Abdulaal et al., 2018, AJMS 1(2): 12-16 DOI:10.5455/ajms.

Arabian Journal of Medical Sciences

http://www.ajms.tk

Physicochemical properties and antibacterial efficacy of ciprofloxacin –phena-

zopyridine drugs in a binary solid dispersion
Mohamed M. Abdulaal a, Fahd M. Alsharif a*, Gamal Zayed b, Mohamed T. Salim c, Yaseen A. Elshaierd*
a
Department of Pharmaceutics and Industrial pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
b
Al-Azhar Centre of Nanosceinecs and Applications (ACNA), Al-Azhar University, Assiut, Egypt
c
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
d
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt

Article Info Abstract

Background: Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Severe
Keywords: pain accompanying UTIs necessitates a combination therapy of antibiotic (ciprofloxacin HCl, CIP.HCl) with
UTIs; UTI analgesic (phenazopyridine HCl, PHZ.HCl). However, the physicochemical properties and the antibacterial
Ciprofloxacin HCl; activity of this combination need to be further explored. Aim: The aim of the present study was to explore the
binary solid dispersion; physicochemical properties and the antibacterial efficacy of CIP.HCl-PHZ.HCl in a binary solid dispersion (SD)
phenazopyridine HCl; system using polyvinylpyrrolidone (PVP). Methods: The SD was prepared using solvent method. The dissolution
dissolution; of CIP.HCl was measured. The physical state and solid-state interactions between CIP.HCl, PHZ.HCl, PVP and
antibacterial SD were explored using FTIR spectroscopy, 1H-NMR and PXRD. Finally, the minimum inhibitory concentration
(MIC) of the prepared SD was compared to a pure CIP.HCl. Results: Data showed improved dissolution behavior
Received Sep 11,
of the prepared SD compared with the pure drug. PXRD showed that CIP.HCl did not convert into amorphous form
Revised Oct 21,
Published Dec 6, 2018 with PVP however; a decrease in the intensities was detected probably due to dilution with the polymer. FTIR and
1H-NMR data showed that HCl molecule was transferred from the piprezinyl group of CIP.HCl to PHZ.HCl. In
another anticipated interaction, both carboxylic and ketone functionalities of CIP.HCl engaged in salt formation and
*Corresponding authors:
hydrogen bonding with PHZ. Conclusions: CIP.HCl antibacterial activity was improved against various pathogens
fahdalsharif2016@gmail.com
suggesting the ability of CIP.HCl, in the SD system, to diffuse more through the bacterial cell membrane. Moreover,
yaseenorganic@yahoo.com
possible interactions between CIP.HCl with PHZ.HCl would help increase the stability of the prepared SD system.

