089. Kamil Kuú, Agnieszka Zakrzewska, Maria Walczak, Validation of LC/MS/MS method for assessment of the in vitro
Ma≥gorzata Szafarz, Anna Gonciarz, Agnieszka Kij, activity of the selected rat cytochrome P450 isoenzymes -
Joanna Suraj, Joanna Szymura-Oleksiak application to early drug metabolism screening.
1101. Urszula Hubicka, Pawe≥ Ømudzki, Barbara Øuromska- Determination and characterization of selected fluoroquinolones
Witek, Pawe≥ Zajdel, Jan Krzek oxidation products under potassium permanganate treatment.
1115. Wei Chen, Lin Li, Tuling Lu, Baochang Cai, Development of a quality control method for Schisandrae
Fangzhou Yin, Wu Yin Chinensis Fructus with micellar electrokinetic capillary
chromatography.
1125. Renata Paprocka, Boøena Modzelewska-Banachiewicz Determination of lipophilicity parameters of new derivatives of
N3
substituted amidrazones by reversed phase thin-layer
chromatography.
1133. Pawe≥ Olczyk, Katarzyna Komosinska-Vassev, Application of electron paramagnetic resonance spectroscopy for
Pawe≥ Ramos, £ukasz Mencner, Krystyna Olczyk, examination of free radical scavenging properties of insulin
Barbara Pilawa analogs.
1141. Ma≥gorzata Do≥owy, Alina Pyka The effect of β-cyclodextrin on the resolution of free and
conjugated forms of deoxycholic and chenodeoxycholic acids by
TLC-densitometry.
DRUG BIOCHEMISTRY
1151. Anna Pude≥ko, Ewa Obuchowicz Desipramine, fluoxetine and tranylcypromine have different
effects on apoptosis induced in rat cortical neurons by oxygen-
glucose deprivation.
1163. Agnieszka Bia≥ek, Andrzej Tokarz, Pawe≥ Zagrodzki Conjugated linoleic acids (CLA) decrease the breast cancer risk in
DMBA-treated rats.
1177. Pawe≥ Olczyk, Katarzyna Komosinska-Vassev, Interactions of Insuman Comb 25 insulin with free radicals -
Pawe≥ Ramos, Krystyna Olczyk, Barbara Pilawa kinetics examination by electron paramagnetic resonance
spectroscopy.
DRUG SYNTHESIS
1183. Saleh I. Alqasoumi, Mansour S. Alsaid, Maged S. Semisynthesis of novel sulfonamides, thioureas, and
Abdel-Kader, Mostafa M. Ghorab biphenylsulfones as a new class of anticancer agents
by using L-norephedrine as strategic starting material.
1193. Korany A. Ali, Mohamed A. Elsayed, Salwa Synthesis and antitumor screening of some new 2,6-bispyridines
M. Elhallouty, Khaled Mahmoud, Ahmad M. Farag functionalized with pyrazole-based heterocycles.
APPHAX 72 (6) 1057 ñ 1320 (2015)

7. NATURAL DRUGS
1201. Aminu Mohammed, Neil Anthony Koorbanally, Phytochemistry, anti-oxidative and anti-diabetic effects of various
Md. Shahidul Islam parts of Eugenia caryophyllata Thunb. in vitro.
1217. Agnieszka Kicel, Monika Anna Olszewska, Preliminary study on the composition of volatile fraction of fresh
Aleksandra Owczarek, Maria Wolbiú flowers and leaves of Robinia pseudoacacia L. growing in Poland.
1223. Youshan Li, Qi Zheng, Jianhui Qin Effect of TCM Yinhuangsan on rat's diabetic ulcer healing
morphology and recovery factors.
1233. Imran Shair Mohammad, Haji Muhammad Shoaib Khan, In vitro characterization and assessment of cosmetic potentials of
Atif Iqbal Arshad, Hira Ijaz, Parikshit Banerjee, W/O emulsion cream containing 2% Prosopis cineraria extract.
Asif Ullah Khan, Aftab-Ullah, Ajkia Zaman Juthi
1239. Aleksandra Owczarek, Jan Gudej, Monika Anna Antioxidant activity of Geum rivale L. and Geum urbanum L.
Olszewska
PHARMACEUTICAL TECHNOLOGY
1245. Ramzi Shawahna, Mashhour Ghanem, Ayat Ghanem, Establishing similarity between multisource betahistine
Abdul-Fattah Mansour, Nema Ahmad, Abdel Naser Zaid hydrochloride oral dosage forms using in vitro methods.
1253. Przemys≥aw Zalewski, Daria Szymanowska-Powa≥owska, The radiolytic studies of ceftriaxone in the solid state.
Piotr Garbacki, Magdalena Paczkowska, Alicja
TalaczyÒska, Judyta Cielecka-Piontek
1259. Valentyn V. Mohylyuk, Lena L. Davtian Interaction of weak base drug trimetazidine and carbopol as
further retardation in the matrix tablet.
1263. Przemys≥aw Zalewski, Robert SkibiÒski, Alicja Kinetics and mechanism of degradation of cefozopran
TalaczyÒska, Magdalena Paczkowska, Piotr Garbacki, hydrochloride in the solid state.
Judyta Cielecka-Piontek, Anna JeliÒska
PHARMACOLOGY
1269. Mohammad Ayaz, Fazal Subhan, Jawad Ahmed, Citalopram and venlafaxine differentially augments antimicrobial
Arif-ullah Khan, Farhat Ullah, Abdul Sadiq, properties of antibiotics.
Nawazish-i-Husain Syed, Ihsan Ullah, Sajid Hussain
1279. Ewelina Dziurkowska, Marek Weso≥owski, Changes of salivary cortisol level after venlafaxine treatment.
Maciej Dziurkowski
GENERAL
1289. M·rton Argay, Andrea MeskÛ, Rom·na ZelkÛ, Therapy reminder message for Hungarian patients with type 2
Bal·zs HankÛ diabetes.
1295. Daniela Minarikova, Adamos Panayotis Electronic prescription services system in Greece - pilot study.
1303. Mariola Drozd, Kazimierz Drozd, Monika Safety of OTC analgesic drugs in the opinion of Polish patients -
Szkultecka-DÍbek, Anna Kijewska, Nina Kiepurska preliminary study.
SHORT COMMUNICATION
1315. Abdulmohsen H. Al Rohaimi Neuropharmacological and toxicity study of newly prepared N-[5-
(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2-substituted
acetamides.