Phase solubility studies of poorly soluble drug molecules by using O -phosphorylated calixarenes as drug-solubilizing agents

Article abstract of DOI:10.1021/je200992c

This study is the first report on the solubilizing effect of O-phosphorylated calix[n]arenes that form complexes with neutral molecules such as nifedipine, niclosamide, and furosemide by host-guest complexation. These complexation studies were carried out by using the phase solubility technique. From the obtained results, it was observed that the solubility of guest molecules such as nifedipine, niclosamide, and furosemide was significantly increased in the presence of host molecules tetrakis-O-(diethoxyphosphoryl)-p- tert-butylcalix[4]arene (1), tetrakis-O-(diethoxyphosphoryl)-calix[4]arene (2), bis-O-(diethoxyphosphoryl)-p-tert-butylcalix[4]arene (3), bis-O- (diethoxyphosphoryl)-calix[4]arene (4), and octakis-O-(diethoxyphosphoryl)-p- tert-butylcalix[8]arene (5). The increase in solubility of drugs by the calixarene host 1 to 5 was most probably due to inclusion complexation between drug molecules and cavities of the calixarene skeleton similar to drug-cyclodextrin complexes.

Full text of DOI:10.1021/je200992c

ARTICLE
pubs.acs.org/jced
Phase Solubility Studies of Poorly Soluble Drug Molecules by Using
O-Phosphorylated Calixarenes as Drug-Solubilizing Agents
†
,‡
†
,†
Mevl €u t Bayrakcı, S- eref Ertul, and Mustafa Yilmaz*
†
Department of Chemistry, University of Sel c- uk, 42031, Konya/Turkey
Department of Chemistry, University of Ni ꢀg de, 51100, Konya/Turkey
‡
ABSTRACT: This study is the first report on the solubilizing effect of O-phosphorylated calix[n]arenes that form complexes with
neutral molecules such as nifedipine, niclosamide, and furosemide by hostÀguest complexation. These complexation studies
were carried out by using the phase solubility technique. From the obtained results, it was observed that the solubility of guest
molecules such as nifedipine, niclosamide, and furosemide was significantly increased in the presence of host molecules tetrakis-
O-(diethoxyphosphoryl)-p-tert-butylcalix[4]arene (1), tetrakis-O-(diethoxyphosphoryl)-calix[4]arene (2), bis-O-(diethoxyphos-
phoryl)-p-tert-butylcalix[4]arene (3), bis-O-(diethoxyphosphoryl)-calix[4]arene (4), and octakis-O-(diethoxyphosphoryl)-p-tert-
butylcalix[8]arene (5). The increase in solubility of drugs by the calixarene host 1 to 5 was most probably due to inclusion
complexation between drug molecules and cavities of the calixarene skeleton similar to drugÀcyclodextrin complexes.
’
INTRODUCTION
(FDA) has currently not approved the use of calixarenes in
medicines to date, calixarenes have showed neither toxicity nor
immune responses. Studies of calixarenes on human fibroblast
The molecular design of host systems based on calixarenes
21
which can form molecular complexations is a focus of interest
and research activity within supramolecular chemistry.
1
À3
cells using inhibition of cell growth have been showed that
2
0
4
calixarene derivatives have the same level toxicity as glucose.
The calixarenes represent, along with the crown ethers and
5
Furthermore, it has been observed that the calix[4]arene phos-
the cyclodextrins, one of the three major groups of synthetic
phonic acid derivative showed no effects on the cell growth of
macrocyclic host molecules in supramolecular chemistry. Calix-
arenes are macrocyclic molecules that are generally derived from
cheap starting materials as formaldehyde and phenol and can
easily be used as building blocks for the design and synthesis of
more sophisticated supramolecular structures. Such macro-
cycles possess a well-defined hydrophobic upper rim and hydro-
20
human fibroblasts. On the other hand, more recently it has
been observed that solid lipid nanoparticles based on amphipi-
hilic calix[4]arenes show zero hemolytic effects at concentrations
À1 22
6
ranging up to 300 mg L . This situation is in contrast to the
3
behavior of the solid lipid nanoparticles based on amphipihilic
2
3
cyclodextrins which show significant hemolytic effects. There-
fore, this situation increases interest in their use instead of cyclo-
dextrins in the biopharmaceutical applications beyond their
current use for the complex forming agents to remove molecules
philic lower rim surrounding a hollow cavity with varied dimension7s
that depends on the number of the phenolic units incorporated.