1. Introduction
Urinary tract infections (UTIs) are among the most common bac-
terial infections that affect urinary system; however, women are more
likely to experience a UTI more than men (Foxman, 2010). Several
microorganisms cause UTI but the major urinary tract pathogen is
Escherichia coli which accounting for more than 80% of uncompli-
cated UTI (Karlowsky et al., 2002, Lüthje and Brauner 2016). An-
tibiotics in combination with analgesics are drugs that could be used
to treat UTIs. The first line treatment of acute uncomplicated UTI in-
cludes nitrofurantoin monohydrate and the second line treatment in-
volves fluoroquinolones (FQs) (Locke, 2018, Solh et al., 2017). FQs
play an important role in the treatment of resistant UTIs because they
are effective against a broad spectrum of Gram-positive and, partic-
ularly, Gram-negative bacteria (Goldstein et al., 1997, Mascellino
et al., 1998, Marcelín-Jiménez et al., 2006). Currently, a number of
FQs are available for clinical use including levofloxacin, norfloxacin,
ciprofloxacin (CIP), ofloxacin, gatifloxacin and moxifloxacin. CIP
(Fig. 1A) [1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperaz-
inyl)-3-quinolinecarboxylic acid] is the most effective second-gener-
ation FQ compound against E. coli and other species of Enterobacte-
riaceae in addition to Pseudomonas (Marcelín-Jiménez et al., 2006;
Wise et al., 1983). It acts via inhibition of bacterial DNA gyrase,
hence, blunting DNA replication and transcription.
Phenazopyridine (PHZ, Fig. 1B) [(2,6-diamino-3-(phenylazo)
pyridine] is an azo dye derivative that has been used to reduce UTI
pain due to its analgesic effect on the urinary tract mucosa (Marcelín-
Jiménez et al., 2006, Gaines, 2004). PHZ may be given alone or in
combination with co-trimoxazole or FQs for treatment of UTIs. In
12
this regard, it was reported that the bioavailability of CIP was en-
hanced by PHZ co-administration (Marcelín-Jiménez et al., 2006).
However, PHZ did not affect CIP absorption or elimination but a
significant delay in half-life of CIP from 1 to 1.5 h has been ob-
served suggesting the probability of a physicochemical interaction
between the two moieties during the in vivo dissolution of drug
crystals. However, the authors did not speculate or explain the na-
ture of this physicochemical interaction.
Solid dispersion (SD), using inert carriers, is one of the most
common pharmaceutical approaches applied for enhancing the
solubility of poorly soluble drugs and consequently the therapeu-
tic efficacy (Huang and Dai 2014, Leuner and Dressman, 2000,
Marcelín-Jiménez et al., 2006). It has been reported that the aque-
ous solubility of CIP is 0.06 and 0.08 mg/ml at 25°C and 37°C, re-
spectively (Mesallati et al., 2016; Mesallati and Tajber, 2017). This
poor aqueous solubility would contribute to the poor bioavailability
and hence, limited antibacterial activity. Moreover, the very low
aqueous solubility of CIP is mainly contributed to the strong crystal
lattice structure of the drug powder (Mesallati and Tajber, 2017).
This strong crystalline structure lattice of the drug is anticipated to
be converted to the amorphous form via SD formulation (Leuner
and Dressman, 2000, Mesallati and Tajber, 2017). SD is highly en-
ergetic amorphous dispersion of a drug in a hydrophilic solid carrier
which is either a small molecule or a polymer (Dohetry and York,
1987, Mesallati et al., 2017, Tantishaiyakul et al., 1999, Yu, 2001,).
In spite of the advantages and implications of SD formulation as
a technique for enhancing drug solubility and bioavailability, only
 Abdulaal et al., 2018, AJMS 1(2): 12-16 DOI:10.5455/ajms.9
few studies have been conducted on CIP solid dispersion formula-
tions. Nevertheless, it was reported that the aqueous solubility of CIP
was significantly improved when the drug was formulated as SD in
polyvinylpyrrolidone (PVP) using milling technique (Mesallati et al.,
2017). PVP is a hydrophilic polymer that has been commonly used
to increase the aqueous solubility of poorly soluble drugs through
SD formation (Leuner and Dressman, 2000, Tantishaiyakul et al.,
1999). Another method for improving aqueous solubility of poorly
soluble drugs is salt formation. In this regard, HCl salt of ciproflox-
acin was developed and used as oral tablets. It has been reported that
aqueous solubility of CIP.HCl is approximately 42 mg/mL in water
at 37°C (Parojčić et al., 2011). However, the solubility of CIP.HCl
is decreased in the stomach due to common ion effect (Florence AT,
Attwood et al., 2011).
The stability of the SD system is improved through molecular
interaction such as hydrogen bonding or salt formation among SD
components (Al-Remawi et al., 2017). Taking into account the an-
tibacterial activity of CIP along with the analgesic effect of PHZ on
urinary tract, a novel solid dispersion formulation containing both
drugs is prepared using PVP as a hydrophilic carrier. This combina-
tion in one dosage form would help increase patient`s compliance
due to administration of both drugs in a single formulation and also
would help reduce treatment cost. Although, the effect of PHZ.HCl
on bioavailability of CIP was previously studied (Marcelín-Jiménez
et 2006), the present study was designed to further investigate the
physicochemical properties and antibacterial activity of CIP.HCl in
presence of PHZ.HCl in a binary SD system. To this end, a binary SD
containing CIP.HCl and PHZ.HCl was prepared via solvent evapora-
tion method. The prepared SD system was evaluated for dissolution
and characterized by PXRD, FTIR and 1H-NMR. Also, the antibac-
terial potency of CIP.HCl in the formulated SD was assessed using
minimum inhibitory concentration (MIC).
Fig. 1. Chemical structures of CIP (A) and PHZ (B).
2. Materials and Methods
2.1. Materials
Ciprofloxacin HCl (CIP.HCl) was kindly gifted by Internation-
al Pharmaceutical Industries Co. (EIPICO), 10th of Ramadan City,
Egypt. Phenazopyridine HCl (PHZ.HCl) was kindly gifted by Cai-
ro Chemicals Co, Cairo, Egypt. Polyvinylpyrrolidone (PVP K30),
tetramethylsilane (TMS), chloroform-D (CDCl3), dimethyl sulf-
oxide (DMSO), dimethyl sulfoxide-D6 (DMSO-d6), methanol and
dichloromethane were purchased from Sigma Aldrich, St. Louis,
MO, USA. Hydrochloric acid, Cork-borer LA737 was procured
from HiMedia Laboratories, Mumbai, India. Nutrient broth medium
(Oxoid™ Cat. No CM0001B) and Nutrient agar (Oxoid™ Cat. No.
CM0003) were purchased from Oxoid Limited, Hampshire, UK. All
other chemicals and reagents used in this study were of analytical
grade. All bacterial strains were kindly provided by the Assiut Uni-
versity Mycological Centre (AUMC), Assiut, Egypt.
2.2. Preparation of CIP-PHZ amorphous solid dispersion
by solvent method
13
The solid dispersion system of CIP.HCl and PHZ.HCl was
prepared using the common solvent evaporation method. Briefly,
both drugs and polymer were dissolved in a minimum volume of
methylene chloride and methanol (2:1) mixture. In a round bottom
flask, 120 mg drugs (100 and 20 mg of CIP.HCl and PHZ.HCl, re-
spectively) and 240 mg PVP were dissolved in 3 ml solvent mixture
with agitation using magnetic stirrer (Stuart Scientific, Staffordshire,
UK). Then, solvents were allowed to evaporate at room temperature.
Remaining solvents were removed in desiccation overnight and the
dried solid was scratched, powdered and stored in desiccator until
use.
2.3. Dissolution Testing
Dissolution testing instrument (Validata Dissolution Tester,
Hansen research Chatswarth, Ca, USA), was used to investigate
the dissolution behavior of the SD system and free CIP.HCl. The
dissolution was accomplished in compliance with USP-32 using an
apparatus 2 (paddles) at 50 rpm and 900 mL of phosphate buffered
saline (PBS) as a dissolution medium (80 g NaCl. 2 g KCl, 21.7
Na2HPO4 and 2.59 g KH2PO4 in 1 Liter) at 37°C. Various sam-
ples (5 mL) were taken at different time intervals (5, 10, 20, 30,
45, 60 and 90 min). An equal volume of fresh medium was added
to maintain sink conditions. The withdrawn samples were filtered
and analyzed spectrophotometrically for drug concentration using
UV-double beam spectrophotometer (Shimadzo, Kyoto, Japan) at
wavelength 271.5 nm (Maswadeh et al., 2015). It was confirmed
that the method was valid for CIP in the presence of PHZ because
of the difference of wavelengths (PHZ wavelength is 428 nm) (Attia
et al., 2016). In the present study, an independent model method
employing a difference factor (f1) and similarity factor (f2) was used
to compare the dissolution profiles of the SD system and that of pure
drug. Factor f1 calculates the percentage difference (dissimilarity)
between the SD system and CIP.HCl, while f2 is the logarithm of
the reciprocal square root transformation of the sum squared error. It
indicates the average percentage of similarity between two dissolu-
tion profiles. An f1 value over 15 indicates significant dissimilarity
and an f2 value over 50 indicates significant similarity. Additionally,
the dissolution efficiency (DE), relative dissolution rate (RDR) and
mean dissolution time (MDT) were also calculated as previously re-
ported (Attia et al., 2016).
2.4. Powder X-ray diffraction (PXRD)
X-ray diffraction patterns of pure CIP.HCl, PHZ.HCl, PVP,
physical mixture and the prepared SD were obtained using Philips
X-ray diffractometer Almelo, Netherland. The physical mixture was
prepared simply by mixing the components in a beaker using the
same proportions of contents used in the SD formulation. Samples
were scanned over the range of 2θ from 2 to 40°, under Cu K α radi-
ation, at a voltage of 40 kV and a current of 30 mA.
2.5. Solid State Fourier Transform Infrared Spectroscopy
(FTIR)
FTIR study was conducted to investigate the possibility of inter-
molecular interactions between CIP.HCl, PHZ.HCl, PVP and the SD
system. FTIR spectra were recorded as KBr disks using SHIMAD-
ZU IR-470 spectrophotometer, Kyoto, Japan. The IR wave lengths
(ν) are expressed as cm-1.
2.6. 1H-NMR
To further demonstrate any chemical shifts as a result of possible
interaction between the SD components, 1H-NMR spectra for pure
CIP.HCl, PHZ.HCl and SD formulation were determined. 1H-NMR
spectra were run on BRUKER Avance III400 MHz spectrophotom-
 Abdulaal et al., 2018, AJMS 1(2): 12-16 DOI:10.5455/ajms.9