A majority of the studies on calixarenes have focused on the
calix[4]arenes, primarily because they possess open and rigid struc-
tures that are desirable for molecular recognition. It is well-known
that calixarenes are used for the molecular recognition of ions,
peptides, amino acids, sugars, hormones, proteins, and nucleic acids
which are basic substrates in biological and artificial processes.
2
4À26
8
from the environment.
To date several works about the effect
of the water-soluble p-sulfonic calix[n]arenes on the solubility of
27À29
drugs has been reported.
There is no other published solu-
8
À12
bility study between poorly soluble drug molecules and lower rim
functionalized phosphonate calix[n]arene receptors. The inclu-
sion behaviors of water-soluble o-phosphonate calix[n]arene
receptors toward nifedipine, niclosamide, and furosemide have
not been explored so far by means of phase solubility process.
Therefore, the aim of the present study was to explore the use of
water-soluble o-phosphonate calix[n]arene as drug solubilizing
agents toward nifedipine, niclosamide, and furosemide.
Furosemide (5-aminosulfonyl-4-chloro-2-(2-furanyl methyl)amino
benzoic acid), niclosamide (5-chloro-N-2-chloro-4-nitrophenyl-
2
4
-hydroxybenzamide), and nifedipine (3,5-dimethyl-2,6-dimethyl-
-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate) are
poorly water-soluble drug molecules and used as loop diuretics,
1
3À15
anthelmintics, and calcium channel blockers, respectively.
The main problem of these molecules is poor aqueous solubility.
Supramolecular complexation is a commonly used technique to
1
6,17
increase the solubility of poorly water-soluble drugs.
Among
’
MATERIALS AND METHODS
the macromolecules used to solubilize drugs, cyclodextrins are
the most widely used. Cyclodextrins are a family of three major
well-known cyclic oligosaccharides. The negligible cytotoxic
effects of cyclodextrins are an important attribute in application
of drug carriers. Calixarenes may selectively include various guests
according to their size and hydrophobicity in a manner similar to
Materials. All starting materials and reagents used were of
standard analytical grade from Alfa Aesar, Merck, and/or Aldrich,
18
Received: October 14, 2011
Accepted: November 7, 2011
Published: November 17, 2011
1
9,20
cyclodextrins.
Although the Food and Drug Administration
r 2011 American Chemical Society
233
dx.doi.org/10.1021/je200992c
|J. Chem. Eng. Data 2012, 57, 233–239

Journal of Chemical & Engineering Data
ARTICLE
Table 1. Characteristics of Reagents
chemical name
source
initial mole fraction purity
purification method
final mole fraction purity
analysis method
acetonitrile
Sigma-Aldrich
Merck
0.999
0.999
0.970
0.980
0.990
0.998
0.980
0.980
0.980
methanol
a1
b
diethyl chlorophosphate
bromotrimethylsilane
triethylamine
acetic acid
Alfa Aesar
Merck
distillation
0.980
GC H NMR
Merck
Merck
niclosamide
Sigma-Aldrich
Sigma-Aldrich
Sigma-Aldrich
furosemide
nifedipine
a
b
Gas chromatography. Nuclear magnetic resonance.
and some of them were used without further purification (Table 1).
Analytical thin layer chromatography (TLC) was performed
using Merck prepared plates (silica gel 60 F254). All reactions,
unless otherwise noted, were conducted under a nitrogen atmo-
Niclosamide, furosemide, and nifedipine eluted on a Supelco
Discovery RP Amide C16 column (25 cm  4.6 mm, 5 μm,
Bellefonate, PA) after (14, 8, and 13) min, respectively. The
mobile phase was 0.75:0.25 mole fraction (methanol/NH H PO
4
4
2
À1
sphere. The drying agent used was anhydrous MgSO . All
(0.05 mol kg in water) for niclosamide, 0.60:0.40:0.01 mole
4
3
aqueous solutions were prepared with deionized water that had
been passed through a Millipore milli-Q Plus water purification
system.
fraction (water/acetonitrile/acetic acid) for furosemide and
3
À1
nifedipine, flow rate of 1 cm min , and injection volume of
3
20 μL. Each determination was conducted in triplicate.
1
13
31
Apparatus. H, C, and P NMR spectra were recorded on a
Varian 400 MHz spectrometer in CDCl or D O. Melting points
3
2
were determined on an Electrothermal 9100 apparatus in a sealed
capillary and are uncorrected. IR spectra were obtained on a
Perkin-Elmer spectrum 100 FTIR spectrometer (ATR). UVÀvis
spectra were obtained on a Shimadzu 160A UVÀvis spectro-
photometer. Elemental analyses were performed using a Leco
CHNS-932 analyzer. A Crison MicropH 2002 digital pH meter
was used for the pH measurements.
’ RESULTS AND DISCUSSION
Calixarenes 1 to 5, containing dihydroxyphosphoryl groups at
the lower rim, have been synthesized by reactions with diethyl
chlorophosphate and triethylamine or sodium hydride in chloro-
32
form at reflux for 20 h (Scheme 1). Obtained phospho-ethyl
ester groups on lower rim of calix skeleton have been easily
converted the corresponding phosphoric acid moieties by using
bromotrimethylsilane in chloroform for 24 h at room tempera-
ture. Then treatment of the trimethylsilyl esters P(O)(OSiMe3)2
with absolute methanol results in cleavage of the PÀOÀSi bonds
and formation of the corresponding acids derivatives 1 to 5 in
Synthesis. Tetrakis-O-(diethoxyphosphoryl)-p-tert-butylcalix-
4]arene (1), tetrakis-O-(diethoxyphosphoryl)-calix[4]arene (2),
[
bis-O-(diethoxyphosphoryl)-p-tert-butylcalix[4]arene (3), bis-
O-(diethoxyphosphoryl)-calix[4]arene (4), and octakis-O-(di-
ethoxyphosphoryl)-p-tert-butylcalix[8]arene (5) were prepared
3,31
high yields. Related NMR data and some physical properties
30À32
according to the modified literature methods.
of compounds 1 to 5 have been given in Tables 2 and 3.
Solubility Measurements. The aqueous solubility of niclos-
amide, furosemide, and nifedipine in water was determined at
increasing concentrations of the p-phosphonate calixarenes. The
’
PHASE SOLUBILITY STUDIES
33
solubility method of Higuchi and Connors was used. An excess
amount of drug powders was added into the screw capped amber
Furosemide. Furosemide is a derivative from the anthranilic
3
vials containing 3 cm of water solution and the complexing agents
acid, whose structure is presented in Figure 1, representing a
powerful loop diuretic that is widely used in the treatment of
hypertension and edema. It is usually commercialized as tablets
or parenteral solutions. The oral bioavailability of furosemide is
very poor due to aqueous solubility at gastrointestinal pH, making
solubility the rate-determining step in the gastric absorption of
À3
À1
at increasing concentrations ((1.0 to 7.0) 10 mol kg ). The
3
3
vials were rotated at 60 rpm while being kept at 303 K. After
equilibrium was reached (24 h), the solutions was filtered through
0
.45 μm cellulose acetate filters and analyzed for drug content by
high-performance liquid chromatography (HPLC). All of the
solubility experiments and HPLC analysis were carried out in the
dark to prevent photodegradation of the drug molecules. Phase
solubility diagrams were constructed by plotting the molal con-
centration of drugs dissolved versus the molal concentration of
complexing agents.
29
furosemide. Several techniques have been used to increase its
3
4,35
aqueous solubility, including cyclodextrin complexation.