eter (Bruker AG, Fällanden, Switzerland). Tetramethylsilane (TMS)
was used as an internal standard and CDCl3 or DMSO-d6 as a sol-
vent. Chemical shift (δ) values are expressed in parts per million
(ppm) and coupling constants (J) in Hertz (Hz). The signals are des-
ignated as follows: s; singlet, d; doublet, t; triplet, q; quartet, m; mul-
tiplet, brs; broad singlet.
2.7. In vitro antibacterial activity
To evaluate the antibacterial activity of the prepared SD formu-
lation against pure CIP.HCl, seven bacterial strains representing both
Gram-positive and Gram-negative strains were used. These strains
are common contaminants of the environment in Egypt and some of
which are involved in human and animal diseases (Staphylococcus
aureus, Escherichia coli, Bacillus cereus, Pseudomonas aeruginosa,
Micrococcus luteus, Serratia marcescens and Salmonella typhimuri-
um). To prepare inocula for bioassay, bacterial strains were individ-
ually cultured for 48 h in 100 ml conical flasks containing 30 mL
nutrient broth medium. Bioassay was done in 10 cm sterile plastic
Petri plates in which microbial suspension (1 mL/plate) and 15 mL
appropriate agar medium (15 mL/plate) were poured. Nutrient agars
were respectively used for bacteria. After solidification of the media,
5 mm diameter cavities were cut in the solidified agar (3 cavities/
plate) using sterile cork-borer. Later, known amount of the solid dis-
persion system equivalent to 3.75 µM/mL of CIP.HCl was dissolved
in DMSO at a concentration of 3.75 µM/mL and pipetted in the cav-
ities (50 µl/cavity). In addition, a solution of free CIP.HCl at 3.75
µM/mL in DMSO was used as a standard antibacterial agent. Cul-
tures were then incubated at 28°C for 48 h. Results were expressed
as the diameter (in mm) of inhibition zone around cavities.
IR spectrum of PHZ, the NH2 functionality changed from forked 2924
cm-1 (pure) to 2908 cm-1 (formulation). Unlikely, the IR chart of PVP
exhibited no change in IR peaks before and after formulation as can be
seen in table 3. The PVP carbonyl was detected at 1658 and 1660 cm-1
before and after formulation, respectively. This probably indicates
that PVP does not participate in any interaction with either CIP or
PHZ. On the other hand, the IR peaks of both CIP and PHZ were shift-
ed after their formulation. Based on structure features of both drugs,
an interaction between CIP and PHZ is potentially anticipated. The
formation of intermolecular hydrogen bond between the NH2 group
in PHZ and the carbonyl in CIP to form the cyclic structure is one of
the proposed interactions as depicted in Scheme 1. Another possible
interaction is the formation of ionic salt between NH2 of PHZ and the
COOH terminal of CIP. Accordingly, in order to further elucidate this
interaction clearly, 1 H-NMR interpretation was required.
Table 1: CIP‧HCl dissolution parameters including dissolution efficiency (DE),
Relative dissolution rate (RDR), percent drug dissolved (PD), mean dissolution
rate (MD) and similarity and dissimilarity factors (ƒ2 and ƒ1, respectively).
Dissolution parameters Free Binary solid
CIP‧HCl dispersion of
CIP‧HCl
Dissolution Efficiency (DE) at 45 min 42.47944 54.34278
Relative Dissolution Rate (RDR) after 30 1 1.22
min
Percent Drug Dissolved (PD) 58.66 72.28
Mean Dissolution Time (MD) 17.72 12.13