Ob-
tained results show that furosemide drug molecules are encapsu-
lated into hydrophobic cavity of cyclodextrins and a significant
increase in the solubility and dissolution rate of furosemide. Also,
calixarene compounds might form hostÀguest complexes with
furosemide. Therefore, we have performed some preliminary
evaluations to investigate solubilizing agent properties of calix-
arene phosphonate hosts 1 to 5 toward guest molecule furose-
mide by a phase solubility process. From the solubility studies,
calixarene phosphonates 1 to 5 were found to be an effective host
HPLC Analysis of Drugs. Drug content was analyzed by an
HPLC Agilent 1200 Series were carried out using a 1200 model
quaternary pump, a G1315B model diode array, and multiple
wavelength UVÀvis detector, a 1200 model standard and pre-
parative autosampler, a G1316A model thermostatted column
compartment, a 1200 model vacuum degasser, and an Agilent
Chemstation B.02.01-SR2 Tatch data processor at (254, 342, and
À3
molecule for practically water-insoluble furosemide (38 μg cm at
303 K in water).
3
338) nm for niclosamide, furosemide, and nifedipine, respectively.
2
34
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Journal of Chemical & Engineering Data
ARTICLE
Scheme 1. Synthetic Pathway and Structures of the Studied O-Phosphorylated Calixarene Receptors 1 to 5. i: C H O,
6
6
Paraformaldehyde, NaOH, Xylene, ii: Diethylchlorophosphate, NaH, THF, iii: CH O, NaOH, C H OC H , iv: Diethylchloro-
2
6
5
6 5
phosphate, NaH, THF, v: AlCl , C H O, Toluene, Diethylchlorophosphate, NaH, THF, vi: Diethylchlorophosphate, K CO ,
3
6
6
2
3
vii: Diethylchlorophosphate, K CO
2
3
À1
Obtained results showed that both the molecular size and the
concentration of the calixarenes significantly influenced the increase
in the solubility of furosemide. The largest increase in solubility
compound 1 was observed at a 0.007 mol kg concentration of
3
calixarene compounds 1 and 5 in water (Figure 2 and Table 4).
Also, the largest increase in solubility of furosemide in water for
calix[4]arene compounds 2, 3, and 4 was seen around 7.30 (
0.03, 7.20 ( 0.03, and 6.20 ( 0.04 10 mol kg at a 0.007
mol kg concentration of calixarene compounds, respectively.
À3
À1
of furosemide in water from (2.78 ( 0.04) 10 mol kg to
3
3
À3
À1
À1
À3
À1
(
0
10.11 ( 0.03) 10 mol kg for compound 5 and (2.44 (
3
3
3
3
À3
À3
À1
À1
.04) 10 mol kg to (9.11 ( 0.03) 10 mol kg for
3
3
3
3
3
2
35
dx.doi.org/10.1021/je200992c |J. Chem. Eng. Data 2012, 57, 233–239

Journal of Chemical & Engineering Data
ARTICLE
Table 2. NMR Spectra of the Receptors (1 to 5)
1
31
compounds
chemical shifts in H and P NMR spectra
1
t
1
2
3
4
5
H NMR: δ 6.85 (s, 8H, ArH), 4.70 (bs, 4H, ArCH
2
Ar), 3.25 (bs, 4H, ArCH
2
Ar), 1.13 (s, 36H, Bu )
3
1
3
1
3
1
3
1
3
1
P NMR: 20.15
H NMR: δ 6.83 (s, 8H, ArH), 4.40 (bs, 4H, ArCH
2
Ar), 3.25 (bs, 4H, ArCH
2
Ar)
1
P NMR: 20.00
t
t
H NMR: δ 7.05 (s, 4H, ArH), 6.70 (s, 4H, ArH), 4.40 (bs, 4H, ArCH
2
Ar), 3.40 (bs, 4H, ArCH
2
Ar), 1.15 (s, 18H, Bu ), 0.85 (s, 18H, Bu )
1
P NMR: 21.10
H NMR: δ 7.20 (d, 4H, ArH), 6.80À6.70 (m, 8H, ArH), 4.45 (bs, 4H, ArCH
2 2
Ar), 3.45 (bs, 4H, ArCH Ar)
1
P NMR: 20.10
t
H NMR: δ 7.07 (s, 16H, ArH), 4.30 (bs, 16H, ArCH
2
Ar), 1.11 (s, 72H, Bu )
1
P NMR: 20.05
Table 3. Some Physical Properties of the Receptors (1 to 5)
bonding, πÀπ interactions, dipoleÀdipole bonding, or electro-
static interaction between hydrophobic cavity or phosphonate
groups of receptors and phenyl, furan ring, or substituted group
of furosemide. With the help of one or a combination of these
forces furosemide most probably formed noncovalent inclusion
complexes with the calixarene receptors 1 to 5 similar to the
a
compound
empirical formula
color
T /K
yield
1
2
3
4
5
C
C
C
C
C
44
28
44
28
88
H
H
H
H
H
56
24
56
24
O
O
O
O
15
15
10
10
P
P
P
P
4
4
2
2
Na
Na
Na
Na
2
4
2
2
6H
4H
3H
2H
2
2
2
2
O
O
O
O
pale brown
white
>573
>573
>573
>573
>573
90
90
90
90
90
3
3
3
white
27
complexes it forms with 4-sulfonic calix[n]arenes. Comparing
pale brown
pale brown
3
8
27
para-sulfonate calix[n]arene and ortho-phosphonate calix-
112
O
32
P
8
Na
6H
2
O
3
[
n]arene, phosphorylated calixarene compounds having both
a
T: melting point.
tert-butyl groups and phosphoryl (PdO) groups was seen to be
an effective drug-solubilizing agent by supramolecular complexa-
tion for practically water-insoluble furosemide.
Comparing calixarenes 1 to 5, the calixarene derivatives, espe-
cially having tert-butyl groups, gave better results for furosemide
drug molecules. The cavity of the calixarene with tert butyl groups
is large enough to include furosemide. This situation is accor-
dance with similar literature results because the structural changes in
the calixarenes like removing the para substituents affect the
Nifedipine. Nifedipine as a L-type calcium-channel blocker is
used extensively for the clinical management of a number of
cardiovascular diseases such as essential hypertension, congestive
15
heart failure, and cerebral ischemia. A major pharmaceutical
problem associated with nifedipine is its poor aqueous solubility,
À3
36
(5 to 6) μg cm over a pH range of 2 to 10, which may account
molecular interactions. Generally, removal of tert-butyl groups
at the para position decreased the molecular interaction of calix-
arenes significantly. Furthermore, p-H-calix[4]arene compounds
indicated greater flexibility than in analogues with p-tert butyl
substituents, and this situation is effect the inclusion complexa-
3
39
for its highly variable bioavailability in humans. Obtained
solubility results showed that the nifedipine drug molecule could
be dissolved by calixarene receptors 1 to 5 in water. The solubility
of nifedipine in water was changed the some extent with calixarene
receptors 2 to 5 but did significantly increase with calixarene
receptor 1. In contrast to obtained literature results, it was
observed that the O-phosphorylated water-soluble calix[4]arene
derivative 1 was an effective host molecule for nifedipine in water
37
tion behavior of calixarene skeleton. The increased solubility of
furosemide indicated that the calixarenes must interact with
furosemide to form more soluble nifedipineÀcalixarene com-
plexes. The almost linear increase in the solubility diagram of
2
7
(
1
Table 5). This is probably due to rigid structure of calix receptor
having tert-butyl groups as explained for furosemide. Although
both receptors 3 and 5 have similar tert-butyl groups, calix-
8]arenes are more flexible than the calix[4]arenes. This situa-
furosemide as shown in Figure 2 represents Type A phase
L
solubility profiles, indicating the formation of 1:1 furosemide/
33
calixarene complexes.