3. Results and Discussion ƒ2 Similarity Factor - 46

3.1. Dissolution behavior of the prepared SD system
Compared to free CIP.HCl, the solid dispersion enhanced CIP. ƒ1 Difference(Dissimilarity) Factor - 23
HCl dissolution rate (Fig. 2). The amount of drug released was high-
er in solid dispersion than that from pure drug. Moreover, Table 1
shows various CIP.HCl dissolution parameters in pure form and in
solid dispersion system. It was noted that dissolution efficiency, rela-
tive dissolution rate (RDR) and % dissolved of CIP.HCl in SD were
higher than those of the pure drug. Furthermore, similarity factor
(ƒ2) value was <50 and ƒ1 value was >15. This indicates the higher
dissolution rate of CIP.HCl from the solid dispersion system com-
pared to free drug.

3.2. Powder X-ray diffraction (PXRD)

In order to investigate the drug-carrier interaction and physical
state of the drug whether amorphous or crystalline before and after
formulation, powder X-ray diffractometry study was conducted for
the pure drugs, pure polymer and SD formulation. As can be seen in Fig. 2. Dissolution behavior of CIP‧HCl solid dispersion and free
Fig. 3, the peaks of pure CIP.HCl could be observed in the physical CIP‧HCl in distilled water.
mixture with a decrease in their intensities probably due to dilution
with the polymer (PVP). Likely, CIP.HCl was not converted into 3.4. 1H-NMR data
amorphous form with PVP solid dispersion as indicated by X-ray
of the SD. However, the intensities of the peaks were also reduced. 1
HNMR spectra for pure CIP.HCl, pure PHZ.HCl, and the SD
This finding was in accordance with Masellati et al. 2017 where CIP formulation were measured. The aliphatic region of pure CIP.HCl
was not converted into amorphous form and was just diluted by the revealed the following resonances: δ 1.19 ppm (2H), δ 1.34 ppm
polymer, PVP. (2H), δ 3.31 ppm (4H), δ 3.59 (4H), and δ 3.86 ppm (1H). Similarly,
aromatic protons resonate at δ 7.59 ppm (d, 1H), δ 7.87 ppm (d, 1H),
3.3. FTIR data
and δ 8.64 ppm (s, 1H). In addition to aforementioned aliphatic and
The IR spectra were demonstrated in Table 3. Both carbonyl in
aromatic signals, it illustrated two deshielded peaks at δ 9.70 (brs,
CIP were shifted from 1624 cm-1, 17071cm-1 (pure) to 1636 cm-1,
1H) indicating the NH of piprazinyl moiety and at δ 15.04 (brs, 1H)
1660 cm-1 (formulation), respectively. Also, 3528, 3377 cm-1 in pure
indicating the OH functionality. The proton of NH for piprazinyl
were overlapped and disappeared with the formula. With regard to
14
 Abdulaal et al., 2018, AJMS 1(2): 12-16 DOI:10.5455/ajms.9
Scheme 1. Suggested interaction pathways between CIP‧HCl and PHZ‧HCl showing hydrogen bonding or salt formation and HCl shift from
CIP‧HCl to form di-hydrochloride salt of PHZ
group was shifted downfiled probably due to its protonated with HCl.
Moreover, the 1H NMR spectrum of phenazopyridine HCl in pure
form, showed the pyridine ring signals were observed as broad signals
at δ 6.40 (d, 1H), at δ 8.29 (d, 1H). The benzene ring has its protons
at δ 7.2-7.9 (m, 5H). Taking into account the 1H-NMR for CIP.HCl
and PHZ.HCl separately, the next step was directed to compare their
1
H-NMR with that of the SD formulation. Interestingly, 1H-NMR of
CIP.HCl in formula exhibited upfield shift of the NH of piprazinyl
moiety to the aliphatic region.
On the other hand, the carboxylic proton showed downfield
shift from δ 15.04 brs (pure form), to δ 15.14 (in formula from).
However, NH2 of PHZ.HCl exhibited downfield shift from δ 8.29
(brs, 4H) to δ 9.33 (brs, 4H). Judging from 1H-NMR data, the NH of