33
[
Higuchi and Connors have classified complexes based on
tion may affected the dissolution of nifedipine by calix[8]arene
receptor 5. Furthermore, phosphate groups of calix[n]arenes
could involve hydrogen bonding between the calix[n]arenes and
substituted groups of nifedipine because calixarenes with phos-
phoryl (PdO) groups are capable of binding effectively different
their effect on the solubility of the substrate as shown in Figure 3.
“
A type” phase-solubility profiles are obtained when the solubility
of the drug increases with increasing ligand concentration. The
AL model shows the association constant of K1:1 indicating one
molecule of drug forms a complex with one molecule of ligand
4
0
and a linear relationship exhibits. The type A system indicates
cations and organic molecules with hydrogen-bond donors.
P
that one molecule of drug forms a complex with two molecule of
ligand and a positive deviation from linearity is obtained. Also the
AN type profile, which is the least encountered system, shows a
negative deviation which indicates a decrease with increasing
ligand concentrations. Generally, the most common stoichi-
ometry of drug/calixarene inclusion complexes is 1:1 and is often
studied by the phase solubility studies. “B type” phase-solubility
profiles indicate the formation of complexes with limited solu-
bility in the aqueous complexation medium. This interaction is
attributed to the weak interaction forces including hydrogen
From the phase solubility profiles of the nifedipine, a linear
increase in solubility of nifedipine as shown in Figure 4 repre-
sents type A phase solubility profiles attributable to the forma-
L
tion of 1:1 nifedipineÀcalixarene complexes. In the same time,
weak interaction forces such as πÀπ interactions, dipoleÀdipole
bonding, and/or electrostatic attraction as mentioned above for
furosemide may be another important contributions to the interac-
tion between receptors 1 to 5 and nifedipine.
38
Niclosamide. Niclosamide is active against most tapeworms,
including the beef tapeworm, the dwarf tapeworm, and the dog
2
36
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Journal of Chemical & Engineering Data
ARTICLE
Figure 1. Structures of the drug molecules.
Figure 2. Phase solubility diagrams of furosemide by host receptors 1 to
5
in water at 303 K.
Figure 3. General phase solubility profiles of drugs.
Table 4. Concentration Values of Furosemide with Increas-
À1
ing Calixarene Concentrations (mol kg in Water)
3
Table 5. Concentration Values of Nifedipine with Increasing
concentration values
À1
Calixarene Concentrations (mol kg in Water)
3
a
a
a
a
compounds
0.001
0.003
0.005
0.007
concentration values
b
1
2
3
4
5
2.44 ( 0.03
1.34 ( 0.03
1.52 ( 0.03
0.92 ( 0.03
2.78 ( 0.04
4.66 ( 0.04 7.04 ( 0.04
3.21 ( 0.04 5.22 ( 0.04
3.74 ( 0.04 5.93 ( 0.04
2.89 ( 0.04 4.64 ( 0.04
9.11 ( 0.04
7.32 ( 0.03
7.91 ( 0.03
6.22 ( 0.04
a
a
a
a
compounds
0.001
0.003
0.005
0.007
b
1
2
3
4
5
5.92 ( 0.03
3.84 ( 0.04
3.52 ( 0.03
3.79 ( 0.03
4.64 ( 0.04
7.87 ( 0.04 9.52 ( 0.04 11.20 ( 0.04
4.51 ( 0.03 5.22 ( 0.04
4.34 ( 0.03 4.93 ( 0.04
4.11 ( 0.03 4.34 ( 0.04
6.32 ( 0.04
5.11 ( 0.04
4.72 ( 0.04
8.11 ( 0.04
5.38 ( 0.04 7.81 ( 0.04 10.11 ( 0.03
a
b
Concentration values of calixarenes. Averages and standard deviations
calculated for data obtained from three or four independent solubility
5.94 ( 0.04 6.98 ( 0.04
experiments.
a
b
Concentration values of calixarenes. Averages and standard deviations
calculated for data obtained from three or four independent solubility
experiments.
4
1
tapeworm. This drug is also used as a molluscicide for the treat-
28
ment of water in schistosomiasis control programs. Niclosa-
mide is practically insoluble (230 ng cm ), which may severely
À3
À1
was observed at a 0.005 mol kg concentration of calixarene
3
3
4
2
limit its efficacy. From the extraction results, it was observed
that the niclosamide drug molecule could be extracted from the
organic phase into the aqueous phase. Comparing the solubiliz-
ing efficiency of calix[n]arenes 1 to 5, it was seen that O-phos-
phorylated water-soluble calix[4]arene derivative 1 was an effective
moleculer receptor for niclosamide. From the phase solubility
experiments, the increase in solubility of niclosamide from
compound1 in water (Figure 5 and Table 6). However, as the con-
centration of calixarene receptors 1 to 5 increased, the solubility
of the drug is exceeded, indicating a decrease in the solub-
ility of drug. This situation is probably due to insoluble com-
plexes formed at higher host concentrations, or the drug was
2
8
removed from the inclusion complexes. Niclosamide is a
43
highly hydrophobic molecule as nifedipine and furosemide. There-
fore, similar interactions to dissolve the drug molecule between
À6
À1
À6
À1
(
2.21 ( 0.03) 10 mol kg to (4.37 ( 0.03) 10 mol kg
3
3
3
3
2
37
dx.doi.org/10.1021/je200992c |J. Chem. Eng. Data 2012, 57, 233–239

Journal of Chemical & Engineering Data
ARTICLE
(
PdO) groups, suggesting that the complexation mechanism
could involve hydrogen bonding between the calixarenes and the
substitute group of niclosamide.
’
CONCLUSIONS
In the course of this study, several O-phosphorylated calixar-
ene receptors were easily synthesized. Also, aqueous solubility
studies of niclosamide, furosemide, and nifedipine drug mol-
ecules were performed in water, and obtained results showed that
the molecular size or the concentration of the calixarenes signifi-
cantly influenced the increase in the solubility of drug molecules.
Furthermore, phase solubility profiles of drugs revealed that
O-phosphorylated calixarene receptors 1 to 5 might be useful host
molecules as drug-solubilizing agents toward niclosamide, furosemide,
and nifedipine. Especially comparing the drug molecules, it was
observed that these receptors 1 to 5 improved the solubility of
furosemide the most. It could be concluded that the solubility
properties of drug molecules by hostÀguest complexation depend
on the structural properties of the water-soluble O-phosphorylated
calixarene such as hydrophobic cavity diameters, hydrogen binding
ability, stability, or rigidity and also depend on ionÀdipole attraction
or electrostatic interaction between calixarenes and drug molecules.
Figure 4. Phase solubility diagrams of nifedipine by host receptors 1 to
5
in water at 303 K.
’
AUTHOR INFORMATION
Corresponding Author
*
E-mail: myilmaz42@yahoo.com.
Funding Sources
The authors gratefully would like to thank S.U. Research
Foundation (BAP: 10101016) for financial support.
Figure 5. Phase solubility diagrams of niclosamide by host receptors 1
to 5 in water at 303 K.
Table 6. Concentration Values of Niclosamide with Increas-
’ ACKNOWLEDGMENT
À1
ing Calixarene Concentrations (mol kg in Water)
3
The authors gratefully acknowledge support of this study
produced from a part of the Ph.D. Thesis of Mevl €u t Bayrakcı
by the Research Laboratory of Sel c- uk University.
concentration values
a
a
a
a
compounds
0.001
0.003
0.005
0.007
’
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b
b
1
2
3
4
5
2.21 ( 0.04
1.84 ( 0.04
1.52 ( 0.04
1.79 ( 0.04
1.78 ( 0.04
3.44 ( 0.04 2.21 ( 0.04
2.51 ( 0.04 1.84 ( 0.04
2.34 ( 0.04 1.52 ( 0.04
2.31 ( 0.04 1.79 ( 0.04
4.37 ( 0.04
3.32 ( 0.04
3.11 ( 0.04
2.72 ( 0.04
4.11 ( 0.04
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