CIP.HCl was shifted to upfield and became shielded indicating the
PHZ deprotonates the NH and transfer the HCl from CIP to PHZ (salt
transformation). In addition, the proton of carboxyalte was shifted
downfiled/deshielded indicating hydrogen bond formation. Based
on IR and 1H-NMR data, we can envision that this new combination
makes a new molecule with head (PHZ.2HCl) and tail (CIP).
Fig. 3. X-ray diffraction patterns of free CIP‧HCl (A), free PHZ‧HCl
(B), PVP (C), physical mixture (D) and solid dispersion (E).
15
3.5. In vitro antibacterial activity
As influence of PHZ.HCl on the solid and physical states of CIP.
HCl was explored. It was very important to figure out the effect of
PHZ.HCl on the antibacterial efficacy of CIP.HCl as well. The an-
tibacterial activity of the solid dispersion formulation was assessed
in comparison to free CIP.HCl against different pathogens. As can
be seen in table 2, the antibacterial activity of the SD formulation
was improved against M. luteus, S. marcescens and Ps. aeruginosa.
The MICs of CIP.HCl solid dispersion system against M. luteus and
S. marcescens were 2-fold and 40-fold that of the free CIP.HCl, re-
spectively. However, the MICs against Ps. aeruginosa were the same
(0.0073 mg/ml) in both CIP.HCl alone and the SD system, greater
inhibition zone was recorded (8 mm) with regard to the SD system ac-
tivity. In particular and more importantly, however the MICs obtained
with the formulated solid dispersion system and free CIP.HCl were
almost the same (0.0292 and 0.03, respectively), the antibacterial
activity of the formulated CIP.HCl-PHZ.HCl binary solid dispersion
against the major urinary tract pathogen, E. Coli, was improved as
indicated by the higher inhibition zone compared with free CIP.HCl
(15 and 11 mm, respectively). In contrast, the antibacterial activity
against S. aureus was similar for both the free CIP.HCl and the solid
dispersion system where there was no difference in either the inhibi-
tion zone (8 mm) or the MIC (0.0292 mg/mL). Based on these data,
it seems that CIP.HCl antibacterial potency was not reduced in the
bacterial species studied, however, it was improved against some of
these strains. This improved antibacterial activity of CIP.HCl, when
formulated in a binary solid dispersion formulation with PHZ.HCl,
probably may be contributed, in part, to the improved dissolution of
CIP.HCl. This improved dissolution of CIP.HCl increases the propor-
tion of CIP.HCl diffusing across the bacterial cell membrane. This
finding was in agreement with a previous report where CIP bioavail-
ability was improved by co-administration with PHZ.HCl (Marcelín-
Jiménez et al., 2006). However, PHZ does not affect CIP absorption
or metabolism, a significant delay in in tmax of CIP was noted. How-
ever, the authors contributed this delay in tmax to a physicochemical
interaction between CIP and PHZ crystals during the in vivo disso-
lution, they did not explore the nature of this interaction Marcelín-
Jiménez et al., 2006).
In the current study, more attention was given to explore the
physicochemical changes associated with co-administration of CIP.
HCl with PHZ.HCl. It has been found that PHZ.HCl interacts with
CIP.HCl to form bi-HCl salt of PHZ and the possibility of hydrogen
bonding and salt formation. Moreover, this interaction is anticipated
to increase the stability of the prepared SD system via increasing the
stability of the formulated SD.
 Abdulaal et al., 2018, AJMS 1(2): 12-16 DOI:10.5455/ajms.9

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